Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br-].[Br-].B.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Agent: B
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
1M solution of boran tri-bromide in DCM (0.839 mL, 0.839 mmol) was added to a stirred solution of 7-methoxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (26A: 90 mg, 0.335 mmol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (5% methanol in DCM). The reaction mixture was quenched with chilled water and extracted with DCM. The organic layer was washed with NaHCO3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (3% methanol in DCM) afforded 40 mg of the product (47% yield).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH:5]([CH3:24])[CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:8].[Cl-].[NH4+].C(OCC)(=O)C>CCCCCC>[CH2:18]([C:10]1[N:9]([C:7](=[O:8])[CH2:6][C@@H:5]([CH3:24])[CH2:4][C:3]([OH:25])=[O:2])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1cc2ccccc2n1C(=O)CC(C)CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1cc2ccccc2n1C(=O)C[C@@H](C)CC(=O)O
Reaction time: 24 h

Procedure:
To a solution of 5-(2-hexyl-indol-1-yl)-3-methyl-5-oxo-pentanoic acid methyl ester in hexane and buffer was added lipase and was stirred for 24 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]([O:14]C=O)[C:11]([NH2:13])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: COc1cccc(Cl)c1C(OC=O)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(Cl)c1C(O)C(N)=O

Procedure:
2-(2-Chloro-6-methoxyphenyl)-2-formoxyacetamide (10 g.) was dissolved in 50 ml. of ethyl acetate by brief warming. The resulting solution was equilibrated with 30 ml. of saturated sodium bicarbonate by stirring for 30 minutes. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered through a bed of diatomaceous earth and concentrated in vacuo to a foam. Trituration with hexane gave 2-(2-chloro-6-methoxyphenyl)-2-hydroxyacetamide [6.7 g., pnmr/CDCl3 /delta: 7.9 ppm peak gone, includes 2 doublets between 5.1 and 5.9 ppm (OC--CH splitting) which collapse to a singlet at 5.6 ppm (CH) on D2O exchange].
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:1][CH2:2]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C(=O)O)COC(c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a round bottom flask was added sequentially 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (10.0 g, 74.5 mmol), acetone (75.0 mL), benzaldehyde dimethyl acetal (17.02 g, 111.0 mmol) and para-toluenesulfonic acid monohydrate (0.71 g, 3.7 mmol). The resulting mixture was stirred at ambient temperature for 4 h and then filtered. The filter cake was rinsed with cold acetone and dried under vacuum to give the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.46-7.48 (m, 2H), 7.34-7.36 (m, 3H), 5.49 (s, 1H), 4.65 (d, J=10.8 Hz, 2H), 3.70 (d, J=11.4 Hz, 2H), 1.11 (s, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[N:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:31]([C:33]1[CH:34]=[C:35]([CH2:36][O:13][C:14]2[CH:15]=[C:16]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=1)#[N:32]
Reactant: N#Cc1cccc(CO)c1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br.Br[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: BrCc1cccnc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Br
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 3-(bromomethyl)pyridine hydrobromide in the same manner as in Example 32.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:14])[N:10]=[C:11]([O:12][CH3:13])[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
2-Amino-6,7-dichloro-3-methoxyquinoxaline (1.16 g, 4.75 mmol) and ethyl chloroformate (1.03 g, 9.50 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (751 mg, 9.50 mmol) was added. The mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.29 g of the titled compound (yield, 86%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]([C:9]1[C:10](=[O:22])[N:11]([CH3:21])[C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[NH2:8].C(N(CC)CC)C>O1CCOCC1>[CH3:21][N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[N:18]=[C:9]([NH:7][NH:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:10]1=[O:22]
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2c(c1)nc(NNC(=O)C1CC1)c(=O)n2C

Procedure:
Cyclopropylcarboxylic acid chloride (6.60 g., 6.32 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (52.6 mmol) and triethylamine (6.38 g., 63.2 mmol) in 500 ml. of dioxane and the mixture stirred at room temperature for 20 hours. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried under vacuum to give a crude yield of 12.8 g. (95%). A 4.8 g. sample of this material is recrystallized from 100 ml. of acetonitrile to obtain purified product.
Reaction SMILES: ClCCl.Cl.[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].Cl>C(N(CC)CC)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[NH:5][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1Cc2ccccc2C1
Reaction time: 12 h
Yield: 87.2 %

Procedure:
200 ml of dichloromethane, then 15 ml, i.e. 10.9 g (107.6 mmmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred, then 2.6 ml (29.5 mmol) of propionyl chloride were added and stirring was continued at room temperature for 12 h. Dilute hydrochloric acid was added, the precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.87 g of beige solid were isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3](N=NC2C=CC=CC=2O)=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1C1C=CC=CC=1.O.[NH2:26]N>CO.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[NH2:26]
Reactant: NN
Reactant: Cc1cc(O)c(N=Nc2ccccc2O)c(C)c1-c1ccccc1
Agent: [Ni]
Solvent: O
Solvent: CO
Product: Cc1cc(O)cc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
3,5-Dimethyl-4-phenylazophenol (132.0 g, 0.583 mol) was dissolved in methanol (500 mL) and pure (100%) hydrazine hydrate (113 mL, 2.33 mol), and Raney nickel [50% slurry in water (Aldrich), (2.5 mL)] was added to give an exothermic reaction. The mixture was stirred for one hour at ambient temperature and then heated to gentle reflux for three hours. The solution was filtered hot and cooled to room temperature. The crystals which formed were collected by filtration and dried to afford 3,5-dimethyl-4-aminophenol (42.4 g, 60% yield) as a white solid; m.p. 180.5-182.5; 1H-NMR (DMF-d7). δ 2.10 (s, 6H, CH3), 5.32 (s, 2H, NH2), 5.32 (s, 1H, OH), 6.45 (s, 2H, aromatic).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH2:9][CH2:10][CH2:11][C:12]2=[O:13]
Reactant: O=C1CCCO1
Reactant: Cc1ccc(C)cc1
Product: Cc1ccc(C)c2c1CCCC2=O
Yield: 23.2 %

Procedure:
Using the same reactor as in Example 1, 3.20 g of the 10 wt % HSiW/SiO2 catalyst (0.097 mmol-HSiW) as the catalyst produced in Example 1, 100 ml of p-xylene (799 mmol) and 1 ml of γ-butyrolactone (14.8 mmol) were reacted at 196° C. for 3 hours to obtain 5,8-dimethyltetralone (yield based on γ-butyrolactone: 30.4%). After removing the supernatant by filtration, 100 ml of p-xylene (799 mmol) and 1 ml of γ-butyrolactone (14.8 mmol) as raw materials were charged again and then reacted at 196° C. for 3 hours. As a result, 5,8-dimethyltetralone (yield based on γ-butyrolactone: 23.2%) was obtained. The catalyst could be reused.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:17])(=O)C>N>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Agent: N
Product: COc1cc2ncnc(Cl)c2cc1O
Temperature: 10 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in WO01/66099; 10.0 g, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10° C. in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65 g, 67.8%); 1H NMR Spectrum: (DMSO ds) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum: (M+H)+ 211
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]2[N:18]([CH3:19])[C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[C:9]([F:22])[CH:8]=1.Cl>N1C=CC=CC=1>[C:20]([C:17]1[N:18]([CH3:19])[C:14]([C:10]2[C:9]([F:22])=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]=2[F:13])=[CH:15][CH:16]=1)#[N:21]
Reactant: Cn1c(C#N)ccc1-c1c(F)cc(N)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1c(F)cc(NS(C)(=O)=O)cc1F
Temperature: 50 °C
Yield: 44.9 %

Procedure:
A mixture of methanesulfonyl chloride (0.046 mL, 0.66 mmol) and 5-(4-amino-2,6-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.100 g, 0.429 mmol) in pyridine (1.5 mL) was heated to 50° C. for 4 hours. The reaction mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/acetone, 97/3) to afford the title compound (0.060 g, 45%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2,3-dimethylphenyl)piperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2)C1CC1

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(cyclopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M33) (200 mg, 0.313 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (54 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[NH3:36].C(O)(C)C>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:21])[CH3:23])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:26])=[O:27])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (156 mg, 0.281 mmol) and ammonia in isopropanol (15 mL, 30 mmol), the title compound was obtained as a white solid (56 mg, 35% yield). MS (ESI): 536 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:14]1[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=1[O:20][CH3:21])(=[O:17])=[O:18]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., 5-bromo-2-methoxybenzenesulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.07 g of N-(2-aminophenyl)-5-bromo-2-methoxybenzene sulfonamide. 1H NMR (CDCl3, 400 MHz): δ 4.08 (s, 3H), 4.22(bs, 2H), 6.52 (m, 2H), 6.75 (m, 2H), 7.01 (d, 1H), 7.03 (m, 1H), 7.65(dd, 1H), 7.88 (d, 1H) ppm.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[C:38]([O:57][CH3:58])=[C:39]([CH:54]=[CH:55][CH:56]=1)[C:40](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:28]([CH2:29][O:30][C:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:39]3[CH:54]=[CH:55][CH:56]=[C:37]([O:36][CH3:35])[C:38]=3[O:57][CH3:58])[C@@H:26]([OH:27])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 96.7 %

Procedure:
N4-Benzoyl-2'-O-nonylcytidine (2.67 g, 0.0056 mol) was treated with dimethoxytrityl chloride (2.0 g, 1.1 eq) as per the procedure of Example 72 to give 4.2 g of pure product. Anal. Calcd. for C46H53N3O8.1/2H2O: C, 70.39; H, 6.93; N, 5.35. Found: C, 71.20; H, 6.88; N, 5.41.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][C@H:6]3[C:5]=12.[Cl:18]N1C(=O)CCC1=O.CN(C)C=O>O>[Cl:18][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][C@H:6]3[C:5]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCN12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2-n2cnc(Cl)c2[C@@H]2CCN12
Reaction time: 0.67 h

Procedure:
0.54 g (2.4 mmol) of (S)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one and 0.32 g (2.4 mmol) of N-chlorosuccinimide are treated with 10 ml of dimethylformamide and the mixture is stirred at 90° for 40 minutes. The mixture is poured into 50 ml of water and extracted four times with chloroform. The combined chloroform extracts are washed three times with water, dried over magnesium suphate and evaporated. The crude product is chromatographed on silica gel using chloroform/methanol (19:1) for the elution and subsequently recrystallized from ethyl acetate. There is obtained (S)-1-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 210°-214°.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=O)=[CH:4][CH:3]=1.O[C:14]1C=CC(C(OCCC)=O)=C[CH:15]=1.[Na].C(O)(=O)C1C=CC=CC=1>>[CH:14]([C:4]1[CH:3]=[CH:2][CH:12]=[CH:11][C:5]=1[CH3:6])=[CH2:15]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCOC(=O)c1ccc(O)cc1
Agent: O=C(O)c1ccccc1
Agent: [Na]
Product: C=Cc1ccccc1C

Procedure:
Ethyl para-hydroxybenzoate (E 214) and propyl para-hydroxybenzoate (E 216) and their sodium compounds (E 2 15 and E 2 17) up to 5 grams per kilogram of product calculated as benzoic acid on a dry weight basis
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(2-bromophenyl)propanoic acid (prepared in 2 steps from 2-bromobenzyl bromide, 2.0 g, 8.73 mmole), oxalyl chloride (1.14 ml, 13.1 mmole) and methylene chloride (20 ml) was cooled in an ice bath and N,N-dimethylformamide (34 μL, 0.44 mmole) was added dropwise. The mixture was stirred at room temperature for 3 hours. Concentration in vacuo gave 3-(2-bromophenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude. Step 2:
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)(=[O:3])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)N1CCCC1c1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 47.4 %

Procedure:
4-(1-Acetyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.32 g, 1.5 mmol) and methyl thiosalicylate (1.02 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (8:1, v/v) were collected, concentrated and recrystallized from diethyl ether-methanol to give the titled compound (0.25 g, 48%) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([O-:15])=[O:14])([CH3:3])[CH3:2].[Li+].[ClH:17].[Cl-].[Li+]>O>[ClH:17].[CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C(=O)[O-])nc2ccccn12
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(C)c1c(C(=O)O)nc2ccccn12

Procedure:
A solution of compound 4-C (0.764 g, 3.64 mmol) in water (7 mL) was treated with 1N HCl (7.45 mL, 7.45 mmol), and the resultant solution was filtered then frozen on a dry ice/acetone bath. The water was lyophilized away to leave a mixture of compound 4-D with lithium chloride (1.01 g, 98%) as a colorless solid, used as is in the subsequent reaction. 1H-NMR (CD3OD): δ 8.84 (d, J=7.1 Hz, 1H), 7.74-7.89 (m, 2H), 7.35-7.40 (m, 1H), 4.32-4.43 (m, 1H), 1.55 (d, J=7.3 Hz, 6H); MS: m/z 205.2 (MH+).