Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>[OH-].[Na+].CC(C)=O>[C:2]([NH:3][C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:1]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: N#CNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Cyanamide (5.04 g, 120 mmol) was dissolved in 40 mL of 40% sodium hydroxide. To this solution at 0° C., phenylacetyl chloride (3.97 mL, 30 mmol) in 30 mL of acetone was added over 1 h. After stirring at room temperature for 2 h, the reaction mixture as acidified with concentrated HCl to pH 2. Acetone was removed in vacuo. The resulting suspension was extracted with methylene chloride (30 mL×4). The combined organic extracts were washed with brine and dried over magnesium sulfate. Solvent was removed in vacuo to give N-cyano-2-phenylacetamide (3.96 g, 82%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCc2cc(Br)ccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
5-Bromoindoline (1.98 g, 10 mmol) was dissolved in methylene chloride (100 mL) and triethylamine (4.3 mL, 30 mmol) was added. The mixture was treated with ethanesulfonyl chloride (1.41 mL, 15 mmol) and stirred for 2 hours. The mixture was diluted with methylene chloride, washed with water, 2N HCl, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, 1% ethyl acetate in methylene chloride) afforded 5-bromo-1-(ethylsulfonyl)indoline (2.1 g) as a white solid. MS (EI) m/z 286.9; HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5μ acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 3'-(2,4-difluorophenoxy)-4'-nitroacetophenone (2.5 g), iron powder (2.5 g) and ammonium chloride (0.25 g) in ethanol (40 ml) and water (20 ml) was refluxed with stirring for 30 minutes. The insoluble materials were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][CH2:47][CH2:48][N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: O=C1CCCN1CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.2 g, 1.89 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (0.23 mL, 2.08 mmol) and tributylphosphine (0.75 mL, 2.84 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.74 g, 2.84 mmol) under stirring at room temperature, and the mixture was stirred for 14 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-ethyl acetate) to give the title compound (0.91 g, yield 65%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=1.N.[OH:20]O.O>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[C:11]([CH:10]=[C:9]([C:15]([F:18])([F:16])[F:17])[CH:8]=2)[C:12]([NH2:13])=[O:20])[CH:6]=1
Reactant: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Reactant: OO
Agent: N
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(C(N)=O)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-benzonitril (3.5 g, 13.93 mmol) in NMP (28 mL) is treated with aqueous ammonia (9.8 mL, 25%) and aqueous hydrogen peroxide (3.5 mL, 30%). The resulting mixture is stirred for 1 hour at 20-25° C. and then poured into chilled water (420 mL). The resulting suspension is filtered and the filter cake is washed with water (50 mL), and dried in vacuo at 50° C. to give 3.2 g of the title compound (XXIII) (85.4%) as white crystals (98% area by HPLC).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH2:17]([O:19][C:20](=[O:31])/[C:21](/[CH3:30])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:30])[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:31])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C(C)=C/c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.55 g, 6.54 mmol) in CH2Cl2 (5 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(4-Chloro-phenyl)-2-methyl-acrylic acid ethyl ester (1.00 g, 4.45 mmol; preparation described in J. Org. Chem. 1966, 31: 4043-4047) and trifluoroacetic acid (0.034 mL, 0.44 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 24 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:8) afforded 0.85 g (54%) of the title compound as a colorless oil. ES-MS m/e: 358.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C3C(F)=C(F)C(F)=C(F)C=3F)=O)=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>N1C=CC=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([N:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[CH:45][CH:44]=3)=[O:20])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one (0.100g, 0.029 mmol) was agitated with 4-morpholinoaniline (0.155 mg, 0.87 mmol) in 10% pyridine in dimethylformamide (2 ml) for 24 h. The resin was filtered and washed liberally with dimethylformamide, MeOH, DCM, and dried under vacuum. The dry resin was cleaved in 60% trifluoroacetic acid in dichloromethane (2 ml) for 2 h at room temperature. The supernatant was evaporated under vacuum, and the crude product was purified by preparative TLC (eluent: 10% methanol in dichloromethane to give product as a white solid. Yield 6.6 mg (50%). MS (m/z): 457.2 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH2:24][CH2:23]3)=[O:21])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH2:26][CH2:27]3)=[O:21])[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)C4)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCNC4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl 3-(4-chlorophenyl)-3-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate (25 mg, 0.048 mmol) in DCM (2.5 mL) was added to a 4.0M HCl solution in dioxane (0.8 mL). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone dihydrochloride (24 mg, 100%). LCMS (APCI+) [M+H]+ 426.2; Rt: 2.09.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([S:9][C:10](=S)[CH2:11][C:12](=[O:27])[C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C>C(O)C>[N:1]1([C:10](=[S:9])[CH2:11][C:12]([C:13]2[C:26]3[S:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCSC(=S)CC(=O)c1cccc2c1Sc1ccccc1S2
Reactant: C1COCCN1
Solvent: CCO
Product: O=C(CC(=S)N1CCOCC1)c1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Morpholine (0.96 ml, 11 mmol) was added to a solution of 3-oxo-3-thianthren-1-yl-dithiopropionic acid ethyl ester (3.99 g, 11 mmol) in ethanol (20 ml). The reaction was refluxed for 8 hours and was then cooled to room temperature. The precipitate formed was filtered and dried to give the desired product as a bright orange solid (3.50 g, 82%). m/z (LC-MS, ESP), RT=4.81 and 5.33 min same (M+1)=388
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(OC(=O)CC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butylacetyl chloride (9.0 l) and N,N-diisopropylethylamine (28 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[CH3:38][O:39][CH2:40][C@H:41]1[CH2:43][O:42]1>CO>[OH:42][C@@H:41]([CH2:40][O:39][CH3:38])[CH2:43][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: COC[C@H]1CO1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: CO
Product: COC[C@H](O)CN1CCN(Cc2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
Into an 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (70.0 mg, 0.134 mmol), (R)-2-Methoxymethyl-oxirane (0.0154 g, 0.174 mmol), and Methanol (5.00 mL) were added. The reaction was stirred at room temperature over the weekend. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The selected fractions were concentrated. The residue was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered wand washed with DCM. The solvent was removed under vacuum to give N-[2-(2-{4-[4-((R)-2-Hydroxy-3-methoxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide a yellow solid (32 mg, 39%). LCMS (E/I+) 610.15 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.92-7.98 (m, 1H), 7.88 (d, 1H, J=8.26 Hz), 7.72 (s, 1H), 7.60-7.67 (m, 1H), 7.50-7.78 (m, 2H), 7.00 (d, 1H, J=4.66 Hz), 6.96 (d, 1H, J=4.66 Hz), 6.92 bs, 1H), 6.72 (d, 1H, J=8.26), 4.47 (bs, 1H), 3.82 (s, 3H) 3.71 (bs, 1H), 3.39 (bs, 2H), 3.25-3.31 (m, 2H), 3.24 (s, 3H), 3.17-3.23 (m, 1H) 3.04 (s, 3H), 2.88 (s, 3H), 2.20-2.42 (m, 9H).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([NH:27][C:28]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)=[O:29])[CH:25]=[CH:26][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.27 min, MH− 458. NMR: δH [2H6]-DMSO 10.12, (1H, s), 9.29, (1H, t), 9.15, (1H, d), 8.35-8.32, (2H, m), 7.86, (1H, s), 7.78, (1H, d), 7.68-7.65, (3H, m), 7.32-7.24, (2H, m), 6.94, (2H, m), 6.84, (2H, d), 4.51, (2H, d), 3.75, (3H, s), 2.32, (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:55])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:55][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 4.72 mmol), benzoyl peroxide (0.114 g, 0.472 mmol) and NBS (1.093 g, 6.14 mmol) was suspended in carbon tetrachloride (31.5 mL) and heated to reflux for 4 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) was added, and the mixture was stirred at 100° C. for 24 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) was added, and the mixture stirred for 3 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) and NBS (0.250 g, 1.42 mmol) were added, and the mixture was heated for 2.5 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 502.0 (M+H+).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][OH:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][O:41][CH2:2][O:3][CH3:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Yield: 97.1 %

Procedure:
Chloro(methoxy)methane (0.201 mL, 2.65 mmol) was added dropwise to a solution of 6-(N-(4-bromo-3-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.724 g, 1.06 mmol) and DIEA (0.555 mL, 3.18 mmol) in tetrahydrofuran (10 mL) under N2. The mixture was heated to 50° C. overnight. Cooled down to room temperature and aqueous NaHCO3 was added, the aqueous layer was extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4. The crude residue was purified by chromatography on silica gel eluted with 0-50% EtOAC in hexane to give the product (0.65 g, 97%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (dd, J=8.78, 5.27 Hz, 2H) 7.64 (s, 1H) 7.57 (d, J=2.73 Hz, 1H) 7.50 (d, J=8.78 Hz, 1H) 7.47 (s, 1H) 7.18-7.26 (m, 3H) 5.79 (d, J=4.49 Hz, 1H) 4.74 (s, 2H) 4.61 (s, 2H) 3.39 (s, 3H) 3.25 (s, 3H) 3.01 (d, J=4.88 Hz, 3H) 2.08-2.18 (m, 1H) 0.75-1.14 (m, 3H) 0.58 (br. s., 1H). LCMS (m/z, ES+)=633 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][S:7][C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]1([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][S:7][C:6]=3[CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Nc1csc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1csc2cc(OCc3ccccc3)ccc12
Yield: 83.6 %

Procedure:
A mixture comprising 2 g (8.4 mmol) of ethyl (6-hydroxybenzo[b]thien-3-yl)carbamate, 2.16 g (12.6 mmol) of benzyl bromide and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile is heated at reflux for 11 hours. The mixture is filtered, the solvent is evaporated under reduced pressure and the residue is triturated in petroleum ether. 2.3 g of product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 4-hydroxypyridine (0.57 g, 6.0 mmol) to give the titled compound as pale yellow solid substance(1.05 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][P:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].Br[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([P:5]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:6])[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:32]2[C:28](=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44])[CH2:29][O:30][C:31]2=[O:41]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added a solution of 1N NaN (TMS)2 in THF (0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 30 minutes, whereupon a solution of 6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by addition of a saturated aqueous solution of ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg (48%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; MS (m/z) 701.2 [M+Na]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](O)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B.C1COCC1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCO)c1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
To a solution of 2-(3-nitrophenyl)acetic acid (1.8 g, 0.01 mol) in THF (20 ml) at 0° C., was added BH3THF dropwise (1 M, 22 ml, 0.022 mol), removed ice bath and stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc, washed with water and brine, dried over Na2SO4. Concentrated to get crude 2-(3-nitrophenyl)ethanol as light yellow solid (0.9 g).