Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:8]1[C:9]2[N:10]([N:25]=[CH:26][N:27]=2)[C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]3)=[CH:12][N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([NH:7][C:8]3[C:9]4[N:10]([N:25]=[CH:26][N:27]=4)[C:11]([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]5)=[CH:12][N:13]=3)=[CH:33][CH:32]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)CCNC3=O)n2ncnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21

Procedure:
A solution of (4-morpholin-4-yl-phenyl)-[5-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (30 mg, 0.055 mmol) in a 1:1 mixture of TFA:DCM (1 drop of H2O), is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue partitioned between ethyl acetate and sat. NaHCO3 (aq). The water layer is extracted with ethyl acetate (2×). The organic layers are combined and evaporated to afford a residue purified by silica gel column chromatography eluting with ethyl acetate. The title compound is isolated (18 mg, 75%) and converted into the mesylate salt (16.6 mg, 97%) using 0.1M methanesulfonic acid (0.317 mL) in MeOH. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.36 (3H, s MsOH), 3.04 (2H, t), 3.21 (4H, m), 3.47 (2H, t), 3.83 (4H, m), 7.11 (2H, d), 7.95-8.02 (6H, m), 8.05 (1H, s), 8.74 (1H, s), 10.09 (1H, br s). LCMS: Rt 2.81 min (97.9%), m/z (APCI) 442 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2=[N:8][C:7](=[O:9])[N:6]=[C:5]2[CH:10]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])=NC(=O)N=2
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: Cc1cc2c(cc1N)=NC(=O)N=2
Temperature: 65 °C
Reaction time: 78 h
Yield: 92.8 %

Procedure:
0.01 g of ammonium vanadate and 5 g of titanium dioxide extrudate containing 1% by weight of metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 500 ml of water and 19.3 g of 5-methyl-6-nitrobenzimidazolone. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 65° C. for 78 hours. During this time, 105% of the theoretical amount of hydrogen, based on the 5-methyl-6-nitrobenzimidazolone, is adsorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 100 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 50 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 15.1 g (93%) of 5-amino-6-methylbenzimidazolone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.Cl.[F:17][C:18]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([S:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[C:31]2[CH:30]=[N:29]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:7][C:8]1[O:12][C:11]([C:13]([N:41]2[CH2:42][CH2:43][CH:38]([S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]4[N:28]([C:19]5[CH:20]=[CH:21][C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:18]=5[F:17])[N:29]=[CH:30][C:31]=34)[CH2:39][CH2:40]2)=[O:15])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C(O)c1ccc(Br)o1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCN(C(=O)c5ccc(Br)o5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.5 %

Procedure:
Oxalyl chloride (0.51 mmol, 45 μL) and DMF (catalytic amount) were added to 5-bromo-furan-2-carboxylic acid (0.18 mmol, 36 mg) in dichloromethane (3 mL). The reaction mixture was stirred for 40 minutes at room temperature. The organic solvents were removed in vacuo. The concentrate was re-dissolved in dichloromethane and 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.16 mmol, 70 mg) and triethylamine (0.47 mmol, 66 μL) were added and stirred for 1.5 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided Compound A115 as a white solid (45 mg, 41%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.74 (s, 1H); 8.25 (s, 1H); 7.87 (m, 3H); 7.00 (d, 1H); 6.49 (s, 1H); 4.50 (h, 1H); 4.34 (m, 2H); 3.42 (s broad, 2H); 2.70 (s, 3H); 2.28 (m, 2H); 1.85 (m, 2H). Exact mass calculated for C22H19BrFN5O4S2 580.45, found 582.3 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22](C3(NC(=O)OC(C)(C)C)CCC3)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.C1(B(O)O)C=CC=CC=1>>[C:19]1([C:3]2[N:4]3[C:5]4[CH:18]=[CH:17][CH:16]=[N:15][C:6]=4[NH:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]3=[N:1][CH:2]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3cnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: OB(O)c1ccccc1
Product: c1ccc(-c2cnc3n2-c2cccnc2Nc2ccccc2-3)cc1

Procedure:
The title compound was synthesized according to the procedure described in the synthesis of tert-butyl {1-[4-(9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (above) using phenylboronic acid instead of tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate. 1HNMR (DMSO-d6) 400 MHz δ: 8.58 (br s, 1H), 8.14 (dd, J=4.6, 1.7 Hz, 1H), 7.92-7.86 (m, 1H), 7.45 (s, 1H), 7.40-7.26 (m, 5H), 7.18-7.13 (m, 2H), 7.10-7.05 (m, 1H), 7.00-6.95 (m, 1H), 6.85 (dd, J=8.0, 4.6 Hz, 1H); LC/MS: 311 [M+H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:19](=O)[CH2:20][CH3:21].Cl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:20]([CH:21]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6](=[O:8])[O:7]1)[CH3:19]
Reactant: CCC=O
Reactant: O=C(O)c1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC1OC(=O)c2ccsc21
Temperature: -50 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of thiophene-3-carboxylic acid (1.00 g, 7.8 mmol) in THF (10 mL) is added dropwise to a cold (−80° C.) solution of lithium bistrimethylsilylamide (8.6 mL of a 2M solution in solvent) in THF (15 mL). The resulting pale yellow solution is warmed to −50° C. and is stirred at −50° C. for 1 hr during which time a white precipitate is formed. The reaction mixture is cooled to −80° C. and treated dropwise with propionaldehyde (1.2 mL, 16.6 mmol). The reaction mixture is warmed to −20° C. and stirred for 30 min. The reaction mixture is then poured into aqueous 2M HCl solution (120 mL). The resulting suspension is stirred at room temperature while a stream of air is blown into the reaction vessel to assist in the evaporation of THF. The white precipitate which forms is collected by filtration and dissolved in Dichloromethane (5 mL) and Et3N (5 mL). The reaction mixture is treated with p-toluenesulfonyl chloride (0.38 g, 2.0 mmol) and stirred overnight. The reaction mixture is treated with NaHCO3 solution and the organic phase is collected, dried over Na2SO4, filtered and concentrated to give the title compound (0.33 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=C1OCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step C (47.48 mmoles) in acetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene (52.23 mmoles) and potassium carbonate (189.92 mmoles). The reaction mixture is stirred at reflux for 4 hours under nitrogen. The reaction mixture is brought to ambient temperature and then diluted with 500 ml of DCM and 100 ml of water. Extraction with DCM (2×200 ml) is carried out and then the organic phases are combined. The organic phase obtained is washed with saturated NaCl solution and is then dried over sodium sulphate, filtered and concentrated to about 75 ml. After formation of a precipitate in suspension, ethyl ether (150 ml) is added, and stirred is carried out overnight at ambient temperature. The precipitate is filtered off, washed with ethyl ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1>CN(C(OC)OC)C.C1(C)C=CC=CC=1.CC(O)=O>[CH3:1][N:2]([CH3:12])/[CH:3]=[CH:10]/[C:9]([C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:12])=[CH:4][CH:5]=1)=[O:11]
Reactant: CC(=O)c1ccc(N(C)C)cc1
Agent: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C)/C=C/C(=O)c1ccc(N(C)C)cc1
Yield: 35.8 %

Procedure:
A solution of 1-[4-(dimethylamino)phenyl]ethanone (500 mg, 3.1 mmol) in DMF-DMA (10 mL), toluene (10 mL), and AcOH (2 drops), was heated under reflux conditions for 48 h. The solution was concentrated and purified by flash column chromatography (hexanes:EtOAc=8:2˜1:1) to give the title compound (121 mg, 18%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[S:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Cl:38][C:35]1[S:34][C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])=[CH:37][CH:36]=1
Reactant: O=C(CBr)c1ccc(Cl)s1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(Cl)s3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(5-chloro-2-thienyl)ethanone (0.74 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.79 g, 56%).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([NH:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]
Reactant: Cc1c(O)ccc(F)c1N
Reactant: Cc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2c(F)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (intermediate III(e)) (580 mg, 2.3 mmol, 1.1 eq) in CH2Cl2 (10 mL) at 0° C., was added oxalyl chloride (812 mg, 6.4 mmol, 3 eq) dropwise. DMF (10 drops) was added and the mixture was stirred at room temperature for 3 h. The organic solvent and excess reagent were removed under reduced pressure. The residue that remained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (300 mg, 2.1 mmol, 1 eq) and K2CO3 (1.47 g, 10.6 mmol, 5 eq) in THF (20 mL) at 0° C. After addition was completed, the reaction was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 10:1) to give the title compound as a white solid (200 mg, 25%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH2:12].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CCN(C(C)C)C(C)C.C([N:44]=[C:45]=[S:46])(=O)C1C=CC=CC=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:45]([NH2:44])=[S:46]
Reactant: NCCc1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=S)NCCc1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 86 %

Procedure:
{2-(1H-Benzimidazol-2-yl)ethylamine was made as the dihydrochloride salt according to a procedure described by Nicolaou et al. Bioorg. Med. Chem., 1998, 6, 1185-1208 and pretreated with DIPEA (2.07 mL, 11.86 mmol) for 5 minutes.} To a suspension of 2-(1H-benzimidazol-2-yl)ethylamine (1.39 g, 5.93 mmol) in dichloromethane (20 mL) was added benzoyl isothiocyanate (0.88 mL, 6.52 mmol). After 1 h, the reaction mixture was concentrated in vacuo. Ammonia in methanol (7N, 30 mL) was then added and the reaction stirred another 4 h. The excess ammonia and methanol were removed in vacuo and dichloromethane (15 mL) was added. The solid was removed by filtration and the filtrate concentrated in vacuo and purified by flash chromatography (methanol/dichloromethane, 5% then 10%) to give the title compound as a solid (1.12 g, 86% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1

Procedure:
The pyridyl bromide (161)(100 mg, 0.27 mmol) was coupled to phenylboronic acid (30 mg, 0.25 mmol) using Method E. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH2:29][NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[NH:14][C:13](=[O:28])[N:12]=4)[CH:9]=3)[NH:4][N:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cccc(CNc2n[nH]c3ccc(-c4cc(-c5ccccc5OCC(C)C)[nH]c(=O)n4)cc23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a 50 mL round bottom flask were added commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (130 mg, 0.35 mmol), m-anisaldehyde (420 μL, 3.5 mmol, 10 eq), dimethylformamide (10 mL) and glacial acetic acid (10 drops). The reaction mixture was heated to 50° C. in an oil bath and stirred for 1 h. The mixture was allowed to cool before adding sodium cyanoborohydride (1M THF solution (Aldrich), 3 mL, 3 mmol) and subsequently stirred at room temperature for 1 h. Formation of product was confirmed by LC/MS and was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 40 mg (98%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.78 (s, 1H), 11.64 (s, 1H), 8.73 (s, 1H), 8.06 (d, 1H), 7.60 (d, 1H), 7.46-7.54 (m, 1H), 7.28-7.34 (m, 1H), 7.15-7.26 (m, 2H), 7.06-7.12 (m, 1H), 6.96-7.01 (m, 1H), 6.73-6.81 (m, 1H), 4.42-4.48 (m, 2H), 3.82-3.88 (m, 2H), 3.72 (s, 3H), 1.94-2.07 (m, 1H), 0.90-0.95 (m, 6H). MS (EI) for C29H29N5O3: 495 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:15]#[N:16].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:4]2[CH:5]=[C:6]([Cl:7])[C:2]([Cl:1])=[C:3]2[C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(Cl)c(Cl)cn1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of 3,4-dichloro-1-(4-methylphenyl)pyrrole-2-carbonitrile (1.25 g), 2,2'-azobisisobutyronitrile (10 mg) and N-bromosuccinimide (1.068 g) in carbon tetrachloride (25 ml) was refluxed for 3 hours, cooled to ambient temperature, and filtered. The filtrate was concentrated in vacuo. The residue was crystallized from 10% ethyl acetate in n-hexane to yield 1-(4-bromomethylphenyl)-3,4-dichloropyrrole-2-carbonitrile (1.01 g).
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:22][C@@H:23]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Yield: 74.6 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ 0.73 (d, J=7 Hz, 6 H), 1.30 (d, J=7 Hz, 6 H), 1.45 (m, 2 H), 1.87 (m, 1 H), 2,5-2.7 (m, 4 H), 2.87 (s, 3 H), 3.23 (heptet, J=7 Hz, 1 H), 3.57 (m, 1 H), 3.81 (m, 1 H), 3.93 (m, 1 H), 4.15 (m, 1 H), 4.44 (AA', 2 H), 4.62 (d, J=6 Hz, 1 H), 5.13 (AA', 2 H), 6.01 (d, J=9 Hz, 1 H), 6.89 (d, J=9 Hz, 1 H), 7.1-7.2 (m, 11 H), 7.68 (d, J=9 Hz, 1 H), 7.85 (s, 1 H), 9.05 (s, 1 H). Mass spectrum: (M+H)+ =721. Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: [CH:1]([Mg]Cl)([CH2:3][CH3:4])[CH3:2].[CH3:7][Si:8]([O:11][CH3:12])(Cl)Cl.[Cl-].[NH4+]>>[CH:1]([Si:8]([CH:1]([CH2:3][CH3:4])[CH3:2])([CH3:7])[O:11][CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CO[Si](C)(Cl)Cl
Reactant: CCC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(C)[Si](C)(OC)C(C)CC
Yield: 80 %

Procedure:
The sec-butyl magnesium chloride as prepared above was added dropwise to the methylmethoxydichlorosilane solution as obtained in Example 7, in the same manner as in Example 3(c), to effect the Grignard reaction. The resulting Grignard reaction solution was post-treated with the saturated aqueous ammonium chloride solution as used in Example 3(c) in a reduced amount of 80 ml, instead of the 120 ml. The organic layer was separated and was subjected to a fractional distillation, thereby to afford 31 g of di-sec-butyl methylmethoxysilane as a fraction boiling at 76° C.-78° C./16 mmHg (yield; 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@@:11]23[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C@H:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([F:29])[CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@]2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1F
Temperature: 50 °C

Procedure:
To a solution of trans-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one in DMF (4 mL) was added Selectfluor®. The reaction mixture was heated at 50° C. overnight, cooled to rt and water was added to precipitate the desired product. The product was isolated by filtration washing with water then dried under vacuum to provide a colorless solid. 1H NMR CDCl3 400 MHz) δ 7.61 (d, 2H), 7.53 (d, 2H), 7.19-7.14 (m, 1H), 6.55-6.49 (m, 1H), 5.20 (d, 1H), 4.74 (dd, 2JH-F=46.7 Hz, 3JH-F=11.8 Hz, 1H) 4.66 (d, 1H), 3.18 (t, 1H), 2.9 (m, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.18 (m, 1H); LCMS (MH+) 431.
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Cc1c(N)cccc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Amino-2-methylbenzoic acid (6.16 g) was heated at reflux for 30 minutes in concentrated HBr. The mixture was cooled to 0° C. and treated with a solution of NaNO2 at 0° C. (2.8 g in 5.6 mL H2O). The resultant diazonium salt solution was slowly added to a preheated (60-70° C.) solution of CuBr (3.8 g) in 3.2 mL concentrated HBr. After the addition, the mixture was stirred overnight at room temperature and filtered. The recovered filter cake was washed first with water and then with 10% HCl, and dried in air to yield 6.93 g of 3-bromo-2-methylbenzoic acid as a light purple powdery solid. This material was dissolved in ethyl acetate, washed twice with 5% HCl dried over Na2SO4, and recrystallized from 4:1 hexanes:ethyl acetate first at room temperature and then under refrigeration. 1H NMR (DMSO, 200 MHz), δ (ppm): 7.72 (dd, 2H), 7.2 (t, 1H), 2.5 (s, 3H).