Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1.Br[C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH2:26]2)=[CH:21][CH:20]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]1([C@H:31]([N:27]2[CH2:28][CH2:29][O:30][C@@H:25]([C:22]3[CH:23]=[CH:24][C:19]([NH:12][C@@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[CH:20][CH:21]=3)[CH2:26]2)[CH3:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: N[C@@H]1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)(C)O
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N[C@@H]3CCOC3)cc2)C1
Temperature: 90 °C
Yield: 53.5 %

Procedure:
(R)-(+)-3-Aminotetrahydrofuran toluene-4-sulfonate (2.0 g, 7.7 mmol) was added to a suspension of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (2.4 g, 6.9 mmol), palladium acetate (65 mg, 0.29 mmol), 2-(di-t-butylphosphino)biphenyl (170 mg, 0.57 mmol), and sodium tert-butoxide (3.4 g, 35.4 mmol) in tert-butanol (50 ml) at room temperature. After heating at 90° C. for 6 hours, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to afford 4-((1R)-1-phenylethyl)-(2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)morpholine (1.3 g, 53%) as white crystals.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[C:37]1([C@H:43]([NH2:45])[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]=1)[C:16]([NH:45][C@@H:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:44])=[O:18]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Product: C[C@@H](NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1)c1ccccc1

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and (R)-1-phenylethanamine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C32H37N3O2: 496.2959, found: 496.2958.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.B(OC)(OC)OC.CO.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[OH:17][CH2:16][C:15]1[CH:19]=[CH:20][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: COB(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (200 mg, 0.74 mmol, 1.0 eq.), trimethyl borate (0.5 mL, 4.4 mmol, 6.0 eq.) in THF (7.0 mL) was added borane tetrahydrofuran complex solution (1.5 mL, 1.0 M in THF, 1.5 mmol, 2.0 eq.) dropwise under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The mixture was carefully treated with MeOH (2 mL) and poured into EtOAc (10 mL) and sat. NaHCO3 (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 5-(4-hydroxymethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white solid. LCMS (m/z) 279 (M+23); 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.34-7.38 (m, J=8.7 Hz, 2H), 7.01-7.05 (m, 2H), 6.96 (dd, J=8.0, 2.1 Hz, 1H), 6.91-6.93 (m, 1H), 5.18 (t, J=5.7 Hz, 1H), 4.91 (s, 2H), 4.49 (d, J=5.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:9])=[O:8].Br[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=1[O:48][CH:49]([F:51])[F:50].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)(C)C.O1CCOCC1>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=2[O:2][CH3:1])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:9])=[O:8])=[CH:11]3)=[C:42]([O:48][CH:49]([F:50])[F:51])[CH:43]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Reactant: FC(F)Oc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC(F)F)cccc3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (130 mg, 0.229 mmol), 1-bromo-4-chloro-2-(difluoromethoxy)benzene (Intermediate J) (118 mg, 0.458 mmol) and Pd(dppf)Cl2DCM (37.4 mg, 0.046 mmol). Dioxane (1145 μl) and t-butanol (1145 μl) were added to the reaction vial followed by sodium carbonate in water (362 μl, 0.687 mmol, 1.9 M). The vial was purged with nitrogen and sealed. The mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated in a microwave at 100° C. for 30 min LC/MS indicated complete conversion of boronic ester to the desired product. The reaction was cooled to rt and filtered through a fritted funnel with an aid of DCM (15 mL). The filtrate was acidified with 2N aqueous HCl to a pH of about 1. After stirring for 5 min at room temperature, the product was extracted with DCM (2×20 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. MS (ESI): 639.8 [M+Na]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1CCC(=CC(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(CC(=O)OC(C)(C)C)CC1
Reaction time: 18 h

Procedure:
To a 250 mL round-bottom flask was charged ethyl 4-(2-tert-butoxy-2-oxoethylidene)cyclohexanecarboxylate (Int-4a, 5.38 g, 19.90 mmol) followed by EtOAc (100 mL). The flask was flushed with argon and then 5% palladium on carbon was added. The flask was sealed and degassed under vacuum. H2 (g) was added in a balloon and the reaction was allowed to stir 18 hours under hydrogen atmosphere. After 18 hours, the reaction mixture was filtered through celite. The solvent was removed in vacuo and the resulting oil was taken on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13][C:7]=2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]=1[O:21][CH3:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:30][S:31]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)(=[O:33])=[O:32]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCO)CC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOS(C)(=O)=O)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethanol (2.50 g) and triethylamine (1.68 ml) in acetonitrile (50 ml) was dropwise added methanesufonyl chloride (0.750 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, saturated aqueous sodium bicarbonate was added to the solution with cooling with ice, which was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (3.12 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.Cl.[CH3:24][NH:25][CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:19]([N:25]([CH3:26])[CH3:24])=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid (0.1 g) was reacted with N,N-Dimethylamine Hydrochloride similarly to the conditions described in Example 2 to produce 10-bromo-N3,N3-dimethyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. This intermediate was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 21 mg (16%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3,N3-dimethyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:19]([CH3:20])=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:12]2)=[C:4]([F:21])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:11]2[C:19]([CH3:20])=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:12]2)=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c2c(nn1-c1cc([N+](=O)[O-])c(Cl)cc1F)CCCC2
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c2c(nn1-c1cc(N)c(Cl)cc1F)CCCC2
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A mixture of iron powder (3 g) and a 5% aqueous acetic acid solution (10 ml) was heated at 90° to 100° C. while stirring for 10 minutes. To the resulting mixture, there was dropwise added 2-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (2 g) in acetic acid (10 ml) and ethyl acetate (10 ml), followed by stirring at the same temperature for 1 hour. After cooling, the iron powder was eliminated by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, dried and concentrated. The crystallized residue was collected by filtration and washed with ether to obtain 1.8 g of 2-(4-chloro-2-fluoro-5-aminophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 107°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](O)=[O:21])[CH2:15][CH2:14]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH2:34][O:33][CH2:32][CH2:31][C:29]=2[N:30]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:23][CH2:24][C:25]4[NH:26][C:27](=[O:35])[C:28]5[CH2:34][O:33][CH2:32][CH2:31][C:29]=5[N:30]=4)=[O:21])[CH2:17][CH2:18]3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Solvent: CC#N
Product: O=C(CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 15 %

Procedure:
The title compound (14.8 mg, 0.031 mmol) was prepared following the general procedure of Example 1 from {4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-acetic acid (90 mg, 0.206 mmol, 1 eq) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (41.1 mg, 0.227 mmol, 1.1 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H) 8.23-8.26 (m, 1H) 8.05 (dd, J=8.84, 5.31 Hz, 2H) 7.43-7.47 (m, 2H) 4.34 (s, 2H) 4.20 (d, J=5.56 Hz, 2H) 4.04-4.11 (m, 1H) 3.80-3.83 (m, 2H) 3.17 (d, J=5.05 Hz, 2H) 3.03-3.11 (m, 1H) 3.01 (s, 2H) 2.93-2.99 (m, 2H) 2.27-2.33 (m, 2H) 2.05-2.10 (m, 2H) 1.85-2.01 (m, 2H). HR-MS (m/z, MH+): 469.2001, 470.2061. HPLC retention time: 2.66 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH3:32])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH3:32])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)c(F)c1
Agent: O=C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(F)c(F)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (1.4 g, 2.345 mmol from Example 96) was purified using chiral SFC to afford 475 mg of peak A (Example 96A) and 435 mg of peak B (Example 96B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 25% methanol (0.1% diethylamine) in CO2, 35° C., flow rate mL/min for 14 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=6.1 min, tR (peak B) 9.2 min. The absolute stereochemistry of individual enantiomers (Examples 96A and 96B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 96).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].O[CH:74]1[CH2:79][CH2:78][CH:77]([C:80]([O:82]C(C)(C)C)=[O:81])[CH2:76][CH2:75]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH:74]3[CH2:79][CH2:78][CH:77]([C:80]([OH:82])=[O:81])[CH2:76][CH2:75]3)=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Product: CCn1c(C)c(C(=O)OC2CCC(C(=O)O)CC2)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1

Procedure:
7 was prepared from BM-957 and tert-butyl 4-hydroxycyclohexanecarboxylate according general procedure IV. MS (ESI): m/z 1192.25 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].C[OH:15]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO
Reactant: C=Cc1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CO)cc1F

Procedure:
Into a cooled solution (−78° C.) of 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; see step (i) above) in 40 mL of CH2Cl2 and 5 mL of methanol was to bubbled ozone (50 L/h, 29 g/m3) for 30 min. Argon was subsequently bubbled through to remove excess ozone. Sodium borohydride (0.67 g, 0.018 mol) was added and the cooling bath was removed. The mixture was stirred and allowed to react for 1 h. The mixture was evaporated and 2M HCl was added. The mixture was extracted twice with diethyl ether and the combined ether fraction was dried (Na2SO4) and evaporated. The crude product crystallised. Yield: 1.1 g (81%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CI>C1COCC1.CCCCCC>[CH3:13][O:14][C:15](=[O:28])[C@:16]1([CH3:1])[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 100400.9 %

Procedure:
To a stirred solution of diisopropylamine (2.02 mL, 0.0144 mol) in THF (30 mL) was added dropwise 1.59 M n-hexane solution of n-BuLi (9.06 mL, 0.0144 mol) at minus 78° C. for over 5 min. The resulting solution was stirred for 20 min at minus 78° C. To the solution was added dropwise N-tert-butoxycarbonylproline methyl ester (3.00 g, 0.0131 mmol) in THF (30 mL) at minus 78° C. for over 5 min. The resulting solution was stirred for 10 min at minus 78° C. To the solution was added dropwise MeI (0.900mL, 0.0144 mol) at minus 78° C. The resulting solution was stirred for 30 min at minus 78° C. The solution was quenched by the addition of sat. NH4Cl. The resulting mixture was extracted with CHCl3. The extract was washed with water, dried over Na2SO4, and evaporated in vacuo to afford 3.20 g (q.y.) N-tert-butoxycarbonyl-2-methylproline methyl ester as a yellow syrup. 1H-NMR (CDCl3) δ1.33 (s, 9H), 1.38 (s, 3H), 1.72-2.20 (m, 4H) 3.27-3.59 (m, 2H) 3.63 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([OH:22])=[O:21])=[C:7]([C:11]([C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH3:23][Si](C=[N+]=[N-])(C)C>CO>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1)=[O:12]
Reactant: Cn1ccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cc1c(C(=O)c2nccn2C)[nH]c2cc(Cl)ccc12
Reaction time: 19 h
Yield: 28.7 %

Procedure:
To a stirred solution of [6-chloro-2-(1-methylimidazole-2-carbonyl)indol-3-yl]acetic acid (Example 241, 65 mg, 0.21 mmol) in methanol (10 ml) was added (trimethylsilyl)diazomethane (1.0 M solution in hexanes, 1.05 ml, 2.1 mmol) at room temperature. After stirring for 19 h, the mixture was concentrated. The residue was purified by TLC developing with ethyl acetate-hexane (1:2) to afford 20 mg (23%) of the title compound as yellow solids.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)(=O)C>CN(C)C=O>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Ethyl hydroxyacetate (600 mg, 5.76 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (55%; 277 mg, 0.447 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 30 minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (1.46 mL, 6.34 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1, v/v) to give the title compound (842 mg; yield, 53%) as a colorless oily substance.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=[O:14])[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[S:24][CH2:25][CH2:26][N:27]=1>CC(C)=O>[S:24]1[CH2:25][CH2:26][N:27]=[C:23]1[NH:22][C:13]1([OH:14])[C:8](=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][S:10][CH2:11][C:12]1=[CH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: NC1=NCCS1
Solvent: CC(C)=O
Product: OC1(NC2=NCCS2)C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
A slurry of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5.5 g, 18.9 mmole) in 200 ml of acetone is treated with a solution of 2-amino-2-thiazoline (2.0 g, 19.6 mmole, filtered) in 100 ml of acetone at room temperature. The mixture never becomes homogeneous, but the nature of the solids change (yellow to white). After stirring at room temperature for 2 days, the starting ketone remains as evidenced by tlc. Additional 2-amino-2-thiazoline (1 g, 9.8 mmole, filtered) in 50 ml of acetone is added and the mixture is heated at reflux temperature for 1 day. Upon cooling to room temperature, filtration and washing with acetone affords a combined yield of 6.9 g (92.5%) of product in two crops, m.p. 171°-172.5°).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=O)[CH2:9][CH3:10].[C:12](=O)([O:14]CC)[NH2:13]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[CH:6][C:7]=2[C:8]([CH2:9][CH3:10])=[N:13][C:12]1=[O:14]
Reactant: CCOC(N)=O
Reactant: CCC(=O)c1ccsc1NC
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1nc(=O)n(C)c2sccc12
Temperature: 200 °C

Procedure:
A mixture of 0.59 g of 2-methylamino-3-propionylthiophene, 1.18 g of ethyl carbamate and 0.07 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-ethyl-1,2-dihydrothieno[ 2,3-d]pyrimidin-2-one as crystals having a melting point of 155.5°-156.5°C (after recrystallization from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-1-oxo-2-p-tolyl-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (24 mg, 0.04 mmol) obtained in Step 1 in CH2Cl2 was added trifluoroacetic acid (20 eq, 0.6 mmol). After being stirred for 1 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound.