Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[OH:20])=[O:4].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>C(Cl)Cl.[Ag-]=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][C@@H:6]1[O:20][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1O
Reactant: Cc1ccc(CBr)cc1
Agent: O=[Ag-]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1OCc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 59.3 %

Procedure:
A mixture of (1R,2R,4R) and (1S,2S,4S)-4-(2-chloro-benzenesulfonyl)-2-hydroxy-cyclopentanecarboxylic acid methyl ester (80 mg, 0.251 mmol, example 48, step 5), 1-(bromomethyl)-4-methylbenzene (232 mg, 1.25 mmol) and silver(I) oxide (116 mg, 0.502 mmol) in DCM (2 ml) was stirred at room temperature for 60 h. The reaction mixture was filtered through a pad of Celite, the pad was washed with DCM and the filtrate was evaporated. The remaining grey oil was purified by silica gel chromatography (heptane/EtOAc 80:20-70:30) to obtain the title compound (63 mg, 56%) as colorless oil. MS (EI): 423.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(Cl)(Cl)Cl.[C:17]([O:20][CH:21]([CH2:26][CH2:27][OH:28])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])[CH3:18]>O>[C:17]([O:20][CH:21]([CH2:26][CH2:27][O:28][S:9]([CH3:8])(=[O:11])=[O:10])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(CCO)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CCOS(C)(=O)=O)OC(C)=O
Reaction time: 0.5 h

Procedure:
In an ice bath, 6.1 ml of triethylamine and 2.3 ml of methanesulfonyl chloride were added to a chloroform (15 ml) solution of 2.59 g of methyl 2-(acetyloxy)-4-hydroxybutanoate, and stirred for 30 minutes. Saturated saline water was added to the reaction liquid, extracted with chloroform, and the organic layer was dried. The solvent was evaporated away under reduced pressure to obtain 2.54 g of methyl 2-(acetyloxy)-4-[(methylsulfonyl)oxy]butanoate as a brown liquid.
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[C:1]1([S:7]([C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)([CH3:22])[C:11]#[N:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: N#CC(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
4.0 g (0.014 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile in 40 mL of DMF were treated with 0.69 g (0.016 mol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min at 0° C. 3.07 g (0.022 mol, 1.5 eq) of methyliodide were added, and the ice bath was removed. After 2 hours, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography over silica gel with AcOEt/heptane 1:1 afforded 4 g (98%) of 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile as a racemic mixture of diastereomers, white solid, MS: 292 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>COCCOC.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:19]=[C:16]([CH3:17])[S:18][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1-c1csc(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (2.35 g) and thioacetamide (1.8 g) in a mixture of 1,2-dimethoxyethane (70 ml) and ethanol (70 ml) was refluxed for 7 hours and the reaction mixture was evaporated in vacuo. To the residue was added water, and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate, and evaported in vacuo. The residue was washed with diethyl ether and recrystallized from ethyl acetate to give ethyl 2-amino-5-(2-methyl-4-thiazolyl)-4-thiazolecarboxylate (1.4 g). mp 197°-199° C. (dec.)
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH2:24])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(N)cnc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(NS(C)(=O)=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a stirred solution of 2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 mL) was added methanesulfonyl chloride (372 mg, 3.3 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with ethyl acetate (gradient elution from 1:1 to 1:2) afforded 890 mg (70%) of the title compound as an amber oil: 1H-NMR (CDCl3) δ 8.26 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.2 Hz), 7.00 (1H, br.s), 4.35 (2H, t, J=7.0 Hz), 3.03–3.01 (5H, m), 2.85 (2H, q, J=7.5 Hz), 2.75 (3H, s), 2.35 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=2[N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)[NH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A 250 mL round bottom flask was charged with 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1.6 g, 8.62 mmol; Example 8, Step D), (R)-tert-butyl piperidin-3-ylcarbamate (5.18 g, 25.9 mmol), N-ethyl-N-isopropylpropan-2-amine (4.51 mL, 25.9 mmol), and NMP (15.5 mL). Then N2 was bubbled through the mixture for 5 minutes and stirred at 120° C. under N2 atmosphere for 16 hours to provide the crude (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. LCMS (APCI+) m/z 366.1 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2.[CH2:18]([Li])CCC.IC>O1CCCC1.CCOCC>[C:1]12([CH2:11][N:12]3[C:16]([CH3:18])=[C:15]([Cl:17])[CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2
Reactant: Clc1cnn(CC23CC4CC(CC(C4)O2)C3)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Cl)cnn1CC12CC3CC(CC(C3)O1)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 59A (0.25 g) in tetrahydrofuran (3 mL) was cooled to −78° C. butyllithium was (0.48 mL) added dropwise. Additional tetrahydrofuran (2 mL) was added and the reaction mixture was stirred for 1 hour at −78° C. To the reaction mixture was added iodomethane (0.08 mL) in one portion and the reaction was allowed to warm to 0° C. After 30 minutes, the reaction was diluted with ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 20% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: CN(C)C=O.[NH2:6][S:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8].[CH2:21](Br)[CH:22]=[CH:23][CH3:24].O>C(O)(C)C>[CH2:21]([N:16]([C:10]1[CH:11]=[CH:12][CH:17]=[CH:18][CH:19]=1)[NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:10]([S:7](=[O:9])(=[O:8])[NH2:6])[CH:11]=1)[CH:22]=[CH:23][CH3:24]
Reactant: NNC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC=CCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 0 °C

Procedure:
In a 250 ml round bottomed flask is placed 90 ml of N,N-dimethylformamide and 30 grams (0.092 mole) of 3-amino sulfonyl-4-chlorobenzhydrazide. The mixture was stirred to dissolve the solid, then 18.63 gms (0.138 mole) of crotyl bromide were added. The mixture was heated at 100° for 1.66 hours at which point TLC showed the reaction to be complete. The reaction mixture was cooled and diluted with 200 ml isopropanol. This solution was dripped into a slurry of 1.5 liters of ice and 4 liters of water. The solid which precipitated was collected, washed with water and air dried overnight, yielding the product which could be recrystallized from chloroform/carbon tetrachloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:5]=1[NH2:6].[CH3:16][N:17]1[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]1SC.Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[Cl:3][C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:5]=1[NH:6][C:18]1[N:17]([CH3:16])[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[N:19]=1
Reactant: CSc1nc(C(F)(F)F)cc(=O)n1C
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cn1c(Nc2c(Cl)cc(C(F)(F)F)cc2Cl)nc(C(F)(F)F)cc1=O
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Sodium hydride (60% in oil, 0.31 g, 7.65 mmol) was added to DMF (5 ml) solution of 2,6-dichloro-4-trifluoromethylaniline (0.80 g, 3.48 mmol), followed by stirring for 30 minutes. Then, 3-methyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (0.70 g, 3.13 mmol) was added, followed by stirring at 50° C. for 8 hours. After completion of the reaction, 1 N hydrochloric acid (30 ml) and ethyl acetate (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with water (30 ml×2) and saturated brine (70 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By recrystallizing the thus obtained crude product from toluene and then from chloroform, white solid of 2-(2,6-dichloro-4-trifluoromethylphenyl)amino-3-methyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 28] was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 96 %

Procedure:
Ethyl (2S)-3-[4-(3-{4-[(tert-butoxycarbonyl)amino]phenyl}propoxy)phenyl]-2-ethoxypropanoate (350 mg, 0.742 mmol) was dissolved in THF (10 ml). Under stirring, lithium hydroxide in water (5 ml) was added. The mixture was stirred at room temperature and followed by HPLC. After 4 hours, the reaction was stopped. More lithium hydroxide (9 mg) was added. The mixture was stirred overnight. It was then evaporated in vacuum to remove THF. The residue was extracted with diethyl ether and then acidified with 10% hydrochloric acid, pH˜3, and extracted with ethyl acetate (×2). The organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated and white solid product (315 mg) was left, yield 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[CH3:9][O:8][C:7]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[CH:3][C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COc1ccc(CCNC(=O)c2cc3ccccc3cc2O)cc1Br
Product: COc1ccc(CCNC(=O)c2cc3ccccc3cc2O)cc1-c1ccc([N+](=O)[O-])cc1
Yield: 61 %

Procedure:
The title compound (27 mg) was prepared from 0.05 g (0.1 mmol) of resin-bound N-2-(3-bromo-4-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide and 50.0 mg (0.3 mmol) of 4-nitro-phenyl boronic acid as described in Example 110.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)=O.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Clc1ccncc1
Reactant: COCCO
Agent: O=C=O
Agent: [Na]
Product: COCCOc1ccncc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (9.96 g) in 2-methoxyethanol (100 ml) was added dropwise 4-chloropyridine (42.7 g) under heating at 140° to 145° C. and stirring, which was continued for one hour at 135° C. after the addition. The mixture was cooled to -15° C. and dry ice (5.6 g) was added thereto. The mixture was warmed to 45° C. and then allowed to stand at room temperature. The resulting precipitates were removed by filtration and washed with diisopropyl ether. The filtrate and washings were combined and evaporated. The residual oil was distilled to give 4-(2-methoxyethoxy)pyridine (42.3 g), bp. 98° to 106° C. at 6 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].CCOC([CH:26]([N:35]1C(=O)[O:39][C:37](=[O:38])[CH:36]1[CH3:42])[CH2:27]CC1C=CC=CC=1)=O>>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:35]1[C@H:36]([C:37]([OH:39])=[O:38])[CH2:42][CH2:27][CH2:26]1)=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 81.8 %

Procedure:
In the said patent in the activation reaction of the starting N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine neither the racemization on α-C atom of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride is specified nor possible side reactions (J. Org. Chem., 32, 11, 1967) are mentioned. In the optimum Example 4 the reaction yield up to enalapril (base) is 87%. The separation of enalapril maleate is carried out with a 81.8% yield.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([C:24]1[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 45 ml. dichloroethane is added dropwise, 18.5 g. (0.1 05 mole) o-chlorobenzoyl chloride. The resulting solution is added dropwise to a cooled (0° C.) solution of 1-methylpyrrole-2-acetonitrile in 45 ml. dichloroethane keeping the temperature at approximately 10° C. The mixture is stirred at room temperature for about twenty minutes, and then refluxed for three minutes. It is poured into ice acidified with 3N hydrochloric acid, and the resulting two layers are separated. The aqueous fraction is extracted twice with chloroform. The organic fractions are combined and washed twice with N,N-dimethyl-1,3-propanediamine, once with 3N hydrochloric acid and once with saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting oil is chromatographed on a column packed with neutral alumina using benzene and ether as successive solvents. The first compound-bearing fractions contain the desired product. The solvent is evaporated and the resulting oil crystallizes upon treatment with methanol. The solid product, 5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is purified by recrystallization from benzene:cyclohexane solution, m.p. 80-85° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To 15 g of BOC-piperazine (80.6 mmol) dissolved in acetone (50 ml) was added in alternating portions benzylchloroformate (11.5 ml, 80.6 mmol) and 1N NaOH (15 ml) keeping the pH at 8-8.5 and the temperature 0°-5° C. After 2 hours, starting material was still present (tlc) and an additional quantity of benzylchloroformate (5 ml) and 1N NaOH (5 ml) was added. The reaction mixture was aged at 5° C. overnight and at room temperature an additional 7 hours. Water was added and the mixture extracted with ethyl acetate (3×50 ml), dried with Na2SO4 and concentrated to 21 g of an oil. This oil was dissolved in 10 ml of ethyl acetate, passed through 40 ml of silica gel and eluted with 200 ml of ethylacetate. Crystallization was effected by trituration with petroleum ether and the crystals collected, affording 8.28 g (32%) of N-t-butoxycarbonyl-N'-benzyloxycarbonylpiperazine, m.p. 90.5°-91.5° C.
Reaction SMILES: [C:1]([O-:5])([CH3:4])([CH3:3])[CH3:2].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O-:5])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:32][C:33]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1)=[O:34]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: COc1ccc(N)cc1N1CCN(C(=O)O)CC1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(C)c(Cl)c2)cc1N1CCN(C(=O)O)CC1

Procedure:
A solution of 34.4 mmol (10 g) of 4-(5-amino-2-methoxyphenyl)piperazine-1-carboxylic acid tert-butanolate (described in J. Med. Chem., 1999, p.202) and 37.8 mmol (5.9 g) of 3-chloro-4-methylphenyl isocyanate in 150 ml of toluene is heated at reflux for 2 hours. The reaction mixture is concentrated, and the residue is taken up in 200 ml of 4N hydrochloric acid and then heated at reflux for 4 hours. After cooling, the precipitate formed is filtered off and treated with a 2N sodium hydroxide solution in order to regenerate the corresponding base.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:16][N:17]([CH2:26][C:27]([OH:29])=O)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(OCC)C.C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:29])[CH2:26][N:17]([CH3:16])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: CN(CC(=O)O)C(=O)c1ccccc1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(C(=O)CN(C)C(=O)c1ccccc1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.075 g, 0.34 mmol), 2-(N-methylbenzamido)acetic acid (0.098 g, 0.51 mmol), and DMAP (0.062 g, 0.51 mmol) in dry diethyl ether (1.0 mL) and dry CH2Cl2 (1.1 mL) was cooled to a temperature of about 0° C. under N2. DCC (0.17 g, 0.81 mmol) was added, and the reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction mixture was filtered using additional CH2Cl2 (0.5 mL) to remove solids and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F83 as a white solid (0.12 g, 87%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>CO>[CH2:31]([N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:32][CH2:33][CH3:34]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCN(CCCC)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, butyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.C1(P(=[CH:32][C:33]#[N:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>C1(C)C=CC=CC=1>[C:33]([CH:32]=[CH:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:34]
Reactant: COC(=O)c1ccccc1C=O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1C=CC#N
Temperature: 110 °C

Procedure:
Methyl 2-formylbenzoate (10 g, 60.9 mmol) was dissolved in toluene (200 mL). (Triphenylphosphoranylidene)acetonitrile (20.19 g, 67.0 mmol) was then added to the mixture. The reaction was heated at 110° C. for 20 hours, then cooled to room temperature, concentrated under vacuum and the residue was triturated with ether (2×). The ether solution was passed though a plug of silica gel to provide Example 1A (mixture of E and Z isomers). The mixture of E and Z isomers was used directly for the next step. MS (DCI+) m/z 205.0 [M+NH3]+.