Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]3[NH:33][CH:34]=[CH:35][C:36]=3[N+:37]([O-:39])=[O:38])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]3[NH:33][CH:34]=[CH:35][C:36]=3[N+:37]([O-:39])=[O:38])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(Nc3[nH]ccc3[N+](=O)[O-])cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(Nc3[nH]ccc3[N+](=O)[O-])cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-n-propyl-4-methyl-6-[N-(3-nitro-pyrrol-2-yl)-amino]-1H-benzimidazol -1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13]([OH:20])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH3:14])[CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][O:20][C:13]([CH3:14])([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: CC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of N-[4-bromo-2-(1-hydroxy-1-thien-2-ylethyl)phenyl]-2-chloroacetamide (1.29 g, 3.44 mmol) in anhydrous THF (20 mL) was added at 0° under nitrogen sodium hydride (60% in mineral oil, 0.38 g, 9.5 mmol). After addition, the reaction mixture was stirred for 3 h, treated with an aqueous saturated ammonium chloride solution (30 mL). Ethyl acetate (50 mL) was added and organic layer separated, dried (Mg2SO4), and concentrated to yield the title compound as a white solid (1.1 g, 96%). 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.57 (dd, J=5.0, 1.0 Hz, 1H), 7.47 (dd, J=8.6, 1.4 Hz, 1H), 7.39 (d, J=1.67 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.00 (m, 1H), 6.88 (dd, J=2.6, 0.9 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 4.03 (d, J=16.3 Hz, 1H), 1.99 (s, 3H). MS (ES) m/z 338/340 ([M +H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([C:11]([O:13]CC)=O)[CH:3]=1.O.[NH2:17][NH2:18]>>[Cl:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([C:11]([NH:17][NH2:18])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)sc1S(N)(=O)=O
Reactant: NN
Solvent: O
Product: NNC(=O)c1cc(Cl)sc1S(N)(=O)=O
Temperature: 25 °C
Yield: 89 %

Procedure:
Ethyl 5-chloro-2-sulfamoylthiophene-3-carboxylate (50.0 g; 0.185 mol) was added in one portion to 98% hydrazine hydrate (50 ml) with stirring at ambient temperature. The reaction was slightly exothermic. The solution was stirred for 90 min. and concentrated. The residue was crystallised by trituration with 250 ml of water and the mixture was adjusted to pH 2-3 with conc. hydrochloric acid and stirred for 30 min. at 0° C. The product was isolated by filtration, washed with water and dried to give 42.2 g (89%) of the title compound; 1H-NMR (DMSO-d6): δ 4.7 (br. s, 2H, NH2), 7.49 (s, 1H), 7.71 (br. s, 2H, NH2), 9.94 (br. s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCCCC1NCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-1,2-cyclohexanediamine (200 mg) and 3-((benzyloxycarbonyl)amino)propionaldehyde (65 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (133 mg) and acetic acid (18 μL) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours and 30 minutes. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl (2-((3-((benzyloxycarbonyl)amino)propyl)amino)cyclohexyl)carbamate (C39, 137 mg).
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[S:15][C:16]([C:19](OC)=[O:20])=[CH:17][N:18]=3)=[N:12][CH:13]=2)[CH2:5][CH2:4][NH:3]1.[Li+].[BH4-]>C1COCC1>[OH:20][CH2:19][C:16]1[S:15][C:14]([C:11]2[N:12]=[CH:13][C:8]([O:7][C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)=[N:18][CH:17]=1
Reactant: COC(=O)c1cnc(-c2ccc(O[C@@H]3CCNC3=O)cn2)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCC[C@H]1Oc1ccc(-c2ncc(CO)s2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-methyl 2-(5-(2-oxopyrrolidin-3-yloxy)pyridin-2-yl)thiazole-5-carboxylate (360 mg) in THF (5 mL) was added LiBH4 (100 mg) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After cooling to 0° C., the reaction was quenched by dropwise addition of water (until no more gas was generated). The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water (30 mL×2) and brine (20 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to pure EA) to afford the title compound. MS ESI+: m/z=292 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[O:15][C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=3[NH:19][C:18]3=[C:29]([C:32](O)=[O:33])[NH:30][CH:31]=[C:17]23)=[CH:13][CH:12]=1.C[N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[O:15][C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][C:22]([CH3:27])([CH3:28])[CH2:21][C:20]=3[NH:19][C:18]3=[C:29]([C:32]([NH2:36])=[O:33])[NH:30][CH:31]=[C:17]23)=[CH:13][CH:12]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(=O)O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(N)=O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of 60 mg (0.126 mmol) of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6.6 dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid in 2 ml dimethylformamide was added successively 72 mg (0.189 mmol) of HBTU, 14 mg (0.253 mmol) of ammonium chloride, 74 mg (0.574 mmol) of N,N-diisopropylethylamine in a round bottom flask. The reaction mixture was stirred overnight at room temperature. Water was then added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative LCMS (method C) giving 8.9 mg of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxamide (12% yield). Analytical LC/MS method B: [M+H]+=474.5; retention time: 2.90 min; 70% UV (DAD) purity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccsc1C(=O)OC
Yield: 98.4 %

Procedure:
To a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (2.39 g, 15.2 mmol) in benzene (51 mL) was added K2CO3 (6.30 g, 45.6 mmol) followed by ethyl chloroformate (1.74 mL, 18.2 mmol). After heating at reflux for 12 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (3.43 g), which was used in the next step without further purification. MS: 230.0. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.6 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16]C[CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].ClC1N(C)C(=O)C2C(=C(I)C=CC=2)N=1.Cl.[F:35]CC(N)(C)C>>[F:35][CH2:14][C:13]([NH:12][C:9]1[N:8]([CH3:18])[C:7](=[O:19])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(N)CF
Reactant: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Agent: Cl
Agent: Cn1c(Cl)nc2c(I)cccc2c1=O
Product: Cn1c(NC(C)(C)CF)nc2c(I)cccc2c1=O
Yield: 63 %

Procedure:
This compound (0.71 g, 63% yield) as a yellow crystalline solid was prepared according to the procedure described for intermediate 711, using 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (0.96 g, mmol), 2-fluoro-1,1-dimethyl-ethylamine hydrochloride (AmfineCom Inc; 0.69 g, 5.40 mmol) (AmfineCom Inc.) and TEA (2.1 mL, 15.10 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, d, J=7.2 Hz), 7.96 (1H, d, J=7.4 Hz), 6.95 (1H, t, J=7.6 Hz), 6.16 (1H, br.), 5.04 (1H, s), 4.92 (1H, s), 3.47 (3H, s), 1.58 (6H, s). m/z (ESI, +ve) 375.8 (M+1-1)′).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:57][C@H:56]([CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=1)[CH2:58][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23.1 %

Procedure:
N-[4-((4-[4-(2-Aminoethyl)anilino]-1-piperidinyl]sulfonyl)phenyl]acetamide (0.500 g, 1.08 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.4 g, 0.973 mmol) according to Procedure G to give the title compound (0.185 g, 0.225 mmol).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.II.[BH4-].[Na+]>CO.O1CCCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: COc1cccc(C=O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN2CCC(O)C2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
To pyrrolidin-3-ol (3.4 g, 39 mmol) in methanol (150 mL) was added 3-methoxybenzaldehyde (6.4 g, 47 mmol) and iodine (0.40 g, 32 mmol). After stirring for 5 h, the reaction mixture was cooled to 0° C. and sodium borohydride (2.9 g, 78 mmol) was added portionwise. The reaction mixture was warmed to ambient temperature and stirred overnight. Water (10 mL) was added and most of the tetrahydrofuran was removed in vacuo. Additional water (25 mL) was added and the aqueous layer was extracted with methylene chloride (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to provide 1-(3-methoxybenzyl)pyrrolidin-3-ol (2.0 g, 25%) as a yellow oil: 1H NMR (DMSO-d6, 300 MHz) δ 7.21 (dd, J=8.1, 8.1 Hz, 1H), 6.87-6.77 (m, 3H), 4.66 (d, J=4.5 Hz, 1H), 4.21-4.14 (m, 1H), 3.73 (s, 3H), 3.56-3.45 (m, 2H), 2.64 (dd, J=9.6, 6.3 Hz, 1H), 2.58-2.49 (m, 1H), 2.43-2.34 (m, 1H), 2.28 (dd, J=9.6, 7.5 Hz, 1H), 2.04-1.92 (m, 1H), 1.57-1.51 (m, 1H).
Reaction SMILES: C(OC(=O)/[N:10]=[C:11](/[NH2:35])\[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:34])[C@H:21]([O:31][CH2:32][CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[F:30])=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:37][C:38]([OH:40])=[O:39]>CCO.[Pd]>[C:38]([OH:40])(=[O:39])[CH3:37].[C:11]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20](=[O:34])[C@H:21]([O:31][CH2:32][CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[F:30])=[CH:16][CH:17]=1)(=[NH:10])[NH2:35]
Reactant: CCO[C@@H](C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1ccc(OC)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCO[C@@H](C(=O)NCc1ccc(C(=N)N)cc1)c1ccc(OC)cc1F

Procedure:
A solution of [1-amino-1-(4-{[(R)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-phenyl)-meth-(E)-ylidene]-carbamic acid benzyl ester (195 mg) in EtOH (20 ml) was treated with HOAc (0.05 ml) and Pd/C 10% (20 mg) and hydrogenated over night at normal pressure. The catalyst was filtered off, the filtrate was concentrated to give (R)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide acetate (151 mg, 96.3% ee) as white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[F:43])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]3[CH:21]=[C:20]([N:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:43])[CH:11]=4)[S:16]([CH3:19])(=[O:18])=[O:17])[C:39]([CH:40]4[CH2:41][CH2:42]4)=[CH:38][C:23]=3[C:24]=2[C:34]([NH:36][CH3:37])=[O:35])=[CH:28][CH:29]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(N-(4-(benzyloxy)-3-fluorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (350 mg, 0.565 mmol) was dissolved in ethyl acetate (8.0 mL) and ethanol (8.0 mL). 10% of Pd/C (30.1 mg, 0.283 mmol) was added followed by the addition of H2 (1 atmosphere, balloon). The mixture was stirred for 2 h at RT and filtrated through Celite. The filtrate was concentrated to dryness and rinsed twice with hexane to give the desired product as a white solid which was used without further purification. LCMS (m/z, ES+)=529 (M+H+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([C:22]2[O:26][CH:25]=[N:24][C:23]=2[CH3:27])[CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:25]1[O:26][C:22]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([F:19])([F:21])[F:20])=[C:12]([Cl:11])[CH:13]=2)=[C:23]([CH3:27])[N:24]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.9 %

Procedure:
LiHMDS (1.0 M in THF, 13 ml, 13 mmol) was added slowly via syringe to a solution of Example 45B (3.04 g, 11.6 mmol) in THF (50 mL) at −78° C. The solution was stirred 45 min, and then solid hexachloroethane (4.13 g, 17.4 mmol) was added in one portion. The reaction was allowed to proceed for 12 hr with gradual warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-150 g column) to afford 3.02 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=8.4, 1H), 7.86 (s, 1H), 7.75 (d, J=8.3, 1H), 2.42 (s, 3H). MS (DCI+) m/z 296 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.CN(C)C=O.[F:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[N:25][C:26]=1[F:27]>O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][O:28][C:23]1[CH:22]=[C:21]([F:20])[C:26]([F:27])=[N:25][CH:24]=1
Reactant: Oc1cnc(F)c(F)c1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCCC2OCCO2)cnc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Cesium carbonate (33 g, 100 mmol) and 2-(2-bromoethyl)-1,3-dioxolane (12 g, 67 mmol) were added to an N,N-dimethylformamide suspension (30 ml) of 5,6-difluoropyridin-3-ol (8.8 g, 67 mmol), and stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:chloroform=1:1 to 0:1) to obtain 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2,3-difluoropyridine (5.9 g, yield: 38%) as a pale yellow oil.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[C:13]([F:38])=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][C:16]1[C:17](=[O:34])[O:18][C:19]2[CH:27]=[C:26]([O:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:20]=2[C:21]=1[CH2:22][F:23].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[NH2:5][S:2]([NH:11][C:12]1[C:13]([F:38])=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][C:16]1[C:17](=[O:34])[O:18][C:19]2[CH:27]=[C:26]([O:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:20]=2[C:21]=1[CH2:22][F:23])(=[O:4])=[O:3]
Reactant: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(N)c3F)c(=O)oc2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=CO
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(NS(N)(=O)=O)c3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorosulfonyl isocyanate (0.150 mL) and formic acid (0.065 mL) were mixed at 0° C., and the mixture was stirred at room temperature for 1 hour. Dichloromethane (1.2 mL) was added to this mixture and dissolved, and the mixture was further stirred at room temperature for 4 hours, 0.060 mL was taken from the solution, and added at 0° C. to a solution of dimethylcarbamic acid 3-(3-amino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1h-1-4F) (25.2 mg) in dichloromethane (1.0 mL)/pyridine (0.0065 mL), and the mixture was stirred at room temperature for 3 hours. Saturated sodium hydrogen carbonate was ten added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (aminogel) (dichloromethane:methanol=90:10) to yield the title compound (12.0 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24][CH2:25][CH3:26].C(NCCCC)CCC>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Reactant: CCCCCNCCCCC
Solvent: CCCCNCCCC
Product: CCCCCN(CCCCC)CCCOc1ccc(-c2cn3cccc(C)c3n2)cc1

Procedure:
This compound was prepared according to the procedure described in Example 1 above using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and dipentylamine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis Calc'd for C27H39N3O3HCl; C, 8.03; H, 60.05; N, 7.78. Found: C, 8.35; H, 60.16; N, 7.39.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](N(OC)C)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Br)cc1)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 0.49 mL, 0.79 mmol) was added dropwise to a solution of 4-(4-bromophenyl)morpholine (191 mg, 0.79 mmol; described in: Jones, D. H. J. Chem. Soc. (C), 1971, 132-137 ) in tetrahydrofuran (5 mL) under nitrogen at −78° C. After 10 minutes, a pre-cooled solution (−78° C.) of 4-bromo-N-methoxy-N-methylbenzamide (212 mg, 0.87 mmol; described in: Turnbull, K. Tet. Lett. 1998 39(12), 1509-12) in tetrahydrofuran (3 mL) was added via a double-tipped needle. The mixture was stirred at −78° C. for 5 min. The cooling bath was removed and the mixture was allowed to reach ambient temperature under 30 min. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using heptane/ethyl acetate, 70:30, as the eluent affording 86 mg (32% yield) of the title compound as colorless crystals: mp 177.8-179.2° C.; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=9.0 Hz, 2 H), 7.61 (s, 4 H), 6.89 (d, J=9.0 Hz, 2 H), 3.89-3.85 (m, 4 H), 3.35-3.32 13C NMR(400 MHz, CDCl3) δ 194.5, 154.6, 137.8, 132.8, 131.8, 131.6, 127.7, 126.8, 113.6, 67.0, 47.9; MS (TSP) m/z 346 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:18])[C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[O:10][C:9](=[O:19])[CH:8]=[C:7]2[CH3:20])([O-])=O.[Sn](Cl)Cl.[Sn].Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:18])[C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[O:10][C:9](=[O:19])[CH:8]=[C:7]2[CH3:20]
Reactant: C=CCOc1c([N+](=O)[O-])cc2c(C)cc(=O)oc2c1C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Sn]
Solvent: CCO
Product: C=CCOc1c(N)cc2c(C)cc(=O)oc2c1C

Procedure:
Generally, the diazonium tetrafluoroborate intermediates are prepared by nitration of 7-hydroxycoumarin with nitric acid in sulfuric acid to give 6-nitro-4-8-dimethyl-7-hydroxycoumarin 1 (see Example 1 below) which is then o-allylated by treatment with allyl bromide and potassium carbonate in dimethylsulfoxide to produce 6-nitro-4,8-dimethyl-7-allyloxycoumarin 2 (see Example 2 below). The 6-nitro-4,8-dimethyl-7-allyloxycoumarin is then reduced by treatment with tin(II) chloride, tin, and concentrated hydrochloric acid in ethanol to give 6-amino-4,8-dimethyl-7-allyloxycoumarin 3 (see Example 3 below). Finally, 6-diazoniumtetrafluoroborate-4,8-dimethyl-7-allyloxycoumarin 4 is formed by treatment with sodium nitrite in tetrafluoroboric acid (see Example 4 below).