Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[C:17]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:26]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:26]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.97 g) in dimethylformamide (12 mL) was treated with 55% sodium hydride (0.22 g), stirred for 15 minutes and then 1,2-bis-(phenylmethoxy)-3-(6-bromohexyl)benzene (2.27 g) was added and rinsed in with dimethylformamide (3 mL). The mixture was stirred overnight at room temperature and worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-hexane; 1:9) and crystallized from diethyl ether-hexane to provide 1.7 g of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 39°-42° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:25])(=[O:26])=[O:27])=[CH:20][CH:19]=2)[N:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(CO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 798 %

Procedure:
To a solution of compound 3c (4 g, 1.04 mmol) in 20 mL of THF was added LiAlH4 (1.26 g, 33.2 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAC (30 mL) and water (30 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes in adequate proportions) to give the compound (2.85 g, 80%) as a white solid. mp 165.9-169.3° C. 1H NMR (300 MHz, DMSO-d6): δ 7.81 (d, J=9 Hz, 2H), 7.48-7.43 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H), 6.59 (s, 1H), 5.26 (t, J=6 Hz, 1H), 4.51 (d, J=6 Hz, 2H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:1][C:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)=[CH:41][CH:40]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (500 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (980 mg, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(Cl)nc3)[C@@H]2C1
Yield: 37.8 %

Procedure:
The product of Example 52D (0.23 g, 1.0 mmol) and 2-chloro-5-bromopyridine (0.29 g, 1.5 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, hexane:ethyl acetate, 60:40, Rf 0.3) to provide the title compound (0.13 g, 38% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.24 (dd, J=12.9, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.65 (dd, J=7.8, 3.4 Hz, 1H), 4.08-3.92 (m, 3H), 4.70 (dd, J=5.7, 3.7 Hz, 1H), 5.10 (m, 2H), 6.90 (dd, J=8.5, 3.1 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.54 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 346 (M+2+H)+, 344 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH:17]1[CH2:22][CH2:21][CH:20]([C@H:23]2[CH2:28][CH2:27][Si@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1>[Cu]I.C1COCC1>[CH2:29]([SiH:26]1[CH2:25][CH2:24][CH:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)[CH2:30][CH3:31]
Reactant: CCC[Si@H]1CC[C@H](C2CCC(I)CC2)CC1
Reactant: Fc1ccc(-c2ccc([Mg]Br)cc2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[SiH]1CCC([C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
A 15 ml THF solution of 1.5M 4-(4-fluorophenyl)phenyl magnesium bromide (22.5 mmol) was dripped into a mixed solution of 7.0 g (20.0 mmol) of trans-4-(4-iodocyclohexyl)-1-n-propyl-1-silacyclohexane, 70 mg of copper (I) iodide and 50 ml of THF. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 2.29 g (yield 58%) of the target product, i.e. the trans, trans isomers. The obtained target product exhibited the same physical properties as the product of Example 8.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:39]=[CH:38][C:37](Br)=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.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>[C:17]1([CH2:16][O:23][C:24]2[CH:39]=[CH:38][C:37]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[CH:36][C:25]=2[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Product: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Na2CO3 (0.53 g, 5.00 mmol), followed by pyridin-4-ylboronic acid (0.34 g, 2.75 mmol) and Pd(Ph3P)4 (0.144 g, 0.125 mmol) were added to a mixture of benzyl 2-(benzyloxy)-5-bromobenzoate (may be prepared as described in Description 4; 1.0 g, 2.50 mmol) in 1,4-dioxane (25 ml) and water (5 ml) under nitrogen. After addition, the mixture was stirred at 90° C. for 4 hours. The reaction mixture was evaporated to give brown crude product, which was purified by chromatography (silica gel, 40 g, eluent: ethyl acetate/petroleum ether=1:2, 1.2 L) to yield the title compound as a white solid. 0.81 g.
Reaction SMILES: [Cl:1][P:2](Cl)[O:3][CH2:4][CH2:5][C:6]#[N:7].[CH:9]([N:12]([CH:15]([CH3:17])[CH3:16])CC)([CH3:11])[CH3:10].C(NC(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:9]([N:12]([P:2]([Cl:1])[O:3][CH2:4][CH2:5][C:6]#[N:7])[CH:15]([CH3:17])[CH3:16])([CH3:11])[CH3:10]
Reactant: N#CCCOP(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.54 mL(4.0 mmol) of dichloro(β-cyano)ethoxyphosphine in 40 mL of dichloromethane cooled in an ice-water bath was added 10 mL of diisopropylethylamine, followed by adding 0.64 mL (4.0 mmol) of diisopropylamine under Argon. The reaction mixture was warmed up to room temperature and stirred for 2 h. After adding 0.1 gm of DMAP into the solution, the reaction mixture is ready for the next step reaction.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17])=[O:4]
Reactant: Nc1nccs1
Reactant: COC(=O)C1CCOc2cc(F)ccc2C1=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1CCOc2cc(F)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.6 mmol) and 2-aminothiazol (0.6 mmol) were dissolved in 2.5 ml xylene. Reaction was performed by microwave irradiation for 30 minutes at 140° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. After evaporation of the solvent in vacuo 8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid thiazol-2-ylamide was obtained as a white powder in a yield of 7%. LC-MS: 1.9 min, 307.0 (MH+) 1H-NMR: (DMSO-d6, 500 MHz): d [ppm]: 12.102 (s, 1H), 7.731 (t, 1H, J=7.3 Hz), 7.464 (d, 1H, J=3.2 Hz), 7.234 (d, 1H, J=3.6 Hz), 7.056 (m, 2H, J=7.8 Hz), 4.654 (m, 1H, J=2.6 Hz), 4.340 (m, 1H, J=7.6 Hz), 4.013 (m, 1H, J=7.2 Hz), 2.502 (m, 2H, J=1.8 Hz)
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH:10](OCC1C=CC=CC=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[BH4-].[Na+]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[O:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CCNC(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCNCC(O)c2ccccc2OCc2ccccc2)cc1OC
Yield: 165.9 %

Procedure:
3 g of α-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone hydrochloride, 0.7 g of sodium borohydride and 30 ml of ethanol are treated in the same manner as described in Example 1-(b). 2.5 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzylalcohol hydrochloride are obtained. M.P. 115° - 117° C.(recrystallized from a mixture of ethanol and ether).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.C[Si]([N:31]=[C:32]=[O:33])(C)C.C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:32]([NH2:31])=[O:33])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), (trimethyl)silyl isocyanate (78 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and THF, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (39.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH2:16].[C:18](Cl)(=[O:20])[CH3:19]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]([C:18](=[O:20])[CH3:19])[CH3:11])[C:7]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:5]=1[NH2:16]
Reactant: CNc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
2-Amino-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester (26 mg, 0.96 mmoles) is dissolved in dioxane and after addition of acetyl chloride (54 μL, 1 eq.) the mixture is stirred for 2 h (TLC control) at 80° C. Acetyl chloride (0.9 eq.) is then added and stirring continued for 18 hours at 80° C. The mixture is evaporated to dryness. The residue is dissolved in dichloromethane, filtrated, evaporated and dried under HV. The crude product is purified by flash-chromatography (gradient hexane to ethyl acetate, silicagel) to yield 5-(acetyl-methyl-amino)-2-amino-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (36 mg, 12.8% yield) (MH+291, Rt 5.0 min.). The other monoacetyl derivative (50 mg) and the diacetyl derivative (92 mg) are also isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][S:11]([O-:13])=[O:12].[Na+]>CN(C)C=O>[CH3:10][S:11]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)(=[O:13])=[O:12]
Reactant: BrCc1cccc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 3-bromobenzyl bromide (5.0 g, 20 mmol) in dry dimethylformamide (50 ml) at room temperature under an atmosphere of argon was treated portionwise with sodium methanesulfinate (2.0 g, 20 mmol) with stirring. The mixture was stirred at room temperature for 16 h, and then at 50° C. for 0.5 h. The reaction mix was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate and the solvent removed under reduced pressure to give an oil which was purified by column chromatography on a 50 g isolute silica sep-pak column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as an off-white solid (3.34 g, 67%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:26][CH2:25][CH2:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Reactant: COc1ccc(CCN)cn1
Solvent: C1CCOC1
Product: COc1ccc(CCNc2nc(C(C)(C)C)cn3c(=O)[nH]nc23)cn1

Procedure:
A solution of 50 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 68 mg of 2-(6-methoxy-pyridin-3-yl)-ethylamine in THF (2 mL) was heated in a microwave apparatus (Emrys-Optimizer®, Personal Chemistry Inc., 2 Hampshire St., Suite 100, Foxboro, Mass.) at 150° C. for 10 min. The solvent was removed and the residue was purified by silica gel chromatography to afford the title compound as a white solid after trituration. MS (M+H+)=343.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]([C:18]3[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=3)=O)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:18]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:27][N:26]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Solvent: O
Solvent: CCO
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (477 mg, 1.4 mmol) and hydrazine hydrate (2 mL) in ethanol (30 mL) was heated at 80° C. for 24 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 200 mg (45%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1)(=[O:18])[CH3:17]
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-4-(4-nitro-phenyl)-1H-imidazole (17.3 g) and acetic anhydride (100 ml) was heated at 100° C. for one hour. The resulting solution was evaporated to dryness, and the residue was treated with ether, filtered off and dried to give 18.9 g of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=3)[CH:15]([CH3:26])[C:14]2=[O:27])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)CCC.[Cl-].[Li+]>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.CN(C)C=O>[OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:20]=3)[CH:15]([CH3:26])[C:14]2=[O:27])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2
Reactant: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(-c2ccccn2)c1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
A mixture of 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-4-(3-iodo-phenyl)-3-methyl-piperazin-2-one (example 89; 80 mg, 0.17 mmol), 2-(tributylstannyl)pyridine (73 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0), lithium chloride (42 mg, 0.99 mmol) copper chloride (82 mg, 0.83 mmol), and N,N-dimethylformamide (3 mL) was heated at 100° C. for 16 h, then the reaction mixture was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc-MeOH gradient) afforded the title compound (3.5 mg, 5%). Colorless gum, MS: 435.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H-].[K+].[C:11](=[O:18])([O:15][CH2:16][CH3:17])OCC>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([C:11]([O:15][CH2:16][CH3:17])=[O:18])[C:11]([O:15][CH2:16][CH3:17])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [K+]
Product: CCOC(=O)C(C(=O)OCC)c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 36 %

Procedure:
2-Chloro-4-picoline was added to a solution of potassium hydride (1.80 g, 15.8 mmol) in diethyl carbonate (10 ml) at 0° C. The reaction mixture was allowed to attain room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (15 ml) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford the crude product. Purification by column chromatography over silica gel (60-120 mesh) using 8% ethyl acetate in petroleum ether as eluent afforded 750 mg (36%) of diethyl 2-(2-chloropyridin-4-yl)malonate as colorless liquid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[N:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:23]([F:22])([F:33])[F:34])=[O:27])[CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nn3)nc2c1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4ccccc4[nH]3)nn2)CC1
Yield: 27 %

Procedure:
Following the procedure as described in Example 6, making variations only as required to use 2-(6-piperazin-1-ylpyridazin-3-yl)-1H-benzoimidazole in place of 2-(6-piperazin-1-ylpyridin-3-yl)-1H-benzoimidazole to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white powder in 27% yield (0.122 g). 1H NMR (300 MHz, CDCl3) δ 13.25 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 2H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.42 (d, J=9.6 Hz, 1H), 7.22-7.13 (m, 2H), 3.87-3.56 (m, 6H), 3.26-3.12 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.1, 158.2, 148.1, 142.8, 142.5, 133.7, 133.4, 131.8, 128.4, 126.4, 125.4, 124.9, 124.4, 124.3, 123.9, 121.8, 120.8, 117.8, 112.4, 110.6, 44.8, 42.9, 42.7, 39.6. MS (ES+) m/z 453.3 (M+1).