Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[Cl-].[NH4+:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH2:38])=[O:25]
Reactant: [NH4+]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: [Cl-]
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(N)=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with ammonium chloride.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[N:7][CH:6]=1>N1C=CC=CC=1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:9]=[C:10]2[C:11]([NH2:12])=[N:3][NH:2][C:5]2=[CH:6][N:7]=1
Reactant: NN
Reactant: N#Cc1cc(-c2cccc(F)c2F)ncc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12

Procedure:
Hydrazine hydrate (0.52 ml, 10.7 mmol) was added to a stirred solution of 5-chloro-2-(2,3-difluorophenyl)isonicotinonitrile (1.22 g, 4.9 mmol) in pyridine (12.5 mL). The reaction mixture was stirred at reflux for 2 hours, allowed to cool and concentrated. Purification by column chromatography using a gradient of 5–10% methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: C[O-].[Na+].CO.C([O:14][C@@H:15]1[C@H:19]([O:20]C(=O)C2C=CC=CC=2)[C@@H:18]([CH2:29][O:30]C(=O)C2C=CC=CC=2)[S:17][C@H:16]1[N:39]1[CH:46]=[CH:45][C:43]([NH2:44])=[N:42][C:40]1=[O:41])(=O)C1C=CC=CC=1.C(O)(=O)C>CO>[C@@H:16]1([N:39]2[CH:46]=[CH:45][C:43]([NH2:44])=[N:42][C:40]2=[O:41])[S:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:15]1[OH:14]
Reactant: Nc1ccn([C@@H]2S[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccn([C@@H]2S[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
0.1 mL of a 28% sodium methoxide/methanol solution was added to a suspension of 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in 2.0 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour and was then left overnight. Thereafter, 0.2 mL of acetic acid was added to the reaction mixture, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 2/1), so as to obtain 18 mg of 1-(4-thio-β-D-ribofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([N:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:12](=[O:26])[N:13]([CH3:25])[C:14]3=[O:24])=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C1COCC1>[CH2:27]([N:11]1[C:10]2=[N:9][N:8]([CH2:7][C:6]3[CH:31]=[CH:32][C:3]([CH2:2][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:4][CH:5]=3)[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]2[C:14](=[O:24])[N:13]([CH3:25])[C:12]1=[O:26])[CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(CBr)cc3)nc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(CN4CCCC4)cc3)nc21

Procedure:
2-(4-(bromomethyl)benzyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (30 mg, 0.06 mmol), K2CO3 (16 mg, 0.12 mmol) and pyrrolidine (10 μL, 0.12 mmol) in THF is stirred at room temperature for 2 days. The mixture is then purified by HPLC to give final product as white powder. MS (ESI) m/z 487.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:7][CH:8]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)C(=O)Nc1ccc(CO)cn1
Reactant: BrCC1CC1
Product: CC(C)(C)C(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (1.04 g) and bromomethyl cyclopropane (0.813 g) as a light yellow oil (0.87 g). MS (ESI): 263.1. (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([Cl:12])=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CC(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]=1
Reactant: Clc1ccc2c(Cl)ncnc2n1
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Clc1ccc2c(Nc3ccccc3)ncnc2n1
Reaction time: 48 h

Procedure:
A solution of Example 140D (0.5 g, 2.5 mmol), and aniline (0.23 mL, 2.5 mmol) in THF (25 mL) and 2-propanol (2.5 mL) was stirred at 0° C. for 1 h then at room temperature for 2 days. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Recovered 0.15 g of product (23%). MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:34])[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1.Cl>>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH2:23][N:34]2[C:17](=[O:19])[C:9]3[CH:8]=[C:7]4[CH2:6][CH:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:13][C:12]4=[CH:11][C:10]=3[C:14]2=[O:16])[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(OC)c(OC)c1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with veratrylamine (0.20 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 106 as a white solid (m.p. 233-235° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl3. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>O1CCOCC1>[O:13]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1([CH2:16][CH2:15][C:14]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC#N
Reactant: O=C1CCCCC1c1ccccc1
Solvent: C1COCCO1
Product: N#CCCC1(c2ccccc2)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
Triton B surfactant (500 μL) was added to a stirred solution of 2-phenylcyclohexanone (5 g, 28.7 mmol) in dioxane (40 mL). A solution of acrylonitrile (1.8 g, 33.9 mmol) in dioxane (5 mL) was added dropwise. A slight exotherm was observed. The solution was stirred at room temperature for 3 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (20 mL, 2×). The EtOAc extract was dried (MgSO4), filtered, and concentrated. The residual oil was chromatographed on a silica gel column. Elution with 2% EtOAc in heptane, followed by 5% EtOAc in heptane afforded 3-(2-oxo-1-phenylcyclohexyl)propanenitrile (5.05 g, 77% yield) as a colorless oil. HPLC: tR=2.73 min, YMC Combi S5 ODS 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.2% H3PO4; Final solvent: 90% aq. MeOH—0.2% H3PO4. LC/MS: m/e 228.26 (M+H)+, 250.14 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.246 g, 1.26 mmol) according to the general procedure VI. Obtained as a white solid (0.140 g, 40%). MS (ISP) 407.2 [(M+H)+]; mp 172-190° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15].[NH2:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:22]#[N:23]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]1[C:21]([C:22]#[N:23])=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:16]([CH3:17])=[C:13]1[C:14]#[N:15]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F
Product: CC1=C(C#N)C(c2cc3c(C)n[nH]c3cc2F)C(C#N)=C(C(F)(F)F)N1

Procedure:
Following the procedure described for Example 4, 250 mg (0.411 mmol) (2E)-2-[(6-fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 4A) were treated with 3-amino-4,4,4-trifluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (aceto-nitrile/water gradient, final mixture 90:10 v/v) to yield 159 mg (42% of th.) of the racemic title compound.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[N:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCCl.CC(O)=O>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:18][CH:17]=1
Reactant: Nc1cncc(Cl)n1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:32])[C:18]([C:27]([O:29]CC)=[O:28])=[CH:19][N:20]3[CH2:23][CH2:24][C:25]#[N:26])=[CH:15][C:14]=2[F:33])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:32])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]3[CH2:23][CH2:24][C:25]#[N:26])=[CH:15][C:14]=2[F:33])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)C1
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 20A (0.41 g) in THF (60 mL) and methanol (30 mL) at reflux was treated with 1M LiOH (100 mL), stirred for 3 hours then cooled, concentrated to half volume, acidified with 10% citric acid (90 mL), and filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Br:10]C1C(CBr)=NC(Cl)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: Cc1cc(Br)cnc1Cl
Product: Clc1ncc(Br)cc1CBr
Yield: 33 %

Procedure:
Compound 76B (0.46 g, 33%) was prepared from 76A (1.0 g, 4.9 mmol) using a procedure similar to the synthesis of 55B.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Yield: 85.7 %

Procedure:
19 g (475 mmol) of sodium hydride (60% in oil) are added in small amounts to a solution of 114 g (447 mmol) of tert-butyl (3-bromobenzyl)carbamate in 800 ml of dimethylformamide and the reaction medium is stirred until evolution of gas has ceased. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is maintained for 18 hours. The reaction medium is poured into ice-cold water and extracted with ethyl acetate. The organic phase is separated by settling, dried over magnesium sulfate and evaporated. 115 g of tert-butyl (3-bromobenzyl)-N-methylcarbamate are obtained. Yield=95%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CCCN2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 52 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-(3-chloro-propyl)-morpholine gave the title compound in 52% yield. ES-MS m/e (%): 494.6(M+H+).
Reaction SMILES: [N:1]1([CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[BrH:16]>CC(C)=O>[BrH:16].[Br:16][CH2:3][CH2:2][NH:1][CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1
Agent: Br
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1C[C@H](O)CNCCBr

Procedure:
In another alternate procedure, treatment of (R)-(-)-α-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol, synthesized as described in Example 2(e), with aqueous hydrogen bromide in acetone, as described in The Journal of Medicinal Chemistry, 33, 2608 (1990) , gives the product, mp 149°-150.5° C. (decomposition), 99.3% optically pure by chiral HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>O1CCCC1.C(O)(=O)C>[CH:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)([CH3:25])[CH3:22]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)C)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (300 mg) in tetrahydrofuran (8 ml) were sequentially added acetone (0.4 ml), acetic acid (0.1 ml) and sodium triacetoxyborohydride (780 mg), and the solution was stirred for 2 days at room temperature. The solution was neutralized with ammonia solution, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (309 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[CH:15](/B(O)O)=[CH:16]\[CH3:17]>>[C:1]([C:3]1[CH:8]=[C:7](/[CH:15]=[CH:16]/[CH3:17])[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2]
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Reactant: C/C=C/B(O)O
Product: C/C=C/c1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) and (E)-prop-1-enylboronic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[O:13][NH:12][C:11](=[O:14])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH3:18]>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[O:13][N:12]([CH2:17][CH3:18])[C:11](=[O:14])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NCC1CC(=O)NO1
Product: CCN1OC(CNC(=O)OC(C)(C)C)CC1=O

Procedure:
The product obtained in Step B (0.1 g) was alkylated with bromoethane as described in Example 4, step A to afford the O-alkylated product (18 mg), 1HNMR (CDCl3, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H), 4.2 (q, 2H), 3.35 (m, 2H), 3.00 (dd, 1H), 2.75 (dd, 1H), 1.50 (s, 9H), 1.35 (t, 3H); and the title N-alkylated product (63 mg). 1HNMR (CDCl3, 400 MHz): 4.85 (m, 1H), 4.55 (m, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 2.80 (dd, 1H), 2.60 (dd, 1H), 1.50 (s, 9H), 1.20 (t, 3H).
Reaction SMILES: [Li]CCCC.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.[C:12]1([CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)C1SCCCS1)c1ccccc1
Temperature: -20 °C

Procedure:
n-BuLi (2.5 M in hexanes; 7.50 mL; 18.8 mmol) was added over 2 min to [1,3]dithiane (1.876 g; 15.6 mmol) in dry THF (20 mL) at −78° C. The r×n warmed to −20° C. over 1.5 h then was cooled to −78° C. and chalcone (3.239 g; 15.6 mmol) was added in one portion. After 6 h the r×n was quenched with satd NH4Cl. Aq/organic extractions were followed by partial purification by MPLC (silica eluting with a dichloromethane in hexanes gradient) affording a mixture of [1,2] and [1,4] addition products. 1H NMR (CDCl3; partial spectrum for major product) δ 4.38 (d, J=6.8 Hz, 1H), 3.50 (dd, J=8.2, 17.4 Hz, 1H).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.[CH3:31][NH:32][CH3:33].O>C(O)C>[CH3:31][N:32]([CH3:33])[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: CCO
Solvent: O
Product: CN(C)C1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (500 mg, 1.072 mmol) in ethanol (10 ml) was added 40% dimethylamine in water (0.407 ml, 3.22 mmol) and the mixture was left to stir under an atmosphere of nitrogen overnight. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in iso-hexane to affore the title compound;
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C1NC(=O)c2ccccc2S1
Yield: 61.3 %

Procedure:
Methyl thiosalicylate (6 g, 35.7 mM) and ethyl cyanoacetate (4 g, 35.4 mM) were dissolved in toluene (10 ml), and triethylamine (5 ml, 35.8 mM) was added to the solution, followed by heating for 7 hours under reflux. After the reaction solution was concentrated, ethanol was added to the residue. The mixture was allowed to stand, and the crystals precipitated were taken out by filtration to give crude crystals. The crude crystals were recrystallized from ethanol to give the title compound as needles (5.4 g, 60.7%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15]>C(=S)=S>[Br:12][C:13]([CH3:18])([CH3:17])[C:14]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:15]
Reactant: Fc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(Br)C(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A slurry of 14 g. (0.105 mole) of anhydrous aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 23.8 g. (0.100 mole) of α-bromoisobutyryl bromide over 10-15 minutes at 15°-20°C. The reaction is stirred for 5 minutes at 20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-4'-fluoro-2-methylpropiophenone.