Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClS([N:14]=[C:15]=O)(=O)=O>C(N(CC)CC)C>[C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)#[N:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2ccccc12

Procedure:
3-Cyano analogues are synthesized from the precursor indole No. 141 as shown in Scheme 7. Reaction of the precursor indole No. 141 with chlorosulfonyl isocyanate followed by addition of triethylamine yields the 3-Cyanoindole No. 155. The side chain is made by conversion of the benzylic alcohol of CAS No. [111728-87-1] to the benzylic bromide No. 156 using thionyl bromide in THF. The indole is alkylated by the side chain in DMF using sodium hydride to give the intermediate No. 157. This can then be taken to the final product No. 138 in an analogous fashion to that shown in scheme 4.
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+:18].[K+].Br[CH:21](C(OCC)=O)[C:22]([O:24]CC)=[O:23]>CC(=O)CC>[N+:11]([C:7]1[CH:8]=[C:9]([Br:10])[C:2]2[O:1][C:21]([C:22]([O-:24])=[O:23])=[CH:4][C:3]=2[CH:6]=1)([O-:13])=[O:12].[K+:18]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C([O-])c1cc2cc([N+](=O)[O-])cc(Br)c2o1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
A mixture of 11.0 gm (44.7 mMol) 2-hydroxy-3-bromo-5-nitrobenzaldehyde, 5.56 gm (40.24 mmol) potassium carbonate, and 8.0 mL (46.95 mMol) diethyl bromomalonate in 55 mL 2-butanone was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between 450 mL diethyl ether and 250 mL water and the aqueous phase was adjusted to pH of about 1 by the addition of dilute sulfuric acid. The phases were separated and the aqueous phase was extracted with two 150 mL portions of diethyl ether. The organic phases were combined, washed with 50 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was dissolved in 200 mL ethanol to which were added 4.8 gm (85.5 mMoL) potassium hydroxide. The resulting suspension was warmed on a steam bath for 1 hour. The suspension was then cooled to room temperature. After about 18 hours the mixture was filtered and dried under reduced pressure to provide 14.1 gm (98%) of the desired compound as an orange solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([CH2:16][C:17]#[N:18])[CH2:3]1.N.[H][H]>[Ni].CO>[NH2:18][CH2:17][CH2:16][N:4]1[CH2:5][CH2:6][C@@H:7]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:2]([OH:1])[CH2:3]1
Reactant: N#CCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Yield: 91.6 %

Procedure:
A mixture of 12 parts of trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidineacetonitrile and 320 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 11.2 parts (91.6%) of trans-1-(2-aminoethyl)-4-[(phenylmethyl)amino]-3-piperidinol as a residue (interm. 17).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:24].CN(C)C=O>C(OCC)(=O)C>[CH2:36]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][NH:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:34][CH2:35]1)[CH3:37]
Reactant: CCN(CC)CCCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 60 %

Procedure:
Prepared analogously to Example 109 from 11-[[[2-bromo-ethyl]amino]carbonyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]-piperidine, but using dimethylformamide instead of acetonitrile, in a yield of 60% of theory. Colourless crystals, m.p. 167° C. (ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([C:20]2([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=3)[S:24][CH2:23][N:22]=[N:21]2)[CH2:3]1.[CH3:32]N1[C@H]2[C@@](OC)(C3C=CC=C4C=3C(C2)=CN4)C[C@@](C2N=C(C3C=NC=C(Br)C=3)ON=2)(C)C1>>[CH3:32][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@:6]([O:18][CH3:19])([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:20]2([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=3)[S:24][CH2:23][N:22]=[N:21]2)[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Reactant: CO[C@]12C[C@@H](C3(c4cncc(Br)c4)N=NCS3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Product: CO[C@]12C[C@@H](C3(c4cncc(Br)c4)N=NCS3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Yield: 35 %

Procedure:
Operating as in Example 2, but employing 6-methyl-8β-[5-(5-bromo-pyridin-3-yl)-1,3,4-thiadiazol-5-yl]-10α-methoxy-ergoline instead 6-methyl-8β-methy-[5-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-10α-methoxy-ergoline, the title compound was obtained in 35% yield, m.p.131-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:52])[CH2:47][S:48](Cl)(=[O:50])=[O:49])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:48]([CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:52])(=[O:50])=[O:49])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a stirring solution of Example 158 (0.070 g, 0.160 mmol) in dichloromethane containing N,N-diisopropylethylamine (0.036 mL, 0.208 mmol) was added chlorosulfonyl-acetic acid tert-butyl ester (0.041 g, 0.192 mmol). The reaction mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic layer was washed sequentially with 10% 1N HCl in water, bicarb, and brine. The product was purified by flash chromatography on SiO2 eluting with 0-50% ethyl acetate/hexanes yielding the title compound (0.030 g, 30.5% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.23 (dd, J=9.01, 4.23 Hz, 2 H) 0.25 (d, J=6.62 Hz, 2 H) 0.45 (m, 2 H) 0.85 (m, 1 H) 1.25 (m, 1 H) 1.39 (s, 9 H) 1.57 (m, 3 H) 2.34 (m, 1 H) 4.22 (m, 2 H) 7.55 (m, 2 H) 7.62 (dd, J=10.29, 2.21 Hz, 2 H) 7.75 (m, 3 H) 8.15 (d, J=7.72 Hz, 1 H) 10.61 (s, 1 H) 13.73 (m, 1 H). MS (ESI+) m/z=516 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[CH:22][C:23](O)=[CH:24][CH:25]=1)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:23]2[CH:22]=[CH:21][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:25][CH:24]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
A mixture of 5 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.23 g of methyl p-hydroxybenzoate, 4.38 g of dicyclohexylcarbodiimide, 100 ml of dry dimethylformamide and 20 ml of dry pyridine was stirred at room temperature for 24 hours, and the mixture was treated in the same procedure as in Example 11. The crystals obtained were recrystallized from isopropanolether to obtain 5.7 g (yield: 72.7%) of p-methoxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 163° to 164.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:20]=[C:21]=[O:22])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:21]([NH2:20])=[O:22])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 68 h
Yield: 84.7 %

Procedure:
3(R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3 g, 14.0 mmoles) was dissolved in anhydrous dichloromethane (50 mL) and trimethylsilylisocyanate (9.68 g, 11.4 mL, 84.0 mmoles) was added. The mixture was stirred under argon at 25° C. for 68 h. Additional trimethylsilylisocyanate (4.84 g, 5.7 mL, 42.0 mmoles) was added and the mixture was stirred at 25° C. for a total of 90 h. The mixture was evaporated to dryness and chromatographed on a silica gel column (30×5 cm) using 2% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(tert-butoxycarbonylaminomethyl)piperidine-1-carboxamide (3.05 g, 85%): FABMS: m/z 258.1 (MH+); HRFABMS: m/z 258.1816 (MH+). Calcd. for C12H24O3N3: m/z 258.1818; δH (CDCl3) 1.22 91H, m, CH2), 1.42 (9H, s, —COOC(CH3)3), 1.48 (1H, m, CH2), 1.67 (2H, m, CH2), 1.78 (1H, m, CH), 2.80 (1H, m, CH2), 2.99, 3H, m, CH2), 3.59 (1H, m, CH20 3.69 (1H, m, CH2), 4.76 (2H, bm, CONH2) and 4.98 ppm (1H, bm, NH); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 24.0, 28.3, 43.2, 45.1, 47.8; CH: 36.5; C: 79.4, 156.3, 158.5.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 2: 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.30 g, 1.50 mmol), acetonitrile (3 mL), potassium carbonate (0.21 g, 1.50 mmol), iodoethane (0.12 mL, 1.50 mmol). Microwave irradiation at 100° C. for 20 minutes. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 1:1). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 119-120° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 14), 212 (11), 141 (14), 127 (11), 71 (bp).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a, 3,4, 5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4, 5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. mp 103°-104° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:22])[NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH3:14])=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[OH:21][C:17]1[CH:16]=[C:15]([CH:13]([NH:12][C:11]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[CH:8]=2)=[O:22])[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1sc(C(=O)NC(C)c2cccc(O)c2)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(C)c2cccc(O)c2)sc1C(=O)O
Yield: 96.5 %

Procedure:
A solution of 5-[1-(3-hydroxy-phenyl)-ethyl-carbamoyl]-3-methyl-thiophene-2-carboxylic acid methyl ester (121 mg, 0.38 mmol) in THF/water (3 ml/1 ml) was treated with LiOH.H2O (158 mg, 3.8 mmol) at rt overnight. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (112 mg, 100% yield).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20].[C:21]([Si](C)(C)C)#[CH:22].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]([C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20])#[CH:22]
Reactant: C[C@@H](COc1ccc(Br)c(F)c1)NC(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-bromo-3-fluorophenoxy)-1-methylethyl]carbamate (23.3 g), ethynyl(trimethyl)silane (13.1 g), bis(triphenylphosphine)palladium(II) dichloride (4.70 g), cuprous iodide (1.27 g), triethylamine (14.0 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (200 mL), and tetrabutylammonium fluoride (1.0 M solution in THF, 201 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hr. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and washed with hexane to give the title compound (12.2 g) as a light brown solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:11])[C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:12](=S)=[S:13]>CO>[O:1]1[C:5]2[C:4](=[CH:9][C:8]3[NH:10][C:12]([SH:13])=[N:11][C:7]=3[CH:6]=2)[O:3][CH2:2]1
Reactant: S=C=S
Reactant: Nc1cc2c(cc1N)OCO2
Solvent: CO
Product: Sc1nc2cc3c(cc2[nH]1)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
The mixture (6.48 g) containing 1,3-benzodioxol-5,6-diamine obtained in the step (78b) above was dissolved in methanol (100 ml). To the mixture, carbon disulfide (30 ml) was added and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure. To the solid residue, ethyl acetate was added and filtration was performed. The solid was washed by adding tetrahydrofuran, ethyl acetate and diluted hydrochloric acid and insoluble substance was collected by filtration, dried under reduced pressure at room temperature for 2 hours in a desiccator to obtain the title compound (3.8 g, 56.1% from 5,6-dinitro-1,3-benzodioxol) as a brown solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[OH:9][C:10]1[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](OC)=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[OH:9][C:10]1[C:15]([C:16](=[O:18])[CH2:17][C:31]([CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[O:32])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C1CCOCC1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCOCC1)c1cccc(-c2ccccc2)c1O
Temperature: 0 °C

Procedure:
An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, tetrahydrofuran (10 mL) and lithium diisopropylamide (2.0M in hexanes, 6.9 mL, 13.8 mmol). The mixture was magnetically stirred and cooled to 0° C. under argon gas. 1-(2-Hydroxybiphenyl-3-yl)ethanone (0.92 g, 4.34 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.0 g, 6.94 mmol) in tetrahydrofuran (2 mL) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL) until pH=3. The resulting solution was transferred to a separatory funnel, diluted with water (80 mL), and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give crude 1-(2-hydroxybiphenyl-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione as a brown oil. The crude product was used as is without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]([CH3:23])([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][C:14]([CH3:23])([CH3:13])[CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CC(C)(CN)CN1CCCC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-amino-3-methoxy-benzoic acid (Aldrich; 2 g, 12 mmol) and 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-amine (WO 2004033419; 2.1 g, 13.2 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (3.1 g, 4.2 mL). The reaction was cooled with an ice-bath, and to it was added, portionwise, HATU (5.02 g, 13.2 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated, and the residue was partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3×40 mL), washed with brine (3×40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated. The residue was purified by chromatography on a silica column pre-conditioned with Ethyl acetate and eluted with 10% MeOH-DCM+1% NH3. Those fractions containing the desired product were combined and the solvent was evaporated to yield the title compound as a pale brown gum, which crystallised on standing. (500 mgs; 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:16]([OH:22])[C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=c1c(O)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
N-(4-Chlorophenyl)benzene-1,2-diamine (11.2 g) was added to diethyl oxalate (50 ml) and the mixture heated under reflux for 2 hours. The mixture was cooled and ethanol (40 ml) was added. The precipitated solid was filtered off and recrystallised from ethanol giving the title compound (11.2 g) mp>300° C.
Reaction SMILES: [CH:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[CH:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:26]\[NH:27][C:28]([NH2:30])=[O:29])/[C:8]1=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)Cc1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)Cc1ccccc1
Yield: 52.7 %

Procedure:
By using 1-[2-(N-isopropylbenzylamino)ethyl]isatin and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-[2-(N-isopropylbenzylamino)ethyl]isatin 3-semicarbazone having a melting point of 193°-194° C. (yield: 52.7%, recrystallizing solvent: ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=1.C(N(CC)CC)C.C([O:32][C:33](=O)[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:43]Br)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20]2)[CH:7]=1)[N:21]1[CH2:43][C:35]2[C:34](=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:37][CH:36]=2)[C:33]1=[O:32]
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester (490 mg, 1.5 mmol) and triethyl amine (0.43 ml, 3.1 mmol) in DMF (10 ml) was added 2-bromomethyl-6-nitro-benzoic acid ethyl ester (460 mg, 1.6 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as a yellowish solid (550 mg, 75%). 1HNMR (CDCl3): δ0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.09 (dd, J=7, 15 Hz, 1H), 3.28 (dd, J=9, 15 Hz, 1H), 3.65 (s, 3H), 3.79-3.91 (m, 2H), 4.18 (d, J=17 Hz, 1H), 4.46 (d, J=17 Hz, 1H), 5.83 (dd, J=7, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 7.04-7.05 (m, 3H), 7.58-7.76 (m, 3H).