Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8]O)[CH:7]=1.[ClH:11]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][Cl:11])[CH:7]=1
Reactant: Cl
Reactant: OCc1cc(Br)ccc1Cl
Product: ClCc1cc(Br)ccc1Cl
Temperature: 75 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(5-Bromo-2-chlorophenyl)methanol (11.37 g, 51.22 mmol) was taken in aqueous HCl (35%) (1.54 L) and stirred at 70-80° C. for 18 h. After completion of the reaction as confirmed by TLC, the reaction mixture was cooled in an ice bath. The precipitate obtained was collected over Buchner filter, washed with water (2×500 mL) and dried in vacuo to afford the title compound (12.2 g, 99%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CN[C:56]2[N:64]=[C:63](NCCN3CCCCC3)N=[C:61]3[C:57]=2N=C[N:60]3[C@@H:74]2[CH2:78][C@H:77](N3C=C(CO)C=N3)[C@@H:76](O)[C@H]2O)C=CC=CC=1.N1([C@@H]2CCNC2)CCCC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:60]1([C@@H:61]2[CH2:57][CH2:56][N:64]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[C@@H:11]4[CH2:15][C@H:14]([N:16]5[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]5)[C@@H:13]([OH:23])[C@H:12]4[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:3]=3)[CH2:63]2)[CH2:74][CH2:78][CH2:77][CH2:76]1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: C1CCN([C@@H]2CCNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N6CCCC6)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (R)-[1,3′]bipyrrolidinyl (intermediate EB). MS (ES+) m/e 648.44 (MH+).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[S:6])[CH2:2][C:3]([CH3:5])=O.[OH-].[K+].[CH3:16]I.O>C(O)C>[CH3:5][C:3]([CH3:16])=[CH:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:6]
Reactant: CI
Reactant: CC(=O)CC(=S)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CC(=S)Nc1ccccc1
Temperature: 20 °C

Procedure:
11.6 g of thioacetoacetanilide and then a solution of 3.4 g of potassium hydroxide in 35 ml of ethanol were added to 60 ml of ethanol and the mixture was stirred for an hour at 20° C. 8.5 g of methyl iodide were added thereto and the mixture was poured into 300 ml of water. The precipitate formed was recovered by vacuum filtration, and was dissolved in chloroform. The chloroform solution was dried and concentrated to dryness under reduced pressure to obtain 12g of 3-methylthio-crotonanilide melting at 175° C. After crystallization from acetone, the melting point was 178° C.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][CH:23]=1>>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)/[C:8]([NH:27][C:25]2[S:26][C:22]([F:21])=[CH:23][N:24]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Reactant: Nc1ncc(F)s1
Agent: Cl
Product: CCSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(F)s2)cn1

Procedure:
Condensation of (E)-3-cyclopentyl-2-(6-ethylsulfanylpyridin-3-yl)acrylic acid (Preparation 4, 215 mg, 0.78 mmol) with 5-fluorothiazol-2-ylamine hydrochloride (Preparation 21, 240 mg, 1.55 mmol), by the protocol described in EXAMPLE 5, yielded (E)-3-cyclopentyl-2-(6-ethylsulfanylpyridin-3-yl)-N-(5-fluorothiazol-2-yl)acrylamide: m/z (ES+)=378.2 [M+H]+. Oxidation of this thioether (22 mg, 60 μmol), by the protocol described in EXAMPLE 55, gave the title compound: RTA=3.50 min; m/z (ES+)=394.2 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])OCC.Cl.N[CH2:24][C:25]([NH:31]Cl)([CH3:30])[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC>CO>[OH:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:11]=[CH:10][C:4]=1[C:5]1[NH:9][CH2:24][C:25]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[N:31]=1
Reactant: COC(=O)C(C)(CN)NCl
Reactant: CCOC(=N)c1ccc(OCCOCCOC)cc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCOCCOc1ccc(C2=NC(C)(C(=O)OC)CN2)c(O)c1
Yield: 49.7 %

Procedure:
To a solution of ethyl 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzimidate hydrochloride (0.35 g, crude, ˜1.0 mmol) in MeOH (10 mL) was added methyl 3-amino-2-(chloroamino)-2-methylpropanoate hydrochloride (0.24 g, crude, ˜1.0 mmol) followed by dropwise addition of Et3N (1 mL) at 0° C. The resulting solution was refluxed overnight. The solvent was evaporated under vacuum and the residue was purified by prep-HPLC to obtain the title compound as colorless oil (175 mg, 50%). LC-MS (ES, m/z): 353 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([O:22]C)=[O:21])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([OH:22])=[O:21])[N:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC)c(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of methyl 3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methoxybenzoate (4.0 g, 9.96 mmol) in methanol (50 mL)-tetrahydrofuran (100 mL) was added 5N aqueous sodium hydroxide solution (80 mL), and the mixture was stirred at room temperature for 3 hr. 6N Hydrochloric acid was added to the reaction solution to adjust the pH to about 4.0, and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated to give the title compound (3.70 g, 96%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=O)[CH2:18]Br>CN1C(=O)CCC1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[N:10]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[O:9][CH:18]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
under an N2 atmosphere, 4-nitrobenzamide (5.3 g, 32 mmol) and 3-chlorophenacyl bromide (4.9 g, 21 mmol) were combined in NMP (3.0 mL) and heated to 135° C. After 2.5 hours at 135° C., the reaction was diluted with 20 mL of toluene and allowed to cool to room temperature. The solid was removed by filtration and the filtrate was concentrated in vacuo. The resulting solid from concentration of the filtrate was triturated with ethyl acetate. The solid was collected by filtration and afforded 4-(3-chlorophenyl)-2-(4-nitrophenyl)oxazole (2.74 g, 43% yield). ESI m/z=301.0 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2.[Cl:19][C:20]1[C:25]([NH2:26])=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[Cl:19][C:20]1[C:25]([NH:26][C:9]2[C:8]3[C:13](=[CH:14][C:15]([F:17])=[CH:16][C:7]=3[F:6])[N:12]=[CH:11][N:10]=2)=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][CH:21]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Phosphoryl chloride (4.96 ml) was added over a period of 40 minutes to a stirred mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (6.5 g), chlorobenzene (64.9 ml), 6-chloro-2,3-methylenedioxyaniline (7.08 g) and diisopropylethylamine (7.47 ml) that had been heated to 95° C. under an atmosphere of nitrogen gas. The resultant reaction mixture was heated at 95° C. for 5 hours. The reaction mixture was cooled to 18° C. and stirred for 30 minutes. Stirring was stopped and the reaction mixture was allowed to stand for 30 minutes. The mixture was filtered and the isolated solid was washed with chlorobenzene (2×23 ml) and dried in vacuo at 45° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline as a mono-hydrochloride salt (8.9 g, 96.5% HPLC purity using Method A, retention time 4.46 minutes); m.p. 234-237° C.; NMR Spectrum: (DMSOd6) 5.5-6.0 (br s, 1H), 6.15 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.7 (s, 1H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH2:4](I)[CH3:5]>>[CH3:4][CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:2]/[CH:2]=[CH:4]\[CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:2][CH2:4][CH2:5][CH2:1][CH2:4][CH2:5][CH2:1][CH3:2]
Reactant: CCI
Reactant: [Li]CC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC

Procedure:
Example 8 is repeated, using ethyl-lithium prepared from 156 grams of ethyl iodide.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[CH:12]1
Reactant: O=C1CCc2ccccc21
Reactant: c1ccc2c(c1)CCNC2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCc3ccccc3C2)c2ccccc2C1
Yield: 96.9 %

Procedure:
Tetrahydroisoquinoline (Aldrich Chemical, 18.0 g, 135.1 mmol), 1-indanone (10.0 g, 75.1 mmol) and P2O5 (2.30 g, 16.1 mmol) in 150 mL of toluene were stirred under nitrogen and refluxed for 10 h with water removal via a Dean Stark apparatus. Upon cooling a large amount of fine white powder precipitated (as amine phosphate salts). The dark green solution was filtered under N2 through a medium porosity frit and assayed by NMR after tolune removal (about 85:15 mole ratio of product to ketone). Solvent was evaporated and indanone/amine (about 3.0 g) was removed in vacuo (90-160° C. at 0.5 mm Hg, 76 Pa). The process was stopped and the crude enamine residue recovered under inert atmosphere, giving 18.0 g of dark red-green oil, 95 percent yield. The crude product was analyzed by 1H and 13C NMR and showed less than 2 percent mole ketone.
Reaction SMILES: FC(F)(F)C(O)=O.C(O)(=O)C.[BH4-].[Na+].[CH3:14][C:15]1[C:26]([CH3:27])=[C:25]2[C:18]([CH:19](O)[C:20]3([CH2:23][O:24]2)[CH2:22][CH2:21]3)=[CH:17][C:16]=1[OH:29]>ClCCl>[CH3:14][C:15]1[C:26]([CH3:27])=[C:25]2[C:18]([CH2:19][C:20]3([CH2:23][O:24]2)[CH2:21][CH2:22]3)=[CH:17][C:16]=1[OH:29]
Reactant: Cc1c(O)cc2c(c1C)OCC1(CC1)C2O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(O)cc2c(c1C)OCC1(CC1)C2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred ice-cold solution of trifluoroacetic acid (2 mL) and acetic acid (2 mL) was added sodium borohydride (30 mg). After stirring 10 min, a solution of 7,8-dimethyl-4H -spiro[chromene-3,1′-cyclopropane]-4,6-diol added (30 mg) in 20 mL of dichloromethane was added in one portion. Immediately thereafter, additional 20 mg of sodium borohydride was added to the solution, which was stirred for another 10 min. The mixture was partitioned with dichloromethane and water, and the organic layer was washed, dried and evaporated. The residue was purified by silica gel column eluting with 15% EtOAc in hexane to give 7,8-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-6-ol as a white solid (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([O:11]C2CCCCO2)[CH2:7]1>CO>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (prepared as in Example 35, 1.03 g, 2.57 mmol) in methanol (6.4 mL) was treated with Amberlyst® 15 ion exchange resin (77 mg). The resulting reaction mixture was stirred at 25° C. for 16 h and then was heated at 45° C. for 1 h. The reaction mixture was allowed to cool to 25° C., and the resin was then filtered off and then washed well with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (807.7 mg, 99%) as a yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-tert-butylphenylboronic acid to give [1-(4-tert-butyl-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 343(MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[NH:16][C:15]1=[O:31])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:32][CH2:33][CH2:34]N(C)C.Cl.[OH-].[Na+]>CN(C=O)C>[Cl:32][CH2:33][CH2:34][N:16]1[C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:20][CH:14]([NH:13][C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])[C:15]1=[O:31]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCCl)C1=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (26.4 mg of a 50% dispersion in mineral oil; 0.55 mmol) was stirred under nitrogen in dry DMF (5 ml) in an ice bath. (RS)-1,3-Dihydro-3-(benzyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (0.21 g, 0.54 mmol) in DMF (4 ml) was added, and the mixture stirred 1 hr in the cold. (2-Chloroethyl)-dimethylamine (59.2 mg, 0.55 mmol), prepared by distillation of a mixture of the hydrochloride and powdered sodium hydroxide in vacuo, was added and the mixture stirred 1 hr in the cold, and overnight at ambient temperature. The DMF was removed in vacuo and the residue was treated with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 90:10:1:1 of CH2Cl2 :MeOH:H2O:HOAc and the product fractons were evaporated to dryness in vacuo to provide (RS)-1-(2-chloroethyl)-1,3-dihydro-3-(benzyloxycarbonyl) amino-5-phenyl-2H-1,4-benzodiazepin-2-one. This compound (120 mg, 0.268 mmol) was added to a suspension of 10% palladium/Carbon (70 mg) in 4.5% methanolic formic acid (5 ml) stirred at ambient temperature under nitrogen. After 25 min, the mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was treated with saturated sodium carbonate solution and extracted with ethyl acetate. The combine ethyl acetate layers were washed with water, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was dissolved in THF, cooled in an ice bath, and treated with 3-methoxyphenylisocyanate (35.1 μl). The mixture was stirred in the cold for 30 min. warmed to ambient temperature, and filtered. The filtrate was evaporated to dryness in vacuo, and the residue was treated with ether (30 ml) and re-evaporated three times. The residue was triturated with ether and filtered, and the resulting solid dried at 65° C. overnight to provide the title compound: (mp 213°-215° C.). TLC: Silica gel (80:10:1 of CH2Cl2 :CH3OH:NH3) Rf =0.41
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10](O)[CH3:11])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:52]([C@H:10]([C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH3:11])=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)[C@@H](Cc1ccc(Cl)cn1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])[C@@H](Cc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24 g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosphoryl azide (0.30 mL, 1.4 mmol) in 5 mL anhydrous THF was added diethylazodicarboxylate (0.24 mL, 1.4 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was loaded onto a silica gel column. Elution with 5 to 15% EtOAc in hexane afforded the title compound. 1H NMR (500 MHz, CD3OD): δ 8.35 (d, 1H), 7.52 (dd, 1H), 7.25-7.05 (m, 5H), 6.95 (d, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.15-3.05 (m, 2H), 1.14 (d, 3H).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16].[OH-].[Na+]>O(C(C)C)C(C)C>[Br:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: CC(C)(Cc1c[nH]c2ccc(Br)cc12)[N+](=O)[O-]

Procedure:
5-Bromogramine, 60.0 g., 165 g. of 2-nitropropane, and 10.5 g. of sodium hydroxide pellets were caused to react under the conditions of Procedure 10C. The product was recovered as a dark syrup-like liquid from which the crystalline product was obtained by dissolving in i-Pr2O. The crystalline material was recrystallized from i-Pr2O to yield 48.6 g. of tan crystalline product, m.p. 106°-109°. The structure was confirmed by examination of the NMR spectrum.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([S:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1.[SH:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:9]1[C:4]([CH2:3][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1c(SCc2cccs2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(SCc2cccs2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 56 %

Procedure:
2-Chloromethyl-3-methoxy-4-(2-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 56%, m.p. 124°-127° C. 8. 2-{[[4-(2-Thienylmethylthio)-2,pyridinyl]methyl]thio}-1H-benzimidazole
Reaction SMILES: COC1C=CC2N(C)C3C(SC=2C=1COCOCCOC)=CC(OC)=CC=3.C([Li])CCC.C(N1CCCCC1)=O.[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH3:69])[C:48]3[C:53]([S:54][C:55]=2[C:56]=1[CH:57]=[O:58])=[C:52]([CH2:59][O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[C:51]([O:67][CH3:68])=[CH:50][CH:49]=3.[BH4-].[Li+]>C(OCC)C.O1CCCC1.O1CCCC1>[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH3:69])[C:48]3[C:53]([S:54][C:55]=2[C:56]=1[CH2:57][OH:58])=[C:52]([CH2:59][O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[C:51]([O:67][CH3:68])=[CH:50][CH:49]=3
Reactant: COCCOCOCc1c(OC)ccc2c1Sc1c(ccc(OC)c1C=O)N2C
Agent: COCCOCOCc1c(OC)ccc2c1Sc1cc(OC)ccc1N2C
Agent: O=CN1CCCCC1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOCc1c(OC)ccc2c1Sc1c(ccc(OC)c1CO)N2C
Yield: 70.3 %

Procedure:
A solution of 8.31 g (21.73 mmol) of 3,7-dimethoxy-4-(2-methoxy-ethoxymethoxymethyl)-10-methyl-phenothiazine in 100 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 17.6 ml of n-butyllithium solution (1.6M in hexane) and 3.68 g (32.6 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The resulting 3,7-dimethoxy-6-(2-methoxyethoxymethoxymethyl)-10-methylphenothiazine-4-carbaldehyde was dissolved in 100 ml of tetrahydrofuran and reduced with 22 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The crude product was chromatographed on silica gel with ethyl acetate/hexane (1:1), whereupon, after drying in a high vacuum, 6.44 g (70.3%) of [3,7-dimethoxy-6-(2-methoxy-ethoxymethoxymethyl)-10-methyl-phenothiazin-4-yl]-methanol were obtained as light yellowish oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][C:20]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:34][CH:35]=4)[N:3]=[C:4]([NH:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]4)[C:5]=3[N:11]=2)=[CH:13][CH:14]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4(C(F)(F)F)CC4)c3n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CC3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Temperature: 140 °C
Yield: 50.1 %

Procedure:
A mixture of [2-Chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-(1-trifluoromethyl-cyclopropyl)-amine (51.6 mg) and 4-aminomethyl-benzenesulfonamide hydrochloride (51.4 mg) was dissolved in NMP (1 mL) and treated with diisopropylethylamine (0.065 mL). The reaction mixture was sealed and heated by microwave to 140° C. for 1.5 h. The reaction mixture was cooled and purified by preparative HPLC (5-95% acetonitrile:water with 0.1% TFA) to afford 36 mg (41% yield) of the title compound as its TFA which was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 1.26 (br s, 2H), 1.37 (br s, 2H), 4.80 (d, 2H), 7.34-7.40 (m, 4H), 7.55 (d, 2H), 7.78 (d, 2H), 7.99 (d, 1H), 8.48 (m, 3H), 8.9 (br s, 1H), 10.1 (br s, 1H); MS (m/z): 533.2 ([M+H]+, 100).