Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7].CC(C)=O>O>[N:1]([S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
In a three-necked flask fitted with stirrer and dropping funnel 65 g of sodium azide is dissolved in 900 ccs of water. While stirring and cooling till 0°-5° C a solution of 198 g of m-chlorosulphonyl-benzoic acid in 900 ccs of acetone is added dropwise. Then stirring is continued for 30 minutes whereupon the solution obtained is poured into 2 liters of water. The white precipitate formed is sucked off, washed with water and dried in vacuo. Melting point: 143° C.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[OH:10][CH2:11][C@H:12]([CH3:40])[O:13][C:14]1[CH:15]=[C:16]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=2)=[O:31])[CH:29]=1)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1>CN(C=O)C.O>[N:3]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]3[CH:27]=[C:28]([CH:29]=[C:14]([O:13][C@@H:12]([CH3:40])[CH2:11][OH:10])[CH:15]=3)[C:30]([NH:32][C:33]3[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=3)=[O:31])=[CH:26][CH:25]=2)=[O:23])[CH2:4][CH2:9][CH2:7]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)O)cc3)cc(O[C@@H](C)CO)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
DIPEA (0.4 mL, 2.08 mmol) was added to a suspension of 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carbonyl}phenoxy)benzoic acid (110 mg, 0.26 mmol), HATU (210 mg, 0.55 mmol) and azetidine hydrochloride (49 mg, 0.52 mmol) in DMF (3 mL) and the mixture stirred at RT for 24 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 5% methanol in ethyl acetate, to give the desired compound (55 mg).
Reaction SMILES: BrBr.C(OC([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=O)[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.[C:27]([NH2:30])(=[S:29])[CH3:28].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:28][C:27]1[S:29][C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[N:30]=1
Reactant: CC(N)=S
Reactant: Cc1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Bromine (1.0 mL, 18 mmol) was added to a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (6.0 g, 18 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in N,N-dimethylformamide (50 mL) and to the solution was added thioacetamide (1.4 g, 19 mmol) and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (200 mL) and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. 2N-hydrochloric acid (30 mL) was added to the resulting solid and the mixture was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, the mixture was basified with a 2N aqueous solution of sodium hydroxide (200 mL) and a saturated aqueous solution of sodiumhydrogen carbonate. The resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.8 g of the title compound (yield 54%).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:10][CH:9]=[N:8]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:33])C(=O)C1>C(#N)C>[I:33][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nccs1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1ncc(I)c1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 2-BA-1) in 50 mL of acetonitrile at rt under nitrogen were added TFA (1 mL) and NIS (10.8 g). The reaction mixture was stirred at rt overnight and an additional amount of NIS (0.5 eq to 1.0 eq) was added as needed. The crude reaction mixture was slowly quenched with ˜30 mL of a saturated aqueous Na2S2O3 solution, and ˜30 mL of a saturated aqueous NaHCO3 solution. The reaction mixture was diluted with 50 mL of EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was purified by MPLC (eluted with 0-50% EtOAc/hex) to give 2-(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 4-BA-1). LCMS: 408.0 m/z (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]([C:6]2[C:7]([F:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1>C1COCC1.[OH-].[Pd+2].[OH-]>[F:12][C:7]1[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Fc1ncccc1C1C=COC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2,3-dihydrofuran-3-yl)-2-fluoropyridine (5.26 g, 31.8 mmol) and palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet (2.500 g, 3.56 mmol) in THF (50 mL) was evacuated/purged with hydrogen (3×). The mixture was stirred vigorously under hydrogen (1 atm) at rt overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to give a clear colorless oil. MS (ESI, pos. ion) m/z: 168.1 (M+1).
Reaction SMILES: [CH:1]1([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][CH2:23][O:24][CH3:25]>CN(C)C=O>[CH:1]1([N:11]2[C:15]([C:16]([O:18][CH2:22][CH2:23][O:24][CH3:25])=[O:17])=[CH:14][N:13]=[CH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCCCl
Reactant: O=C(O)c1cncn1C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 1 h
Yield: 46.7 %

Procedure:
4.8 Parts of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxylic acid are dissolved in 94 parts of warm N,N-dimethylformamide. 0.96 Parts of a sodium hydride dispersion 50% are added portionwise to the thus obtained reaction mixture. Upon complete addition, stirring is continued for 1 hour at room temperature. After the addition of 2.0 parts of 1-chloro-2-methoxyethane, the whole is stirred overnight at 90° C. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 2.8 parts (46.7%) of (2-methoxyethyl) 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxylate; mp. 66.8° C. (compound 1.83).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2cccnc2)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CS(=O)(=O)c2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared from 4-(3-pyridylsulfonylmethyl)-2-phenylbenzoic acid methyl ester by saponification of the methyl ester using the procedure of Example 228D, and coupling with methionine methyl ester according to the procedure of Example 186C. mp 152-154° C. 1H NMR (300 MHz, CDCl3) δ 8.95 (d, 1H), 8.87 (dd, 1H), 7.94 (ddd, 1H), 7.66 (d, 1H), 7.43 (m, 4H), 7.30 (m, 2H), 7.21 (dd, 1H), 7.10 (d, 1H), 5.91 (bd, 1H), 4.66 (ddd, 1H), 4.42 (s, 2H), 3.68 (s, 3H), 2.08 (t, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.75 (m, 1H). MS (CI NH3) m/e 516 (M+NH4)+, 499 (M+H)+. Anal calc' for C25H26N2O5S2: C, 60.22; H, 5.25; N, 5.62. Found: C, 60.28; H, 4.94; N, 5.56.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([CH3:48])([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1)[C:17]([NH:19][C@:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:24][C:23](=O)[C@@H:22]([F:27])[CH2:21]1)=[O:18].Cl.[CH2:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52][O:51]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCCl>[CH3:48][C:16]([CH3:15])([C:34]1[CH:35]=[C:36]([C:44]([F:45])([F:46])[F:47])[CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[C:17]([NH:19][C@:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24][C@@H:23]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:50][O:51][CH2:52][CH2:53]3)[CH2:55][CH2:56]2)[C@@H:22]([F:27])[CH2:21]1)=[O:18]
Reactant: C1CC2(CCN1)CCOC2
Reactant: CC(C)(C(=O)N[C@]1(c2ccccc2)CCC(=O)[C@@H](F)C1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)N[C@]1(c2ccccc2)CC[C@@H](N2CCC3(CCOC3)CC2)[C@@H](F)C1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3 %

Procedure:
Sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added to a mixture of (1R*,3S*)-α,α-dimethyl-N-[3-fluoro-4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide (Example 58, 490 mg, 0.97 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride (Description 86, 204 mg, 1.37 mmol) and triethylamine (1.34 mL, 9.7 mmol) in 1,2-dichloroethane (15 mL) and the mixture was stirred at room temperature for 3 days. Further sodium triacetoxyborohydride (103 mg, 0.49 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was basified with aqueous sodium hydroxide (1M) and extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH (97.5:2.5), to give (1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (18 mg, 3%); 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.70 (2H, s), 7.36–7.23 (5H, m), 5.13 (1H, s), 4.98 (1H, br d, J 48.5 Hz), 3.81 (2H, t, J 7.2Hz), 2.89–2.68 (3H, m), 3.67–2.42 (4H, m), 2.41–2.38 (2H, m), 1.89–1.86 (1H, m), 1.73–1.71 (1H, m), 1.68 (2H, t, J 7.2 Hz), 1.63–1.58 (6H, m), and 1.53 (6H, d, 3.4 Hz). m/z (ES+) 615 (M+1); and (1S*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (280 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.81 (2H, s), 7.79 (1H, s), 7.32–7.21 (1H, s), 6.41 (1H, d, J 10.5 Hz), 5.06 (1H, br d, J 50.0 Hz), 3.87–3.83 (2H, m), 3.00–2.96 (1H, m), 2.60–2.39 (4H, m), 2.30–2.22 (2H, m), 2.01–1.93 (1H, m), 1.77–1.70 (3H, m), 1.65–1.50 (8H, m), and 1.60 (6H, d, J 6.9 Hz). m/z (ES+) 615 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:12]([NH:14][C:15]2[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:30][NH2:31].Cl>CCN(CC)CC>[CH3:30][NH:31][C:20]([C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Reactant: CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
2-[2-(4-Methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylic acid (EXAMPLE 127, 399 mg, 0.91 mmol) was condensed with MeNH2.HCl in the presence of NEt3, utilising the general procedure described in EXAMPLE 65, to give the title compound: RTA=2.82 min; m/z (ES+)=452.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:25]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([CH:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)(C)(C)C>C(O)C.CCCCCCC>[NH2:7][C@H:8]1[C@H:25]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C@H:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(N3CCCCC3=O)CN1CC2
Solvent: CCO
Solvent: CCCCCCC
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](N)[C@H](N3CCCCC3=O)CN1CC2

Procedure:
(RS,RS,RS)-[9,10-Dimethoxy-3-(2-oxo-piperidin-1-yl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (580 mg, 1.61 mmol) was dissolved in ethanol/heptane 3:2 (5 mL) and subjected to preparative HPLC (Chiralpak® AD column, heptane/ethanol 80:20).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([CH2:12]O)=[CH:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[S:7]1(=[O:18])=[O:17].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([CH2:12][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[S:7]1(=[O:18])=[O:17]
Reactant: C1COCCN1
Reactant: COCCCN1C(CO)=Cc2ccsc2S1(=O)=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCN1C(CN2CCOCC2)=Cc2ccsc2S1(=O)=O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of the product from Step C (1.30 g, 4.50 mmol) and triethylamine (1.36 g, 13.5 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (1.18 g, 6.75 mmol). After stirring for 30 min, morpholine (5 mL) was added; this mixture was stirred at ambient temperature for 18 h and then heated at reflux for 1 h. The volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to give a viscous oil which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a viscous oil (1.51 g, 94%).
Reaction SMILES: [CH:1]1([CH2:10][C:11]#[C:12][CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>N1C=CC=CC=1.[Pd]>[CH:14]1([CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: [H][H]
Reactant: C(#CCC1C=Cc2ccccc21)CC1C=Cc2ccccc21
Agent: [Pd]
Solvent: c1ccncc1
Product: C1=CC(C/C=C\CC2C=Cc3ccccc32)c2ccccc21
Yield: 112.4 %

Procedure:
A solution is prepared of 20 g (0.0532 moles) of 1,4-bis-(1-indenyl)-but-2-ine in 200 ml of pyridine. The alkyne is then hydrogenated with hydrogen at 1 atm., in the presence of 1.0 g of Pd on BaSO4 (ALDRICH). After 3 hours the absorption of hydrogen stops. The reddish solution is filtered, diluted with water and extracted with diethyl ether. The extract, after evaporation of the solvent, is purified by chromatography on a silica gel column with petroleum ether as eluant. 17 g of 1,4-bis-(1-indenyl)-Z-but-2-ene are obtained with a yield of 85%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([NH:4][CH2:5][C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@H]1CCCN1
Agent: Cl
Solvent: C1CCOC1
Product: C1CN[C@@H](CNC2CC2)C1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
(R)-Pyrrolidine-2-carboxylic acid cyclopropylamide (0.5 g, 3.2 mmol) in THF (4 mL) was added to borane-tetrahydrofuran complex (6 mL, 1 M, 6 mmol) at 0° C. The reaction mixture was refluxed for overnight after which more BH3 was added and heating was continued for another 2 h. The reaction mixture was acidified with 3M HCl soution and refluxed for 0.5 h. The reaction mixture was concentrated and the residue was basified with 2M NaOH solution. It crude reaction mixture was then extracted with 5% methanol in dichloromethane to give 0.4 g (89%) of cyclopropyl-(R)-1-pyrrolidin-2-ylmethyl-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][N:28]1[C:32]([CH3:33])=[CH:31][C:30]([C:34](O)=[O:35])=[N:29]1>>[CH3:27][N:28]1[C:32]([CH3:33])=[CH:31][C:30]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[N:29]1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cc(C)n(C)n5)c4)CC3)cccc2n1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:8]=1F.CO>C(Cl)(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N:15]1[CH2:16][CH2:17][N:13]([C:10]2[CH:9]=[C:8]3[C:7]([C:6](=[O:5])[NH:2][NH:3]3)=[CH:12][CH:11]=2)[C:14]1=[O:25]
Reactant: NN
Reactant: COC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3c(=O)[nH][nH]c3c2)C1=O
Temperature: 120 °C
Yield: 41.2 %

Procedure:
Hydrazine hydrate (10 mL) was added to 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (I-135a: 350 mg, 1.06 mmol) and the resulting mixture was heated to 120° C. for 18 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The aqueous layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (10% MeOH in CHCl3), followed by preparative HPLC afforded 135 mg of the product (41.2% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:16])([O-])=O.C(O)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(-c2cccnc2)ccc1O
Reaction time: 16 h
Yield: 101.6 %

Procedure:
A mixture of 2-nitro-4-pyridin-3-yl-phenol (80 mg, 0.37 mmol), 10% Pd—C (8.0 mg), acetic acid (21 μL, 0.37 mmol) in MeOH (3.7 mL) was hydrogenated at 45 PSI at RT for 16 h. The mixture was filtered through a pad of celite and concentrate to afford 70 mg (100%) of the title compound as a brown oil: 1H NMR CDCl3, 400 MHz) δ 8.57 (d, 1H, J=1.7 Hz), 8.30 (d, 1H, J=5.0 Hz), 7.75 (dt, 1H, J=7.9, 2.1 Hz), 7.25 (dd, 1H, J=7.9, 5.0 Hz), 6.77-6.69 (m, 2H), 3.94 (br s, 3H); 13C NMR CDCl3, 100 MHz) δ 147.0, 146.5, 145.7, 137.6, 135.5, 134.8, 129.3, 124.0, 118.1, 115.4, 114.6; MS (Cl) m/z 187.1 (M+1); HPLC retention time=1.29 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22]([CH2:23][CH2:24][C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.58 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.87 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)c(F)cc1F
Reaction time: 24 h

Procedure:
To a solution of methyl 5-amino-2,4-difluorobenzoate (252 mg, 1.35 mmol) and pyridine (0.13 mL, 1.61 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.12 mL, 1.48 mmol). After 24 h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 2,4-difluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M−H)), which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:12]([O:19][CH3:20])=[O:18])[C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC
Yield: 96 %

Procedure:
75.5 g (500 millimoles) of 3-nitrobenzaldehyde and 73 g (550 millimoles) of dimethyl malonate were stirred for 4 hours at 60° C., similarly to Example 9. After the addition of 5 ml of glacial acetic acid, the mixture was worked up in a conventional manner. The product of melting point 78°-80° C. was obtained in 96% yield.