Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[Br:34]Br.O>C(O)(=O)C>[Br:34][C:8]1[CH:9]=[C:10]([C:12]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=3[C:19]([Br:27])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]=1[OH:28]
Reactant: BrBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a suspension of 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) in glacial acetic acid (60 mL) was added dropwise over a period of 17 minutes a solution of bromine (0.27 mL, 5.3 mmol) in glacial acetic acid (8 mL). The thick reaction mixture was diluted with glacial acetic acid (20 mL). After stirring at room temperature for 2 h the reaction mixture was poured into water (500 mL). The solution was extracted once with diethyl ether (250 mL), and then with diethyl ether (100 mL). The combined extracts were washed twice with water (100 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (98:2), followed by trituation with petroleum ether gave the title compound as a white solid (1.2 g, 52%): mp 189.5-191° C.; (DMSO-d6): δ 9.19 (s, 1H), 8.18 (d, 1H), 7.65-7.61 (m, 1H), 7.50-7.47 (m, 2H), 7.33 (d, 1H), 7.11 (d, 1H), 3.42 (quintet, 1H), 2.43 (s, 3H), 2.00-1.97 (m,2H ), 1.69-1.46 (m, 6H), 1.60 (s, 3H); MS(EI): [M+], 2 bromine isotope pattern, 528 (46%), 530 (100%), 532 (52%); Anal. Calc. for C25H22Br2OS: C, 56.62, H, 4.18, N, 0.00. Found: C, 55.78, H, 4.12, N, 0.05.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][O:10][C:9](=[O:12])[NH:8]1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=12.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22]([N:8]3[C@@H:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:11][O:10][C:9]3=[O:12])=[N:21][C:20]=12
Reactant: O=C1N[C@@H](c2ccccn2)CO1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a solution of (S)-4-(pyridin-2-yl)oxazolidin-2-one (0.20 g, 1.2 mmol) in DMF (20 mL) was added sodium hydride (0.049 g, 1.2 mmol) and the reaction was stirred at ambient temperature for 1 hour. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.28 g, 1.2 mmol) was added and the reaction stirred for an additional 1 hour. The reaction was then poured into water (100 mL) and extracted into ether (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 100% DCM to 15% EtOAc/DCM as eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.25 g, 56.8%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([C@H:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:19])([F:20])[F:18])(=[O:15])=[O:16])[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)C(=O)c1c(C)c(C)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)c(C)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(3,4-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (3.93 g, 9.72 mmol) and (R)-2-methyl-CBS-oxazaoborolidine (0.539 g, 1.94 mmol) in anhydrous toluene (30 mL) at −40° C. was added dropwise a solution of catecholborane (1.40 mL, 13.22 mmol) in toluene (5 mL) over 20 minutes to give a pale yellow reaction mixture. The reaction mixture was stirred for another 20 minutes and quenched with saturated sodium carbonate solution and ethyl acetate was added. The mixture was stirred for 30 minutes, the aqueous layer removed and the organic layer washed with saturated sodium carbonate solution (3×), brine and dried (MgSO4) and filtered. Concentration and purification by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) gave the desired product. LCMS-ESI+ (m/z): [M+Na]+ calcd for C17H17F3NaO6S: 429.37. Found: 428.8.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:31])=[C:5]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCC(=O)O)=C3O)NC2=O)c1
Temperature: 25 °C
Yield: 150.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 474.36 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:4]([C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14])#[N:5]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: N#Cc1c(N)cccc1F
Agent: Br
Product: CC(Nc1cccc(F)c1C#N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 48.4 %

Procedure:
2-amino-6-fluorobenzonitrile (111 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness. The resulting oil was crystallised from ethyl acetate to give 8-(1-(2-cyano-3-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45.0 mg, 64.3%) as a white solid. Mass Spectrum: M+H+ 465. NMR Spectrum (DMSOd6): 1.61 (d, 3H), 2.74 (bs, 3H), 2.95 (bs, 3H), 3.49-3.62 (m, 4H), 3.69-3.77 (m, 4H), 5.17-5.26 (m, 1H), 5.61 (s, 1H), 6.33 (d, 1H), 6.56 (dd, 1H), 6.99 (d, 1H), 7.32 (dd, 1H), 7.69 (d, 1H), 7.81 (d, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C([O-])(O)=O.[Na+]>[CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc(Cc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncc(Cc2ccccc2)cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzylpyridin-2-amine 2 (6.0 g, 32.3 mmol) in CH2C12 (100 mL) cooled to 0° C. was added bromine (5.1 g, 32.3 mmol) dropwise [Kelly, et al., J. Am. Chem. Soc. 112, 8024-8034 (1990)]. The bromine decolorized immediately and the mixture was left stirring for 30 min. The mixture was shaken with saturated NaHCO3 solution (100 mL), the organic layer was then dried over anhydrous Na2SO4, and distilled off to give a yellow residue which was purified by flash chromatography on silica gel (EtOAc:hexane, 3:7). Yield 7.3 g (86%), white solid, mp 110-111° C. 1H NMR (CDCl3, 500 MHz): δ 3.86 (s, 2H, CH2), 4.88 (bs, 2H, NH2), 7.19-7.35 (m, 5H, Ar—H), 7.50 (d, 1H, CH, J=1.5 Hz), 7.94 (d, 1H, CH, J=1.0 Hz). 13C NMR (CDCl3, 125 MHz): δ 37.7, 104.6, 126.4, 126.4, 128.1, 128.6, 128.6, 128.7, 140.2, 140.8, 146.7, 154.0; HRMS (M+H)+ calcd for C12H13BrN2 263.0184, found 263.0184.
Reaction SMILES: ClS(O)(=O)=O.[C:6](#[N:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([C:6]2[N:13]=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:13]=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:13]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ccccc1
Agent: O=S(=O)(O)Cl
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Yield: 68 %

Procedure:
Chlorosulfonic acid has been shown to be an effective catalyst for the trimerization of benzonitrile, providing a 68 percent yield of 2,4,6-triphenyl-s-triazine (J. Chem. Soc., 1941, 278). However, as shown in the following example, chlorosulfonic acid is ineffective to trimerize isobutyronitrile.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1Cl
Reaction time: 8 h

Procedure:
Under an inert atmosphere, 5 g (21.2 mmol) of 4-bromo-2-chlorobenzoic acid, 2.96 g (23.3 mmol) of 4-fluorophenylboronic acid and 31.8 ml (63.6 mmol) of aqueous sodium carbonate solution (2M) in suspension in 40 ml of toluene are introduced. Subsequently 0.80 g (0.70 mmol) of palladium tetrakis(triphenylphosphine) is added. The reaction mixture is subsequently refluxed overnight.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:26]
Reactant: COc1ccc(CSc2nc(Cl)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 741 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine (2.00 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (20 ml), under ice cooling, 60% sodium hydride (0.30 g, 7.6 mmol) was added and stirred for 5 minutes, then methyl iodide (1.08 g, 0.76 mmol) was added and stirred overnight. Water was added to the reaction solution, the precipitated crystals were collected by filtration and washed sequentially with water and ether to obtain 2.06 g (89% yield) of 6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:9](=[C:10]([OH:27])[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]=3[O:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[C:8]2=[O:28])=[CH:4][CH:3]=1.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCCl>[CH2:24]([O:23][C:22](=[O:26])[O:21][C:17]1[C:16]2[N:15]=[CH:14][CH:13]=[N:12][C:11]=2[C:10]([O:27][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:9]2[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=3)[C:19](=[O:20])[C:18]=12)[CH3:25]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Oc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: ClCCCl
Product: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 70 °C
Yield: 69.8 %

Procedure:
Carbonic acid mono-[1-(1-benzyl-4-methylene-2,5-dioxo-pyrrolidin-3-ylidene)-ethyl]ester 243 (1.1 g, 2.68 mmol, 1 equiv.) was dissolved in 1,2 dichloroethane (50 mL, 0.055 M) and to this was added diphenyldiazomethane (1.05 g, 5.35 mmol, 2 equiv.) and heated at 70° C. under a nitrogen atmosphere for 24 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography using 4/1 Hexanes/Ethyl acetate to obtain carbonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ethyl ester 244 (70%, 1085 mg, 1.87 mmol). 1H NMR (300 MHz) CDCl3 δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H),7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H),4.04 (q, J=2.8 Hz,2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 600.2 (M+23). TLC Rf: 0.3 Hexanes/Ethyl acetate (7/3)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][NH:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][N:24]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:23]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC1CNCC1CN
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)C(CN)C3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.22 g) and DBU (0.28 g) was refluxed for an hour and then stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.39 g) as pale yellow powder, mp 222°-224° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:28])[O:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[CH:5]1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Cl:38])[N:32]=1>CN(C)C=O>[Cl:38][CH2:37][C:33]1[N:32]=[C:31]([CH2:30][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([C:17]3[C:16](=[O:27])[O:15][C:14](=[O:28])[C:13]=3[C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]([CH3:3])[CH:5]=3)=[CH:19]2)[CH:36]=[CH:35][CH:34]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)OC2=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CCl)n4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reaction time: 65 h

Procedure:
Sodium hydride (60% dispersion in oil, 42 mg, 1.8 mmol), 3-(1-methyl-indol-3-yl)-4-(indol-3yl)-furan-2,5-dione (236 mg, 0.7 mmol) and dimethylformamide (8 mL) were stirred at room temperature for 1 h. The reaction mixture was cooled with ice and 2,6-bis-chloromethyl-pyridine (520 mg, 3.0 mmol) was added in one portion. Stirring was continued at room temperature for 65 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried with MgSO4, filtered and evaporated. Chromatography (ethyl acetate/heptane:50/50) gave the title compound, which was not pure. Further purification by Kugelrohr distillation (oil pump, 150° C.) afforded 156 mg of the sub-title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[C:4]([Cl:19])[N:3]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:19][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH2:26][C:22]([F:27])([F:21])[CH2:23]2)[N:3]=1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl 3-(2,6-dichloro-4-pyridyl)azetidine-1-carboxylate (1-a, 472 mg, 1.557 mmol), 3,3-difluoropyrrolidine hydrochloride (1.12 g, 5.0 equiv., 7.784 mmol) in NMP (3.0 mL, 31 mmol) in a microwave vial was added DIPEA (1.90 mL, 7.0 equiv., 10.90 mmol)), and the reaction was maintained at 140° C. for 30 min and then at 150° C. for 30 min in the microwave machine. LCMS showed more than 95% conversion. The crude was used without further treatment. LCMS: m/z 374 (M+H).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[C:6](Br)[CH:7]=[N:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H][H]>C(O)C.[Pd]>[NH:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:2][C:3]1=[O:12]
Reactant: O=C1Nc2c(Br)cncc2C1(Br)Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1Cc2cnccc2N1
Yield: 2.2 %

Procedure:
To a solution of 3,3,7-tribromo-5-azaoxindole (6.4 g, 17.3 mmol) in ethanol (1200 ml) was added 10% Pd on charcoal (3.2 g). The mixture was hydrogenated under 3 atm. hydrogen gas for 3 hours using a Parr shaker. The catalyst was removed by filtration of the mixture through a pad of Celite®, washing well with ethanol. On removal of the solvent, a brown solid remained (predominantly the hydrobromide of the desired product), 3.5 g. This was dissolved in water, treated with activated charcoal and filtered through Celite®. The pH of the filtrate was adjusted to 7.5 by the addition of saturated aqueous NaHCO3 solution. The mixture was then extracted with n-butanol (3×). The combined n-butanol extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to leave a solid. This was triturated with butanone and filtered to collect 5-azaoxindole as a tan solid (1.6 g, 69%). After removal of butanone, the mother liquor yielded a solid which was recrystallized from methanol to yield more of the title compound (50 mg), m.p.>250° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.Cl.O1CCOCC1>[Pd].C(O)C>[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2Cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2Cc2ccccc21
Reaction time: 6 h
Yield: 114.8 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(pyrimidin-2-ylamino)1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.17 g, 0.38 mmol), 10% palladium on charcoal (0.085 g, 0.08 mmol), 4 M HCl in dioxane (0.1 mL, 0.4 mmol) and ethanol (5 mL) was shaken under H2 (48 psi) for 6 hr, then the catalyst was removed by filtration through celite®. The filtrate was concentrated to give the title compound (0.19 g) as a yellow oil: MS (ES) 436.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([C:26](=O)[CH:27](Br)[CH3:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:14][C:15]([F:31])([F:32])[C:16]1[CH:17]=[C:18]([C:26]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:27]=2[CH3:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(C)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 105 mg 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one in a manner similar to Example 8, step (a) to give, after preparative thin-layer chromatrography purification, methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (16.2 mg, 11%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.41 (m, 2H), 8.18 (m, 2H), 3.86 (s, 3H), 2.75 (s, 3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C19H13NO2S3F6, 498.0 (M+H), found 497.6.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:3]=1.CN(C)C=O>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Nc1nc(-c2ccncc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(-c2ccncc2)nc1N

Procedure:
A mixture containing 43.2 g. of 2-amino-3-nitro-6-(4-pyridinyl)pyridine, 360 ml. of dimethylformamide, 220 ml. of ethanol and 1 g. of 10% palladium-on-charcoal was shaken in a Parr apparatus under catalytic hydrogenation conditions for about one hour. The reaction mixture was filtered and the filtrate concentrated in vacuo to a volume of about 150 ml. and cooled. The separated solid was collected and dried to produce 20 g. of 2,3-diamino-6-(4-pyridinyl)pyridine which can be used directly in the next step without further purification. In another run, a sample was recrystallized from ethanol using decolorizing charcoal to produce the product, 2,3-diamino-6-(4-pyridinyl)pyridine, melting at 252°-254° C.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:32]=[C:31](Br)[CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>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.CCOCC.O.C1C=CC=CC=1>[NH2:28][C:27]1[CH:29]=[CH:30][C:31]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)=[CH:20][CH:19]=2)=[CH:32][C:26]=1[C:25]([F:35])([F:34])[F:24]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
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: c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(N)c(C(F)(F)F)c3)cc2)CC1

Procedure:
First, 100 ml of ethanol containing 4.91 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 100 ml of benzene containing 10.0 g of 2-trifluoromethyl-4-bromoaniline, 41.7 ml of a sodium carbonate aqueous solution with a concentration of 2 mol/l, and 1.20 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 300 ml flask, and stirred under reflux for six hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane/toluene=4/1), to obtain 14.82 g (Y: 91.3%) of 4-amino-4′-(trans-4-pentylcyclohexyl)-3-trifluoromethylbiphenyl. The purity of the resultant compound was 99.2% as measured by GC.