Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:34]1[C:38]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:34][CH3:38])=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0098 g (0.145 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0275 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-methyl-benzamide (I-200) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:7])=[O:6]
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2

Procedure:
5-[(2,6-Dimethylbenzyl)sulfonyl]-1,3-dihydro-indol-2-one (315 mg, 1 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (170 mg, 1 mmol) to give the titled compound as an orange-brown solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:11])[S:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:11])[S:2]1
Reactant: COC(=O)CCCCNC(=O)CCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCNC(=O)CCCCC1CCSS1
Yield: 53.1 %

Procedure:
The reaction was carried out as described in Example 49, but using 0.65 g of methyl 5-[5-(1,2-dithiolan-3-yl)pentanoylamino]pentanoate (prepared as described in Example 118), 13 ml of methanol and 5.09 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.33 g of the title compound as pale yellowish green crystals, melting at 98 to 100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[O:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[O:23][CH2:24][O:25][CH3:26])[N:4]=1
Reactant: COCOc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (13.12 g), 4-hydroxy-3-methoxymethoxybenzaldehyde (11.0 g), potassium carbonate (8.35 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dried to give 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzaldehyde as pale-brown crystals (16.11 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 102-103° C.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH2:35]5)=[O:33])=[CH:28][CH:27]=4)=[CH:21][C:20]=3[Cl:44])[C:14]2=[O:45])[CH2:9][CH2:8]1)(C)(C)C.C1COCC1.O.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[Cl:44][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([F:42])([F:41])[F:43])[CH2:38][CH2:39]3)=[O:33])=[CH:28][CH:27]=2)[CH:23]=[C:24]([Cl:25])[C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][CH:13]([CH:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:45]
Reactant: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(C4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reaction time: 12 h
Yield: 58.3 %

Procedure:
Treat a mixture of 3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.18 g), THF (6 mL) and water (6 mL) with TFA (2 mL) at room temperature for 1 hour and then at 55° C. for 12 hours. Cool the reaction, dilute with ethyl acetate, and wash with sodium bicarbonate (sat.). Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 50% ethyl acetate in hexanes to 100% ethyl acetate gradient to afford 0.075 g (59%) of the titled product. MS (m/z): 599 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[C:21]=1B1OC(C)(C)C(C)(C)O1)[CH2:17][CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:21]3[C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[CH:28][C:20]=3[O:19][CH2:16][CH2:17][CH3:18])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)OCC)c[nH]c13)OCO2

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-propoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A32) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1)(=[O:12])=[O:11].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2c1OCC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2ccoc12
Temperature: 100 °C
Reaction time: 17 h

Procedure:
Methyl 5-[(2-methoxy-5-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran-7-carboxylate (879 mg, 2.4 mmol; Intermediate 66) was dissolved in chlorobenzene (6 mL). N-bromosuccinimide (432 mg, 2.4 mmol) and benzoyl peroxide (58 mg, 0.24 mmol) were added and the mixture was stirred at 100° C. for 17 h. The mixture was washed with saturated aqueous NaHCO3 and the organic layer was concentrated. Yield: 405 mg (46%) after purification by preparative HPLC (System F; 40-60% MeCN). MS (ESI+) for C18H16O6S m/z 361 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][P:12]([O:17]CC)([O:14]CC)=[O:13])[C@@H:7]1[C:20]([O:22]CC)=[O:21])=O)C.[ClH:25]>>[ClH:25].[P:12]([CH2:11][CH:8]1[CH2:9][CH2:10][NH:6][CH:7]1[C:20]([OH:22])=[O:21])([OH:14])([OH:17])=[O:13]
Reactant: CCOC(=O)[C@H]1[C@H](CP(=O)(OCC)OCC)CCN1C(=O)OCC
Agent: Cl
Product: O=C(O)C1NCCC1CP(=O)(O)O

Procedure:
A solution of 2.7 g of cis and trans ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)pyrrolidine-2-carboxylate is heated under reflux with 6N hydrochloric acid for 6 hours to yield 3-(phosphonomethyl)-pyrrolidine-2-carboxylic acid hydrochloride; NMR (D2O): 4.78, 4.40, 3.95, 3.83, 3.72, 3.20, 3.01, 2.78, 2.69 ppm.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.CO.[OH-].[Na+].Cl>>[Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(Br)s1
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a 25 mL round-bottomed flask at 0° C. was added ethyl 2-bromothiazole-5-carboxylate (0.633 mL, 4.24 mmol) (commercially available from Aldrich), MeOH (4.25 mL, 4.25 mmol), and sodium hydroxide (2.5 M, 1.88 mL, 4.23 mmol). After 3 hours, 3.5 mL 1 N HCl was added and a white precipitate formed. The MeOH was evaporated by rotary evaporation. The white solid was sonicated with water (20 mL) and filtered washing with water (50 mL). The solid material was dried in a vacuum oven at 60° C. to provide the product (0.69 g, 79%) as a white crystalline solid. LCMS (API-ES) m/z (%): 208 (100%, M−H).
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([Br:35])[N:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.CO.[NH3:39]>>[Br:35][C:30]1[N:29]=[C:28]([C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:4]([NH2:39])=[O:3])[C:33]([F:34])=[CH:32][CH:31]=1
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Solvent: CO
Product: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F
Yield: 73 %

Procedure:
A solution of (R)-2-[2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (720 mg, 1.195 mmol) in NH3 7N in methanol (19 ml, 133 mmol) was stirred at 50° C. for 2 days in a sealed 25 ml microwave vial. The solvent was removed in vacuo and the residue (987 mg) was chromatographed over silica gel (cyclohexane/ethyl acetate) affording the title compound as a mixture of two diastereoisomers (500 mg, 73% yield). TLC (cyclohexane/ethyl acetate 1:1) Rf=0.30; LC-MS RtH5=1.05 min (ES+ 573, 575).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[C:28]([O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:28]([O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH:41][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 1.00 g, 3.02 mmol) in methylene chloride (15 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (1.10 mL, 12.61 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 30 min and then slowly warmed to 25° C. over 45 min. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (15 mL) and then cooled to 0° C. To this solution was added a solution of 5-amino-pyrazine-2-carboxylic acid tert-butyl ester (0.71 g, 3.64 mmol) and pyridine (295 μL, 3.65 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at 0° C. and was slowly warmed to 25° C. overnight. The reaction was then quenched with a 1N aqueous citric acid solution (10 mL), stirred at 25° C. for 3 min, and then concentrated in vacuo. The reaction material was partitioned between ethyl acetate (400 mL) and a 1N aqueous citric acid solution (200 mL), and the layers were seperated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (200 mL), water (200 mL), and a saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo onto silica gel (Merck Silica gel 60, 230–400 mesh). Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid tert-butyl ester (0.80 g, 52%) as a white foam: mp 107–111° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H30ClN3O5S (M+H)+ 508.1668, found 508.1666.
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18]([O:20]CC)=O)[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].Cl.[C:34](=[NH:37])([NH2:36])[CH3:35].CO.C[O-].[Na+]>CO>[F:32][C:29]1[CH:30]=[CH:31][C:6]2=[C:7]([CH:28]=1)[O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:20])[NH:37][C:34]([CH3:35])=[N:36][C:23]=3[CH2:24][CH2:25][CH3:26])[CH:13]=[CH:12][C:11]=1/[C:5]/2=[C:3](/[CH3:4])\[C:1]#[N:2]
Reactant: CCCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OCC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
[step 2] (E)-ethyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-3-oxohexanoate (1.18 g, 2.71 mmol) obtained in step 1 was dissolved in methanol (14 mL), acetimidamide hydrochloride (640 mg, 6.77 mmol) and 28% sodium methoxide methanol solution (1.83 mL, 9.48 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure, methanol was added to the obtained residue, and the precipitated crystals were collected by suction filtration to give (E)-2-{3-fluoro-8-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (960 mg, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]1([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccccc2)nn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
A mixture of 6-chloropyridazin-3-amine (2 g, 15.4 mmol), phenylboronic acid (2.83 g, 23.2 mmol), Pd2(dba)3 (0.89 g, 1.6 mmol), X-phos (2.94 g, 6.2 mmol) and Na2CO3 (4.91 g, 46.3 mmol) in dioxane (50 mL) and water (5 mL) was heated to 100° C. with stirring for 6 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give 6-phenylpyridazin-3-amine (2.06 g, 78%) as a white solid. LC-MS: [M+H]+, 172.1, tR=1.04 min.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(C(C)C)CC)(C)C.[CH2:36]([O:38][CH2:39]Cl)[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:37]
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (500 mg, 2.06 mmol) in dry dichloromethane (20 ml) at room temperature was added diisopropylethylamine (1.33 g, 10.3 mmol) and, after 3 minutes, ethoxymethyl chloride (831 mg, 10.3 mmol) in dichloromethane (5 ml). The reaction was stirred for 1 h before diluting with dichloromethane (30 ml), washing with water (2×20 ml), dilute hydrochloric acid (20 ml), saturated sodium chloride solution (20 ml) and drying (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-ethoxymethoxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (567 mg), nD 1.5182. NMR peaks at: 185.3, 181.6, 155.5, 137.1, 133.8, 133.2, 132.0, 131.4, 126.3, 126.2, 33.6, 30.1, 29.5, 29.4, 29.3, 28.9, 24.1, 23.9, 16.7, -1.6; 96.9, 65.8, 15.0 (O--CH2 --O--CH2CH3).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([NH:16][S:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:13]=[C:12]([O:27][CH3:28])[N:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[CH:1]1([NH:4][CH:23]2[CH2:24][CH2:25][N:20]([S:17]([NH:16][C:14]3[CH:13]=[C:12]([O:27][CH3:28])[N:11]=[C:10]([S:9][CH2:8][C:7]4[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:6]=4[F:5])[N:15]=3)(=[O:18])=[O:19])[CH2:21][CH2:22]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NS(=O)(=O)N2CCC(NC3CC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cyclopropylamine (0.08 mL) in DCM (2 mL) was added to a solution of acetic acid (0.025 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step iii) (0.10 g) in DCM (2 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The crude material was purified by reverse phase HPLC (gradient 25-95% acetonitrile in 0.1% aqueous ammonium acetate) to afford the title compound as a white powder. Yield: 21 mg
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:8][C:7]=1[CH3:21])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[S:10][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1sc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CO

Procedure:
In analogy to the procedure described in example 8 c], 4-methyl-2-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester was reduced with lithium aluminum hydride to give [4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol as colorless liquid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=2[N+:20]([O-])=O)[C@@H:6]1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2].[CH2:27](O)CC>[Ni]>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:12]3[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=3[N:20]=[CH:27]2)[C@@H:6]1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: CCCO
Reactant: CC(=O)O[C@H]1[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])CCC[C@H]1OC(C)=O
Agent: [Ni]
Product: CC(=O)O[C@H]1[C@H](n2cnc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(±)-(1R*,2S*,3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclohexanediyl diacetate (part a of this example, 5.65 g, 13.9 mmol) in n-propanol (250 ml) was shaken with Raney nickel (Aldrich, ca. 0.50 g) under hydrogen (50 psi) for 2 h. Filtration through Celite and evaporation of solvent left the 5,6-diaminobenzimidazole intermediate. Triethylorthoformate (250 ml) and 4 drops of methanesulfonic acid were added and the solution stirred at room temperature for 2 days. Volatiles were evaporated in vacuo and the residual material chromatographed on silica gel. Title compound eluted with 2% methanol-ethyl acetate as off-white solid (1.87 g, 35%), m.p. 163-165° C. Anal. Calcd. for C17H18Cl2N2O4: C, 53.00; H, 4.71; N, 7.27; Cl, 18.41. Found: C, 52.85; H, 4.72; N, 7.17; Cl, 18.35.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:31]1[C:35]2[CH2:36][CH2:37][CH2:38][CH2:39][C:34]=2[CH:33]=[C:32]1[C:40](Cl)=[O:41]>>[CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:40]([C:32]1[S:31][C:35]2[CH2:36][CH2:37][CH2:38][CH2:39][C:34]=2[CH:33]=1)=[O:41]
Reactant: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure M using 2-methyl-3-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridin-7-yl}aniline (40.00 mg, 0.10 mmol) and 4,5,6,7-tetrahydro-1-benzothiophene-2-carbonyl chloride (22.22 mg, 0.11 mmol). The title compound was obtained as a white solid (8.00 mg, 14%). HPLC (method F): 82%, RT=4.365. MS: m/z=562 [M+H]+, RT=4.33 min.