Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:10][CH2:9]2.B(Br)(Br)Br>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:10][CH2:9]2
Reactant: COc1cccc2c1CC(N1CCN(c3cccc(C(F)(F)F)c3)CC1)CC2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1cccc2c1CC(N1CCN(c3cccc(C(F)(F)F)c3)CC1)CC2
Temperature: -78 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
1-(1,2,3,4-Tetrahydro-8-methoxy-2-naphthalenyl)-4-[3-(trifluromethyl)phenyl]piperazine hydrochloride (2.7 g, 6.0 mmole) was dissolved in 125 ml of methylene chloride and cooled to -78° C. in a dry ice/acetone bath. To the cold solution was added a mixture of 18.9 ml of 1 M boron tribromide and 25 ml of methylene chloride. The reaction was allowed to come to room temperature and stirred for three days. The reaction was quenched with methanol and concentrated in vacuo. The residue was column chromatographed on 100 g of silica gel with 5% methanol/chloroform as eluent and the crude title compound thus obtained was crystallized first from isopropanol with addition of 4 N isopropanolic HCl and then from acetone to yield 1.2 g of the title compound as the monohydrochloride, m.p. 207°-209° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12](Cl)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O-:24])=[C:20]([CH3:25])[CH:19]=1.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=1[CH3:25])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Reactant: Cc1cc(Cl)ccc1[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
A mixture of 25.1 g of diethyl-2-chloro-propionyl-malonate, 16.5 g of sodium 4-chloro-2-methyl-phenolate and 100 ml of dimethyl formamide is stirred at 60° C. for 48 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed succesively with 100 ml of a saturated aqueous sodium bicarbonate solution and 100 ml of water. The benzene layer is evaporated to give 28.7 g of the desired compound, yield 82%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:7]2=[O:8])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1C(=O)N(CCCCBr)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 1-(4-bromobutyl)isatin (5.64 g), 1-benzhydrylpiperazine (7.56 g) and triethylamine (3.0 g) in N,N-dimethylformamide (48 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (50 g) using chloroform as an eluent. The fractions containing the object compound were collected and evaporated. The remaining oil (3.25 g) was crystallized from diisopropyl ether, washed with diethyl ether, and then recrystallized from acetonitrile to give crystals of 1-[4-(4-benzhydryl-1-piperazinyl)butyl]isatin (2.69 g), mp. 127° to 129° C.
Reaction SMILES: [ClH:1].C([N:9]([C:14]1[CH:19]=[C:18]([CH:20]([OH:39])[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]=3[CH:27]=2)[C:17]([OH:40])=[CH:16][CH:15]=1)[S:10]([CH3:13])(=[O:12])=[O:11])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl>[ClH:1].[CH:27]1[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][C:26]=1[O:25][CH2:24][CH2:23][NH:22][CH2:21][CH:20]([C:18]1[C:17]([OH:40])=[CH:16][CH:15]=[C:14]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:19]=1)[OH:39]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(O)c(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(O)c(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1

Procedure:
According to the procedures described in Example 2, Intermediate 78 and the recovered product from the filtration (total sum of 30 mg) were treated by subjecting them to a hydrogenolysis for 13 hours using 10% palladium/carbon black (30 mg) with subsequent trituration of the resulting crude product from methanol/ethyl acetate, whereby the above-identified compound (9 mg) was obtained. Rf=0.34 (methanol/chloroform of 1/9).
Reaction SMILES: CN1C(=O)C(C)(N2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])C(=O)NC1=O.Cl.[NH2:28][C:29]1([CH2:41][CH3:42])[C:34](=[O:35])[N:33]([CH2:36][CH2:37][CH3:38])[C:32](=[O:39])[NH:31][C:30]1=[O:40]>>[CH2:41]([C:29]1([N:28]2[C:10](=[O:23])[C:11]3[C:16](=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=3[F:22])[C:17]2=[O:18])[C:34](=[O:35])[N:33]([CH2:36][CH2:37][CH3:38])[C:32](=[O:39])[NH:31][C:30]1=[O:40])[CH3:42]
Reactant: CCCN1C(=O)NC(=O)C(N)(CC)C1=O
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Agent: Cl
Product: CCCN1C(=O)NC(=O)C(CC)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19e was synthesized in the same manner as described for 19a from 5-amino-5-ethyl-1-propylbarbituric acid hydrochloride (0.38 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 5-ethyl-1-propyl-5-(tetrafluorophthalimido)-barbituric acid (19e) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(CC2)COc2ccccc23)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 49.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.07 g, 0.14 mmol) obtained in step 2 and ethanesulfonamide (0.076 g, 0.72 mmol), the title compound (0.04 g, 50%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C@@H:36]([OH:38])[CH3:37])(=[O:29])=[O:28])[CH:21]=[CH:20]3)O1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+].CCCC(C)C>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C@@H:36]([OH:38])[CH3:37])(=[O:29])=[O:28])[CH:21]=[CH:20]3)=[N:3][CH:4]=1
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc2c1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: CCCC(C)C
Solvent: O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cn3)ccc2c1

Procedure:
A mixture of 2-bromo-5-fluoropyridine (38 mg, 0.22 mmol), (1S)-1-(2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]sulfonyl}phenyl)ethanol (96 mg, 0.22 mmol), palladium(II) acetate (2.6 mg, 11 μmol), tri(o-tolyl)phosphine (5.2 mg, 17 μmol) and sodium carbonate (51 mg, 0.48 mmol) in DME (2 mL) and water (0.3 mL) was degassed by bubbling nitrogen through for 5 minutes, then was heated at reflux under nitrogen for 3 hours. The slurry was filtered, and the filtrate was washed with saturated sodium hydrogen carbonate solution (10 mL), with saturated sodium chloride solution (10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 40% ethyl acetate in isohexane, then further purified by preparative TLC on silica gel, eluting with 50% ethyl acetate in isohexane. The product was isolated as a colourless solid, which solidified upon trituration with isohexane (13 mg, 15%). 1H NMR (400 MHz, CDCl3): δ 8.61 (1H, d, J=2.7 Hz), 8.55 (1H, s), 8.48 (1H, s), 8.21 (2H, dd, J=8.7, 21.9 Hz), 8.06 (2H, dd, J=8.7, 22.5 Hz), 7.90 (1H, dd, J=4.1, 8.7 Hz), 7.77 (2H, d, J=7.6 Hz), 7.66 (1H, t, J=7.5 Hz), 7.57-7.49 (2H, m), 5.65 (1H, m), 2.48 (1H, s), 1.34 (3H, d, J=6.4 Hz). m/z (ES+) 408 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[C:3]=1[CH3:13].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[C:3]=1[CH3:13]
Reactant: Cc1c(Br)ccc2c1COC(=O)N2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Br)cc([N+](=O)[O-])c2c1COC(=O)N2
Reaction time: 14 h

Procedure:
To a solution of 6-bromo-5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.726 g, 3 mmol) in concentrate H2SO4 (4 mL), KNO3 (0.303 g, 3 mmol) was added at 0° C. Reaction mixture stirred 14 hours and poured over crushed ice. Yellow precipitate was obtained, which was filtered and dried.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[N:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](Br)[CH:14]=[CH2:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C=O)C>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][N:10]=[CH:9][CH:8]=[C:7]12)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=c1[nH]c2ccncc2c(=O)o1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCn1c(=O)oc(=O)c2cnccc21

Procedure:
To a solution of 5-azaisatoic anhydride (1 mmol, Coppola, G. M. Synthesis 1980, 505) and allyl bromide (1.1 mmol) in DMF is added triethylamine (1.2 mmol) dropwise. The reaction mixture is allowed to stir at room temperature for 12 h after which time CHCl3 is added and the organic layer is washed with water, dried (MgSO4) and the solvent is evaporated to give N-allyl-5-azaisatoic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([C:31]2([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:32][CH2:33]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 75 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a colorless oil (75%). MS ISP (m/e): 505.2 (100) [(M+H)]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[N:11]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:34]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:15]2[CH2:16][CH2:17][C:12]3([N:11]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:10](=[O:33])[N:9]=[C:8]3[NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(I)cc1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(C#N)cc1)CC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-[4-(cyclohexylamino)-8-(4-iodobenzyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate (Intermediate I.3.a.1, 150 mg, 0.29 mmol), zinc cyanide (24 mg, 0.20 mmol) in DMF (3 mL) was added tetrakis (33 mg, 0.03 mmol). The resulting solution was allowed to stir at 80° C. for 16 h. After 16 h, the reaction mixture was filtered, concentrated in vacuo and purified by reverse phase preparative HPLC (5- 95% MeCN/H2O containing 0.1% TFA, C18) to provide the desired product. LRMS (M+1)=466.6.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), morpholine (26 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (44 mg, 80% of theory).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.[Cl:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:11][CH2:12][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1
Reactant: Oc1ccc2sccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCOc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzo[b]thiophen-5-ol (0.5 g, 3.3 mmol, prepared in an analogous manner to a literature preparation: Synthetic Communications 21(7), 959-964, 1991) was dissolved in anhydrous acetonitrile (10 mL) was treated with chloroethyltosylate (0.94 g, 3.99 mmol) and cesium carbonate (2.15 g, 6.6 mmol). The mixture was stirred at reflux under nitrogen. After 2 h, the reaction was allowed to cool down to room temperature. The volatiles were removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The ethyl acetate layer was then dried with sodium sulfate and purified by flash chromatography using a gradient of 5 to 25% of ethyl acetate in hexanes to obtain a white solid. Yield=0.676 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]#[C:14][Si](C)(C)C)[CH:10]=[N:9]2)[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[C:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH:12]=1)#[CH:14]
Reactant: Cc1cc(Cn2cc(C#C[Si](C)(C)C)cn2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cnn(Cc2cc(C)on2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
5-Methyl-3-((4-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)methyl)isoxazole (31) (0.55 g, 2.12 mmol) was dissolved in 3 ml THF and stirred at RT. To the stirred solution was then added a 1M solution of TBAF in THF (3 ml, 3 mmol). After 10 minutes, the reaction was diluted with ethyl acetate (20 ml) and water (20 ml). The organic solution was collected, dried and concentrated. The crude product was purified on a short silica column eluting with 5% ethyl acetate in DCM. The pure fractions provided the title compound as a pale brown solid (278 mg, 70%). 1H-NMR (500 MHz, CDCl3) 2.38 (s, 3H), 3 (s, 1H), 5.29 (s, 2H), 5.9 (s, 1H), 7.61 (s, 1H), 7.63 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(CCCCN)P(=O)(OCC)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCCCNC(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of benzoyl chloride (0.73 g, 5.0 mmol) in dichloromethane was added slowly to a solution of tetraethyl 5-aminopentane-1,1-bisphosphonate (1.50 g, 4.5 mmol) from Example 11, part A, and triethylamine (0.76 mL, 5.5 mmol) in dichloromethane at 0° C. After warming to room temperature for 30 minutes, the reaction was quenched by addition of 1N HCl (30 mL). The product was extracted into dichloromethane (2×20 mL) and the combined organic layers were washed with saturated NaHCO3 (2×15 mL), dried (Na2SO4), and concentrated in vacuo. Flash chromatography on silica gel eluting with 15% i-propanol in ethylacetate in EtOAc gave the title compound (0.64 g) as an oil.
Reaction SMILES: I.[PH2](O)=O.[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH:14]=1)([O:7][CH2:8][CH3:9])=[O:6].[CH:17](=O)[CH2:18][CH3:19].N>O.C(O)(=O)C>[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[C:14]=1[CH2:17][CH2:18][CH3:19])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: CCC=O
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: CCCc1c(C(=O)OCC)[nH]c(C)c1C
Yield: 40 %

Procedure:
Hydriodic acid (d 1.95, 10 ml) was slowly added to 10 ml of stirred and cooled acetic acid; hypophosphorous acid (50%, 2 ml) was then added. 2-Carbethoxy-4,5-dimethylpyrrole (0.004 mol) was added to the mixture at room temperature followed by propionaldehyde (0.008 mol). The solution was stirred 21/2 h at ca. 25° C. then poured into 200 ml of water. This was made alkaline with ammonia, extracted with ether, and the ether was evaporated to leave the crude product. This was an oil which solidified after distillation (1 × 10-4 mm). It was recrystallized from aqueous ethanol, then from ethanol m.p. 101°-104° C. (lit. 102° C), yield 40%. ##STR68##
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O.C1COCC1.O>[CH2:22]([O:21][C:19]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
12 g (66.1 mmol) of rac-methyl norleucinate hydrochloride were initially charged in 974 ml of water/THF (8:1), and 28.3 g (204.8 mmol) of potassium carbonate were added. The reaction mixture was cooled to 0° C. 12.3 ml (72.7 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The mixture was diluted with 480 ml of water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate=4:1). This gave 18.0 g (97.6% of theory, purity 100%) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:8]2[C:7]1=[O:18])=[O:5])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:8]2[CH:7]1[OH:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1(C(=O)OCC)Cn2c(cc3ccccc32)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CC1(C(=O)OCC)Cn2c(cc3ccccc32)C1O
Yield: 92.7 %

Procedure:
A solution of 17.7 g of ethyl 2-(ethoxy-carbonyl)-2,3-dihydro-1-oxo-1H-pyrrolo[1,2-a]indole-2-acetate in 200 ml of methanol was treated under a nitrogen atmosphere with 1.5 g of 10% palladium-on-charcoal and 10 g of ammonium formate. The mixture was heated at reflux for 1.5 hours, then cooled and filtered. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with sodium chloride solution and dried. Evaporation of the solvent gave 16.5 g of ethyl 2-(ethoxycarbonyl)-2,3-dihydro-1-hydroxy-1H-pyrrolo[1,2-a]indole-2-acetate
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[S:39].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]3[NH:37][C:38](=[S:39])[O:1][N:2]=3)=[CH:11][CH:10]=2)/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=S)[nH]2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (90 mg, 0.18 mmol; Compound 435, Step 2) and thiocarbonyldiimidazole (50 mg, 0.28 mmol) in anhydrous acetonitrile (1.5 mL) was added DBU (0.11 mL, 0.72 mmol). The solution was stirred at room temperature for 4 h then directly concentrated onto silica gel. Purification by column chromatography (0 to 80% EtOAc/hexanes) afforded 69 mg of the title compound as an orange oil. LCMS: 451 [(M-THP+H)+H]+.