Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.N#N.C1(C[C:12]2(CC3C=CC=CC=3)[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([NH2:22])[C:15]([NH2:23])=[C:14]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]2=3)C=CC=CC=1.[C:36](Cl)(=O)[CH:37]([CH3:39])[CH3:38]>>[C:37]1([CH2:39][N:22]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:12]=2)[C:16]2[C:15]3[N:23]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:14]=3[C:13]3[CH2:12][CH2:21][CH2:20][CH2:19][C:18]=3[N:17]=2)[CH:38]=[CH:27][CH:26]=[CH:25][CH:36]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)CNc1c(N)c(N)nc2c1C(Cc1ccccc1)(Cc1ccccc1)CCC2
Agent: N#N
Product: CC(C)Cn1c(C(C)C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c21)CCCC3
Yield: 136.7 %

Procedure:
Using the general method of Example 65, N2, N2 -bis(phenylmethyl)-5,6,7,8-tetrahydro-N4 -(2-methylpropyl)quinolin-2,3,4-triamine (0.86 g, 2.1 mmole) was reacted with isobutyryl chloride (0.217 mL, 2.1 mmole) to provide 0.67 g of the desired product as a yellow foam.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].N1CCCCC1>C(O)(=O)C>[C:7](/[C:9](=[CH:1]\[CH2:2][CH:3]([CH3:5])[CH3:4])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C/CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a mixture of 3.00 mL (28.0 mmoles) of isovaleraldehyde and 3.00 mL (28.1 mmoles) of ethyl cyanoacetate in 4.0 mL of glacial acetic acid was added a solution of 0.10 mL of piperidine in 1.0 mL of glacial acetic acid. This mixture was subsequently stirred at room temperature for 18 hours, after which the product was isolated by diluting the mixture with 50 mL of 10% aqueous sodium chloride and extraction with ether. The combined extracts were washed thoroughly with 50 mL portions of 10% aqueous NaCl, followed by washes with 50 mL of 1:1 (v/v) 1M aqueous NaOH:saturated brine and saturated brine. The organic extracts were then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether by evaporation at reduced pressure, followed by distillation, afforded 3.91 g (77% yield) of cyanoester 5: bp 78°-90° C. (bath temperature, 0.07 mm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([CH:11]1[CH2:15][N:14]([CH2:16][C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)[C:13](=[O:41])[CH2:12]1)[CH2:9][CH3:10]>C(#N)C>[O:41]=[C:13]1[CH2:12][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:15][N:14]1[CH2:16][C:17]1[N:18]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])[CH:19]=[N:20][CH:21]=1
Reactant: CCCC1CC(=O)N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)OCC)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, ethylbromoacetate (560 μl, 4.95 mmol) is added to a solution of 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.5 g, 3.3 mmol) in 10 ml of acetonitrile. The mixture is stirred at 40° C. for 3 h, 1.65 mmol of ethylbromoacetate is added and stirring is pursued for 48 h at room temperature. The mixture is concentrated in vacuo, 20 ml of a 1/1 mixture of acetic acid and water is added and the mixture is stirred at room temperature overnight. The mixture is filtered, the solvent is evaporated and the residue is dissolved in 25 ml of diluted HCl (pH 1). The aqueous phase is washed with CH2Cl2, basified to pH 10 by addition of solid Na2CO3 and extracted three times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by tin layer chromatography on preparative plates (CH2Cl2/EtOH: 90/10 (v/v)) to give 275 mg of ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate (30%). Ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate hydrochloride x49 is obtained by treatment with a solution of HCl in Et2O and recrystallization from CH3CN/AcOEt.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([CH3:22])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]C2C=CC=CC=2)[CH2:10][CH:9]1[CH3:21])=[O:7].C=O.[H][H]>[Pd].CO>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([CH3:22])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[CH3:21])=[O:7]
Reactant: CC(CCCl)C(=O)N1CCN(Cc2ccccc2)CC1C
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CO
Product: CC(CCCl)C(=O)N1CCN(C)CC1C
Yield: 72.6 %

Procedure:
A mixture of 16 parts of 1-(4-chloro-2-methyl-1-oxobutyl)-2-methyl-4-(phenylmethyl)piperazine monohydrochloride, 200 parts of methanol and 7 parts of a formaldehyde solution 40% was hydrogenated at normal pressure and at 60° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane, yielding 9 parts (72.6%) of 1(-4-chloro-2-methyl-1-oxobutyl)-2,4-dimethylpiperazine monohydrochloride (int. 26).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[C:29]([Si:26]([CH3:28])([CH3:27])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCc1ccccc1)c1ccc(OCCO)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)CCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 1-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propan-1-one from Example N (2.21 g, 8.2 mmol), imidazole (0.67 g, 9.8 mmol), t-butyldimethylsilyl chloride (1.36 g, 9.0 mmol) and CH2Cl2 (70 mL). The product was carried on crude to the next step (see Example SS.)
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[SH:34].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCSc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorobenzenethiol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenylthio)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=412.91). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (m, 2H), 4.32 (m, 2H), 6.56 (m, 1H), 6.72 (m, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.53 (m, 3H), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6OS): C, 55.33; H, 3.42; F, 9 21; N, 20 38; O, 3.88; S, 7.77. Found C, 55.01; H, 3 75; N, 21.95; S, 6.89.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:47])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:13]([NH:15][C@H:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:8](=[O:26])[N:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[O:36])=[C:30]([O:45]C)[CH:29]=1.O>ClCCl>[CH3:47][C:6]1([CH3:5])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:13]([NH:15][C@H:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:8](=[O:26])[N:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[O:36])=[C:30]([OH:45])[CH:29]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
211 μL of boron tribromide were added under argon to a solution of 100 mg (0.169 mmol) of the compound of Example 1 in 20 mL of absolute dichloromethane at −78° C. and the reaction mixture was allowed to warm to 0° C. with ice cooling. After 30 minutes at 0° C., water was cautiously added. The phases were separated and the organic phase was dried over sodium sulfate. After filtration, removal of the solvent in vacuo, chromatographic purification by preparative HPLC and freeze drying of the product fractions, 35 mg (36%) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)O.CCN(CC)CC.CS([Cl:50])(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:38])[C:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[C:21]([Cl:50])[C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])=[CH:5][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc(Cl)c(Cl)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid methyl ester (42 mg, 0.068 mmol) in DCM (1.5 mL) was added Et3N (38 μL, 0.273 mmol) and the mixture was cooled to 0° C. MsCl (8 μL, 0.102 mmol) was added and the mixture was warmed to rt and stirred for 1.5 h. The mixture was heated to 50° C., treated with catalytic DMAP, and stirred overnight. The mixture was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylic acid methyl ester. The crude product was hydrolyzed as in EXAMPLE 2, Part E, to provide the title compound (25% for two steps). HPLC: RT=9.97 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 618.30; m/z found, 581/583 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.82 (s, 1H), 9.37 (d, J=5.1, 1H), 8.48 (d, J=7.1, 1H), 8.34 (dd, J=8.8, 0.9, 1H), 7.96-7.86 (m, 2H), 7.82-7.75 (m, 2H), 7.64-7.55 (m, 3H), 7.11 (dd, J=8.5, 2.0, 1H).
Reaction SMILES: OC1C=CC([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=CC=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CS(C)=O.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:24][C:25]1[CH:26]=[CH:27][C:30]([N:15]([CH2:14][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:8]=2)[S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:31][CH:32]=1
Reactant: CCS(=O)(=O)NCc1cnccc1-c1ccc(O)cc1
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(OCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-(4-(4-hydroxyphenyl)-N-(ethanesulfonyl) pyrid-3-ylmethylamine (1.0 equiv.) in DMSO (0.15 M) was cooled to 0° C. Sodium hydride (1.1 equiv.; 60% dispersion in oil) was added; after 20 minutes at 0° C. 3-methoxybenzyl bromide (Aldrich; 1.3 equiv.) was added and the reaction warmed to ambient temperature. After stirring overnight the reaction was diluted with ethyl acetate and washed with 0.1 M potassium carbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate to give the title compound. Anal Calcd for C22H24N2O4S.0.1H2O: C, 64.06; H, 5.86; N, 6.79. Found: C, 63.78; H, 5.89; N, 6.76. MS found 413.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#N.[CH2:13]([NH:16][CH2:17][CH2:18][NH2:19])[CH:14]=[CH2:15].[Na+].S.[ClH:22]>>[ClH:22].[CH2:13]([N:16]1[CH2:17][CH2:18][N:19]=[C:6]1[CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])[CH:14]=[CH2:15]
Reactant: C=CCNCCN
Reactant: Cc1cccc(OCC#N)c1C
Agent: Cl
Agent: S
Agent: [Na+]
Product: C=CCN1CCN=C1COc1cccc(C)c1C

Procedure:
4.84 g (30 mmol) of 2,3-dimethylphenoxy-acetonitrile, 3.3 g (33 mmol) of N-allyl-ethylenediamine and 260 mg of sodium polysulfide (Na2S4) are stirred together at 50° C. for 4 hours. The excess amine is then stripped off under a high vacuum, ethanolic hydrochloric acid is added to the residue and the hydrochloride is precipitated by addition of ether.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:8])[C:15]=1[CH3:16])(=[O:28])=[O:29]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Reactant: CN1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester was condensed with 1-methyl-piperazine to give the titled compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:22])[CH2:20][CH3:21]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: CCC(=O)Cl
Product: CCC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 (2) Method B was reacted with propionyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([SH:15])[CH:6]=1)[CH3:2].Cl[CH2:18][C:19](=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[CH:8]=[C:7]([S:15][CH2:18][C:19](=[O:21])[CH3:20])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: CC(=O)CCl
Product: CCOC(=O)c1cc(SCC(C)=O)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 40, Step 4, using the following starting materials: 3-mercapto-5-trifluoromethyl-benzoic acid ethyl ester and chloroacetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[NH3:15]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:14])[C:9]([NH2:15])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)C(C)c1ccc(Cl)cc1
Solvent: CC(C)(C)O
Product: C[C@@H](C(N)=O)c1ccc(Cl)cc1
Yield: 42.8 %

Procedure:
A mixture of 5 g of racemic ethyl 2-(4-chlorophenyl)-propionate and 50 ml of tert-butanol is treated at 50° C. with stirring with 1 g of lipase from Candida antarctica (Novozym 435, activity 7000 PLU/g). Ammonia is then passed into the reaction mixture with stirring at 50° C. until it is saturated. The mixture is stirred at 50° C. for a further 28 hours and during the course of this a slow stream of ammonia is continuously passed through the apparatus. The mixture is then worked up by filtering off the biocatalyst, washing it with tert-butanol and ethanol, concentrating the filtrate under reduced pressure and stirring the residue which remains with a mixture of petroleum ether:di-isopropyl ether=9:1. The product obtained in crystalline form is filtered off, washed with petroleum ether and dried. In this manner 1.78 g (42.8% of theory, conversion 44 area per cent GC) of (R)-2-(4-chloro-phenyl)-propionamide having an ee value of 96.1% are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=1[F:11]
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(N)c1F
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. A mixture solution of 3-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: N#CCCCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC1(C)C(=O)N(CCCC#N)c2cc([N+](=O)[O-])c(N)cc21
Yield: 125.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.24 g) is alkylated using 4-bromobutyronitrile (0.1 ml; 1 mmol) and K2CO3 (0.28 g; 2 mmol) at 50° C. for 3 days. After aqueous work-up the crude material (0.4 g) is de-acetylated in MeOH (10 ml) using DBU (0.1 ml) at RT in 3 h. After aqueous work-up 4-(5-amino-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indol-1-yl)-butyronitrile (0.33 g) is obtained and used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([O:14][CH3:15])=[O:13])[CH2:4]3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(N2CCCC(CN)C2)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: COC(=O)c1cccc(N2CCCC(CNC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 82.3 %

Procedure:
Using methyl 3-[3-(aminomethyl)piperidin-1-yl]benzoate (76.2 mg, 0.307 mmol) and 4′-chlorobiphenyl-4-carboxylic acid (77.2 mg, 0.332 mmol), the same procedure was followed as in Step 61e of Example 61 to give 117 mg (82%) of the desired compound as a pale yellow powder.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(Cl)Cl.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])(O)=O.[Na+]>O>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:27][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:31])[CH3:34]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 3 h

Procedure:
6.4 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylate are initially introduced into 30 ml of methylene chloride. A solution of 3.1 g of ethyl 3-amino-propionate hydrochloride in 12 ml of water is added to this. A solution of 1.7 g of NaHCO3 in 20 ml of water is added dropwise to the two-phase mixture with vigorous stirring. After the dropwise addition is complete, the mixture is stirred for a further 3 hours. The phases are then separated, and the organic phase is washed with water and dried over Na2SO4. After concentration, 7.8 g of the title compound remain.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=O)=[CH:24][CH:23]=1>>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: Nc1ccc(CC(=O)O)cc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(N)cc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.88 g (11.4 mmol) of 4-aminophenylacetic acid.