Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[I-:19].[Na+]>[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([I:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Product: O=c1c2cc(I)ccc2ccc2ncc(Cl)cc12
Reaction time: 24 h

Procedure:
A sealed tube was charged with 3-chloro-7-bromo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.0 g, 3.1 mmol), CuI (59 mg, 0.31 mmol), and sodium iodide (0.94 g, 6.2 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (8 mL) was added. The tube was sealed, placed in an oil bath at 110° C., and stirred rapidly for 24 hours. Upon completion, the reaction mixture was cooled and quenched via the addition of 20 mL of a 30% aqueous ammonia solution, poured into 80 mL of water, and extracted three times with 150mL dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 8.99 (d, 1H), 8.43 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H). LRMS (APCI) calc'd for (C14H8ClINO) [M+H]+, 367.9; found 367.9.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:27][N:15]3[N:14]=2)[CH:8]=1)(=O)=O.[CH3:32][S:33]([O-:35])=[O:34].[Na+].O>CN1CCCC1=O>[CH3:31][N:29]([CH3:30])[CH2:28][C:26]1[CH:25]=[C:16]2[N:15]([CH:27]=1)[N:14]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][S:33]([CH3:32])(=[O:35])=[O:34])[CH:8]=1)[N:18]=[C:17]2[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CS(C)(=O)=O)c3)nn2c1
Yield: 27.9 %

Procedure:
Compound 19 (45 mg, 0.1 mmol) and sodium methylsulfinate (41 mg, 0.4 mmol) were dissolved in 2 mL N-methylpyrrolidone. The mixture was under microwave irradiation for 30 minutes at 120° C. with the power of 100 watts. After completion of the reaction, the reaction mixture was poured into water, extracted for three times with ethyl acetate, and extracted for three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to a small volume. The crude product was purified by a preparative plate (dichloromethane:methanol=6:1) to obtain 12 mg of white solid (28.0%). m.p. 143-144° C. 1H NMR (300 MHz, CDCl3): δ 8.32 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 2H), 6.78 (d, J=1.2 Hz, 1H), 4.34 (s, 2H), 4.11 (t, J=4.4 Hz, 4H), 3.88 (t, J=4.4 Hz, 4H), 3.66 (s, 2H), 2.78 (s, 3H), 2.36 (s, 6H). MS (EI) m/e (%): 429 (M+, 12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([OH:18])([C@H:15]([OH:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:26][S:27]([O:17][C@H:15]([CH3:16])[C@:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:18])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=[O:29])=[O:28]
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2R,3R)-2-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (12.4 g) and triethylamine (7.6 ml) in ethyl acetate (200 ml) was added dropwise methanesulfonyl chloride (6.25 g) under ice-cooling. After stirring for 45 minutes at room temperature, the reaction mixture was washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(4-chlorophenyl)-2-hydroxy-1-(1H-1,2,4-triazol-1-yl)-3-butyl methanesulfonate.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[I-:32].[Cs+].COCCOC.N(OCCC(C)C)=O>CO.[Cu]I>[I:32][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: [I-]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4I)ncn3)cccc2s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol, Aldrich), 12 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol, Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture was added isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction was stirred for 1 h at room temperature, at 65° C. for 3 h, and then at room temperature for 18 h. The reaction mixture was diluted with MeOH (2 M in NH3) and concentrated. The residue was taken up in MeOH and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 0.4 to 1.3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid. Mp: 242-243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-])[CH:10]=1.C(Cl)(=O)C1C=CC=CC=1.C[Si]([C:30]#[N:31])(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:30]#[N:31])=[N:9][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)C)nc1C#N
Reaction time: 4 h
Yield: 73.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine-N-oxide (11.5 g, 51 mmol) was dissolved in CH2Cl2 (50 mL) to which benzoyl chloride (12 ml, 102 mmol) and (trimethylsilyl)formonitrile (14 ml, 102 mmol) were added. The mixture was stirred under N2 4 h, quenched with saturated NaHCO3 (150 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×50 mL), dried (MgSO4), and evaporated to give the crude product as a brown oil, which was purified by ISCO (330 g SiO2, 0-40% EtOAc/Hexane) to give 3-(methoxymethoxy)-6-neopentylpicolinonitrile (8.8 g, 74% yield) as a clear oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#N.S(=O)(=O)(O)[OH:35].[OH2:39]>>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:35])=[O:39]
Reactant: N#CCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: O=S(=O)(O)O
Reactant: O
Product: O=C(O)CCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 26 %

Procedure:
A mixture of 1-(8-cyanooctyl)-2,4,5-triphenyl-imidazole (0.8 g), concentrated sulphuric acid (10 ml) and water (10 ml) was stirred at reflux for 4 h. Water (50 ml) was added to the cooled mixture and the mixture was extracted with ethyl acetate (2×25 ml). The organic extracts were combined, washed with water (25 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol/water gave 1-(8-carboxyoctyl)-2,4,5-triphenylimidazole (0.22 g, 26%) as a cream solid, m.p. 149°-150° C.; Found C: 79.32; H, 7.17; N, 5.95%; C30H32N2 requires: C, 79.61; H, 7.13; N, 6.19%.
Reaction SMILES: [S:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].CC([O-])(C)C.[K+].O>CN(C=O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C:5](=[O:7])[CH2:6][S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]1=2
Reactant: Fc1ccccc1CBr
Reactant: O=C1CSc2ccccc2N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSc2ccccc2N1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g, 6.1 mmole) and 1-(bromomethyl)-2-fluorobenzene (0.76 mL, 1.05 equiv) in DMF (10 mL) was added t-BuOK (0.75 g) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and the resulted solid was filtrated, rinsed with water, and dried under vacuum to provide 4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1.51 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:26]
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 68.6 %

Procedure:
2-[2-(N,N-Dimethylamino)pyrimidine-4-yl]-6-(3-fluoropropoxy)benzothiophene (1-39, 50 mg, 70%) was prepared in the same manner as in Example 36 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoro propoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 0.17 mL, 0.34 mmol).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH:18]([CH3:20])[CH3:19].[Li]CCCC.ClN1C(=O)CCC1=O>COCCOC.CO>[CH:18]([O:17][C:3]1[C:4]2[S:8][C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=2[CH:15]=[CH:16][CH:2]=1)([CH3:20])[CH3:19]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(OC(C)C)c2s1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CO
Product: CCNC(=O)Nc1nc2cccc(OC(C)C)c2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
A solution of 1-(6-bromo-7-isopropoxy-2-benzothiazolyl)-3-ethylurea (0.036 g, 0.10 mmol) in 0.5 mL DME was cooled down to about −78° C., and was treated with a solution of 1.6 M n-BuLi in hexanes (0.16 mL, 0.26 mmol, 2.6 eq). It was stirred at the temperature for about 20 min, then a solution of N-chlorosuccinimide (NCS) (0.015 g, 0.11 mmol, 1.1 eq) in 0.5 mL DME was added. It was warmed up to about 0° C. for about 0.5 hour. It was taken up in MeOH and purified by HPLC to give 0.007 g (25%) of the title compound. LC/MS 279.9 (M+1); LC retention time 3.10 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:39]([O:46][C:47](=[O:51])[C@@H:48](O)[CH3:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][C@@H:48]([C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:51])[CH3:49])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 341 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 15 ml of THF, 744 mg of Triphenyl-phosphane and 494 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:14][CH:15]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(-n2cc(Oc3ccc(N)cc3)cn2)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(-n2cc(Oc3ccc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3)cn2)cc1
Temperature: 27.5 °C

Procedure:
4-(1-p-Tolyl-1H-pyrazol-4-yloxy)-phenylamine (100 mg, 0754 mmol), 2,4 Dichloro-benzenesulfonyl chloride (92 mg, 0.754 mmol) was taken in chloroform and 0.2 ml of pyridine was added and the reaction mixture was stirred at 20-35° C. for 3 and half an hours. Chloroform was removed under vacuum and the product was purified though column chromatography using petroleum ether and ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21](OCC)(=[O:24])[C:22]#[CH:23]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:23]=[CH:22][C:21](=[O:24])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Br:15])[C:5]=2[CH:16]=1
Reactant: C#CC(=O)OCC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Br)=NC1
Solvent: CCO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Br)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-chloro-5-(o-bromophenyl)-3H-1,4-benzodiazepine, ethyl propiolate, and ethanol were refluxed. The mixture was chromatographed to give 9-chloro-7-(o-bromophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([NH2:25])=[S:24]>>[BrH:1].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[S:24][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:25]=1
Reactant: NC(=S)Nc1ccccc1Br
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccccc3Br)n2)c(C)s1
Yield: 65.6 %

Procedure:
Methyl 4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methyfthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-bromophenyl thiourea (44 mg) as described in Example 154, step (a) to give 63.1 mg (64% yield) of methyl 4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.65 (s, 3H), 3.82 (s, 3H), 7.00 (m, 1H), 7.33 (s, 1H), 7.40 (m, 1H), 7.64 (dd, 1H, J=1.4, 7.9 Hz), 8.04, 8.11 (s, 1H rotomer), 8.27, 8.37 (dd, 1H 9.60, 9.80 (bs, 1H rotomer, J=1.5, 8.2 Hz), Mass Spectrum (ESI) m/z calcd. for C16H13BrN2O2S3, 441.39 (M+H), found 441.1, 443.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[Na+]>>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(C)cc1
Yield: 93 %

Procedure:
According to the general procedure B, 4-bromotoluene (94 mg, 0.55 mmol) reacted with N,N-di-n-butylamine (65 mg, 0.50 mmol) using 1 mol % of catalyst and sodium tert-butoxide (58 mg, 0.60 mmol) at 40° C. for 24 h to give the title compound (102 mg, 93%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.07 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.4 Hz), 3.28 (t, 4H, J=7.2 and 7.8 Hz), 2.30 (s, 3H), 1.60 (m, 4H), 1.40 (m, 4H), 1.00 (t, 6H, J=7.5 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.17, 129.67, 124.34, 112.19, 50.99, 29.41, 20.38, 20.12, 14.01. GC/MS(EI): m/z 219 (M+), 176, 134.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22][CH2:23]Cl)[CH3:20]>>[ClH:16].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH2:22][CH3:23]
Reactant: CN(C)CCCCl
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 135.4 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and dimethylaminopropyl chloride hydrochloride (4.74 g) were treated to obtain 4.74 g of 1-dimethylaminopropyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 158°-160° C).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:23]([O-])=O)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.ClCCl.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([NH2:23])=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Zinc (1.34 g, 20.5 mmol) was added slowly to a solution of 3-(benzyloxy)-5-(2-chlorophenoxy)-2-nitropyridine (0.730 g, 2.05 mmol) in acetic acid (20 mL) in a water bath. The reaction mixture was stirred 2 hours, then diluted with dichloromethane (100 mL) and filtered through Celite. The pad was washed several times with dichloromethane, and the combined filtrates were concentrated. The residue was partitioned between ethyl acetate and 2N NaOH, and the organic layer was washed with brine, dried, and concentrated to afford 3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-amine (0.66 g, 98.7% yield) as a light yellow oil. 1H NMR (CDCl3) δ 4.85 (bs, 2H), 5.03 (s, 2H), 6.79-6.83 (m, 2H), 7.02 (t, 1H), 7.14 (t, 1H), 7.37-7.47 (m, 7H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:13][N:14]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C=NCCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCCc3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
188 μL (1.2 mmol, 1.5 eq) 3-phenylpropyl isocyanate are added to a solution of 230 mg (0.81 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c) in 10 mL of an 8/2 dichloromethane/triethylamine mixture. The reaction medium is stirred at 40° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 348 mg of ethyl 3-{3′-[1-methyl-3-(3-phenylpropyl)ureido]biphenyl-4-yl}propanoate are obtained in solid form. Yield=96%
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([O:17]CC)=[O:16])[O:11][B:10]([OH:20])[C:9]=2[CH:8]=[C:7]([O:21][C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH:6]=1)#N.[OH-:28].[Li+].Cl.[CH3:31][CH2:32][OH:33]>O>[CH2:32]([O:33][C:1](=[O:28])[CH2:3][O:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][B:10]([OH:20])[C:9]=2[CH:8]=[C:7]([O:21][C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH:6]=1)[CH3:31]
Reactant: [OH-]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCC#N)c21
Reactant: CCO
Agent: Cl
Agent: [Li+]
Solvent: O
Product: CCOC(=O)COc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of ethyl 2-(4-(cyanomethoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.271 mmol) in EtOH (4 mL) was added an aqueous solution of lithium hydroxide (21.9 mg, 0.54 mmol) in water (1 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1N HCl to pH=3. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (30 mg. Yield: 26%). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.31 (s, 1H), 8.55 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.23 (t, J=1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 7.00 (s, 1H), 5.51 (m, 1H), 4.48 (m, 2H), 4.16 (m, 2H), 3.37 (d, J=2.0 Hz, 1H), 2.21 (m, 1H), 1.16 (m, 3H). MS (ESI) m/z=389 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:17]([OH:18])[CH2:16][CH:15](C)[C:14]1=O.[C:21]([O:25][C:26]([NH:28][C:29](=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])SC)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[C:47](OCC)(=[O:49])C>CN(C)C=O>[C:21]([O:25][C:26]([NH:28][C:29]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:14]([CH2:47][OH:49])[CH2:15][CH2:16][C:17]1=[O:18])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1ccc(N2C(=O)C(C)CC2O)c(N)c1
Reactant: CCOC(C)=O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2C(=O)CCC2CO)c(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
The above amine (0.315 g, 1.13 mmol) was dissolved in dry dimethylformamide (12 mL), cooled to 0° C. with an ice bath and then treated with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (Aldrich, 0.493 g, 1.70 mmol), triethylamine (0.358 g, 3.50 mmol), and mercuric chloride (0.369 g, 1.36 mmol). The ice bath was removed and the reaction mixture was stirred under nitrogen at room temperature for 20 h. To the tan reaction mixture was added ethyl acetate (95 mL), and the mixture filtered through a bed of Celite®. The yellow filtrate was washed with water (50 mL), saturated sodium chloride (50 mL), and water (50 mL). The combined aqeuous layers were extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude yellow oil was purified by flash chromatography using 80% ethyl acetate/hexane to give 0.360 g (61%) of 1-{2-{[(tert-butoxycarbonylamino)(tert-butoxycarbonylimino)-methyl]amino}-4-ethoxycarbonylphenyl}-5-hydroxymethylpyrrolidin-2-one as a foamy, yellow solid, mp 104-110° C.