Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[N:21]1C=CC(B(O)O)=CC=1>>[N:21]1[CH:5]=[CH:6][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:2][CH:3]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccncc1
Product: O=C1NCCc2c(-c3ccncc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-pyridylboronic acid (153 mg, 1.24 mmol) were coupled to yield 2-pyridin-4-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 45 mg (15%) as a beige solid: m.p. 250° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.13 (m, 2H), 3.41 (m, 2H), 7.29 (app t, J=7.8 Hz, 1H), 7.63 (m, 3H), 7.72 (dd, J=7.2, 0.9 Hz, 1H), 8.14 (br t, 1H), 8.69 (d, J=6.0 Hz, 2H), 11.82 (br s, 1H). MS (FAB, MH+) 364. Anal. (C16H13N3O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5].C=O.[BH3-][C:27]#N.[Na+].C(O)(=O)C>C(#N)C.CCOCC.O>[CH3:27][NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([O:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:12]1)=[O:5]
Reactant: Nc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
0.2 g (0.00064 mol) of 1-benzyl-piperidin-4-yl 2-amino-benzoate was dissolved in 10 ml of acetonitrile and treated with 0.5 ml (0.0064 mol) of formaldehyde (37%) and 0.24 g (0.0032 mol) of NaBH3CN. The pH was adjusted to 6 by the addition of glacial acetic acid. The mixture was stirred at room temperature for 12 hrs., a further 0.15 g of NaBH3CN and 0.2 ml of formaldehyde were then. added and the pH was again adjusted to 6 by means of glacial acetic acid. After stirring for a further 2 hrs. the mixture was taken up in 100 ml of ether/water (1:1) and the organic phase was washed twice with saturated bicarbonate solution and once with saturated sodium chloride solution and dried over MgSO4. The residue was chromatographed on silica gel with dichloromethanelmethanol (39:1) as the eluent. 0.128 g (61%) of 1-benzyl-piperidin-4-yl 2-methylamino-benzoate was obtained as a colorless oil. MS: me/e=325 (C20H25N2O2 +).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([NH:24][C:25]1[CH:34]=[C:33](I)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:34]=[C:33]([S:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1NC(=O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.15 mL of triethylamine and 0.068 mL of benzyl mercaptan were added to 2 mL of toluene suspension containing 0.20 g of methyl 2-(benzamido)-4-iodobenzoate, 36 mg of 1,1′-bis(diphenylphosphino)ferrocene and 24 mg of tris(dibenzylideneacetone)dipalladium(0) and stirred under nitrogen atmosphere at 80° C. for 2 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. The obtained, residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=10:1] to obtain 0.16 g of methyl 2-(benzamido)-4-(benzylthio)benzoate as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([S:21](C3C=CC=CC=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li][C:32]([CH3:35])([CH3:34])C>C1COCC1>[C:34]1([S:21]([C:14]2[C:13]([C:6]([OH:30])=[O:5])=[C:12]3[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])[CH3:8])[O:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:23])[CH:32]=[CH:35][CH:3]=[CH:1][CH:2]=1
Reactant: [Li]C(C)(C)C
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)c(C(=O)O)c2O1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 35 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (141 mg, 0.338 mmol) in THF (15 mL) cooled at −78° C. was added t-BuLi (1.7M in hexanes, 0.68 mL) dropwise. The reaction was allowed to warm to 0° C. for 3 hours, then it was quenched with CO2 (gas) and diluted with water. The volatiles were removed in vacuo and the aqueous residue was washed with Et2O and then acidified to give a white precipitate that was filtered and dried to afford 7-benzenesulfonyl-2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-chroman-8-carboxylic acid (55 mg, 35% yield) as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:29])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(O)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=2)=[O:4].C1(O)C=CC=CC=1.[CH2:22]([C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[C:39]1[CH:40]=[C:41]([CH2:45]O)[CH:42]=[CH:43][CH:44]=1)=[CH:36][CH:35]=[CH:34][C:33]=2[C:47]([F:50])([F:49])[F:48])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[CH2:45][O:14][C:10]1[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:13]3)=[CH:36][CH:35]=[CH:34][C:33]=2[C:47]([F:50])([F:49])[F:48])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: Oc1ccccc1
Product: O=C(O)c1cc2cc(OCc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)ccc2[nH]1

Procedure:
The title compound was prepared using the procedure of example 69 using 5-Hydroxy-1H-indole-2-carboxylic acid methyl ester as the phenol and [3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenyl]-methanol as the alcohol. MS (ESI) m/z 553.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([NH:24][CH3:25])=[O:23])[N:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[F:36][CH2:37][CH2:38][CH2:39]Br>CN(C=O)C>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([N:24]([CH3:25])[CH2:39][CH2:38][CH2:37][F:36])=[O:23])[N:13]=1)[CH2:31][CH2:32][CH3:33]
Reactant: FCCCBr
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1-c1nc(C(=O)NC)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1-c1nc(C(=O)N(C)CCCF)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 25.2 %

Procedure:
To a solution of 1-(2-tributylstannylphenyl)-N-methyl-3-isoquinoline-carboxamide (105 mg, 0.19 mmol) in DMF (5 mL) was added 60% NaH (65 mg, 1.61 mmol) in one portion. The mixture was stirred under Ar at room temperature for 40 min. Then, 3-fluoropropyl bromide (124 μl, 1.67 mmol) was added. After stirring under Ar at room temperature for 24 h, the mixture was quenched by adding H2O (9 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 5-10% ethyl acetate/hexane, 0.1% Et3N), thereby affording an oil (29.3 mg, 25%), and starting material (62.5 mg). 1H NMR (CDCl3) d 0.32-0.68 (m, 6 H, SnCH2), 0.70 (t, J=7.2 Hz, 9 H, CH3), 0.95-1.32 (m, 12 H, CH2CH2), 2.15-2.28 (m, 2 H, CH2), 3.13 (d, J=11.1 Hz, 3 H, N-methyl), 3.58-3.85 (m, 2 H, N--CH2), 4.48 (qt, J=123.9, 47.4, 5.7 Hz, 2 H, CH2F), 7.42-7.62 (m, 4 H, aromatic), 7.65-7.80 (m, 2 H, aromatic), 7.91-8.15 (m, 3 H, aromatic). HRFABMS Calcd. for C32H46FN2O12OSn: 613.2599. Found: 613.2619.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:4].CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:4]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OC)cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (105.1 g) in tetrahydrofuran (1.4 l) was added methanol (450 ml) and deionized water (450 ml), followed by an equimolar amount of lithium hydroxide monohydrate (12.00 g). After the reaction mixture had stirred about 20 hours, it was acidified to pH 2 by addition of 6N hydrochloric acid (60 ml). Evaporation of the organic solvents resulted in the precipitation of a crude product (104.2 g) which was filtered and dried under vacuum before it was recrystallized by dissolving it in boiling tetrahydrofuran (600 ml), addition of toluene (about 1.2 l) and concentration to about one liter. Following cooling and stirring overnight, filtration, and drying under vacuum, a first crop is (71.1 g) was obtained. A second, similar recrystallization of this material from tetrahydrofuraN (500 ml) and toluene (1 l) afforded 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (58.3 g, 57.7%) as an off-white solid; NMR (300 MHz, DMSO-d6): 3.78 (s, 3H, NCH3), 3.83 (s, 3H, CO2CH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.17 (d, 1H), 7.18 (s, 1H), 7.43-7.50 (m, 3H), 7.75 (dd, 1H) 8.19 (d, 1H); the same benzoic acid obtained by a similar procedure, but purified by flash chromatography, eluting with (methylene chloride:tetrahydrofuran:acetic acid (sequentially, 1:0:0, 1:9:0, and 0:400:1) followed by isolation and drying under vacuum of crystals formed on standing in methylene chloride:tetrahydrofuran fractions, had mp 228.0°-229.5° C. An additional amount of the benzoic acid (23.6 g, 23.3%), as well as recovered diester (11.5 g, 10.7%), was obtained by concentration and flash chromatography of the mother liquors, eluting with methylene chloride:tetrahydrofuran (sequentially, 1:0, 3:1, 2:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:8][C:7]1=2
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/1:1) to give 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as an off-white solid (0.7 g, 25%): mp 236-237° C.; 1H-NMR (DMSO-d6) δ 10.34 (s, 1H, D2O exchangeable), 8.21 (s, 1H), 8.02 (d, 1H, J=8.1 Hz), 7.79 (d, 1H, J=7.7 Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J=8.2 Hz), 1.71 (s, 6H); Anal. Calcd. For C17H14N2O2.0.1 H2O: C, 72.89; H, 5.11; N, 10.00. Found: C, 72.75; H, 5.05; N, 9.65.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[C:9]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH2:55].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH:55][C:12]([C:10]1[S:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(-c3ccccc3)sc2C(=O)O)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a mixture of 5-phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carboxylic acid (prepared according to example 2) (50 mg, 0.134 mmol) in anhydrous dimethylformamide (1.4 ml) were added HATU 152 mg, 0.402 mmol), glycine methyl ester hydrochloride (20 mg, 0.161 mmol) followed by collidine (124 μl, 0.938 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and pre-absorbed on SiO2. Purification chromatography (hexane to hexane:ethyl acetate; 6:4 to dichloromethane:methanol; 95:5) gave 47 mg of a mixture of {[5-Phenyl-3-(toluene-4-sulfonylamino)-thiophene-2-carbonyl]-amino}-acetic acid methyl ester and collidine. 1H NMR (CDCl3, 400 MHz) 7.76-7.73 (m, 2H), 7.61 (s, 1H), 7.57-7.54 (m, 2H), 7.42-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.19-6.17 (m, 1H), 4.14-4.12 (m, 2H), 3.79 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].O>P(=O)(O)(O)O>[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([OH:14])[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1cccc2c(O)cc(C(F)(F)F)nc12
Temperature: 105 °C
Reaction time: 5.5 h
Yield: 17.4 %

Procedure:
2-Methylaniline (5.00 g) was dissolved in 75% phosphoric acid (20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise added thereto at 105° C. The mixture was stirred at 105° C. for 5.5 hr. After allowing to cool, the reaction mixture was added to water. The precipitated solid was collected by filtration to give 2-trifluoromethyl-4-hydroxy-8-methylquinoline (1.84 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([CH:19]=O)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Reactant: Nc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(CNc2ccc3c(CNc4cccnc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde (100 mg, 0.376 mmol) was dissolved in 5 mL ethylendichloride. 3-Aminopyridine (50 mg, 0.532 mmol) and acetic acid (90 mg, 1.50 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (172 mg, 0.811 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 50 mL water. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from dichloromethane. The title compound was obtained as a white solid (50 mg, 39%), MS: m/e=345.0 (M+H+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:8][CH:7]=1.[CH3:28][S-:29].[Na+]>CO>[CH3:28][S:29][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:8][CH:7]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCCCI)s3)n2)CC(C)(C)N1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
Crude compound of Step B (1.4 g, 2.8 mmol) was dissolved in 10 ml MeOH and 0.4 g (5.6 mmol) sodiumthiomethylate were added. This mixture was refluxed for 7 hours. After evaporation the title compound was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 0.82 g (68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:27][CH3:28])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([CH3:29])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:27][CH3:28])[N:10]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:16]=3)[C:6]=2[CH:5]=[C:4]([CH3:29])[N:3]=1
Reactant: CCc1nc2c(Cl)nc(C)cc2n1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(Cl)nc(C)cc2n1-c1ccc(CCN)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of tert-butyl 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate (step 3, 90 mg, 0.22 mmol) in dichloromethane (8.5 ml) was added trifluoroacetic acid (1.0 ml, 13.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min, then at room temperature for 5 h. The mixture was concentrated, and diluted with dichloromethane (50 ml), washed with saturated aqueous NaHCO3 solution (10 ml) and brine (10 ml). The organic layer was dried (MgSO4), and concentrated. Purification by PTLC eluting with ethyl acetate to afford 50 mg (73%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1)#[N:2]>[Pd].C(O)C>[C:1]([CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7][CH2:6]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CC#N)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC#N)CC1

Procedure:
A mixture of tert-butyl {trans-4-[2-cyanovinyl]cyclohexyl}carbamate (0.13 g, 0.52 mmol) and 10% palladium on carbon (52 mg) in ethanol (2 mL) was hydrogenated under balloon pressure of H2 over weekend. The mixture was filtered, and the filtrate was concentrated to give tert-butyl [trans-4-(2-Cyanoethyl)cyclohexyl]carbamate. LCMS calculated for C10H17N2O2 (M-tBu+H)+: m/z=197.1. Found: 197.1. This carbamate intermediate was treated with trifluoroacetic acid (0.4 mL, 5 mmol) in methylene chloride (1 mL) at room temperature for 1 h, and then the solvent removed to give the desired product as TFA salt. LCMS calculated for C9H17N2 (M+H)+: m/z=153.1. Found: 153.2.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(B(O)O)C=CC=CC=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:36][CH:37]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(I)c2)nn1-c1ccccn1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)nn1-c1ccccn1
Yield: 99 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of each of 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (23) prepared in Example B-4 and 4-benzyloxyphenylboronic acid (manufactured by Aldrich) was used in place of Compound 21 prepared in Example B-2 and phenylboronic acid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10](O)([C:11]3[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=3)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[SH:23][CH2:24][CH:25]([CH3:36])[C:26]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31])=[O:27].Cl>C(OCC)(=O)C>[NH2:20][S:17]([C:15]1[CH:16]=[C:11]([C:10]2([S:23][CH2:24][CH:25]([CH3:36])[C:26]([N:28]3[CH2:35][CH2:34][CH2:33][C@H:29]3[C:30]([OH:32])=[O:31])=[O:27])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[NH:9]2)[CH:12]=[CH:13][C:14]=1[Cl:21])(=[O:19])=[O:18]
Reactant: NS(=O)(=O)c1cc(C2(O)NC(=O)c3ccccc32)ccc1Cl
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(CSC1(c2ccc(Cl)c(S(N)(=O)=O)c2)NC(=O)c2ccccc21)C(=O)N1CCC[C@H]1C(=O)O
Yield: 48.4 %

Procedure:
A mixture of 1.69 g chlorthalidone, 2.5 g of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 150 ml ethyl acetate is cooled by an ice bath and then saturated with HCl gas. This mixture is refluxed for one hour. The solvent is evaporated, the residue dissolved in warm saturated sodium bicarbonate solution, and the mixture extracted with ethyl acetate. The aqueous phase is separated and acidified at ice bath temperature. The resulting solid is filtered off, washed with water and dried to yield 1.3 g of the title compound.