Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=O)[NH2:2].[C:36]([C:38]1C=C(S(Cl)(=O)=O)C=CC=1)#N>>[CH2:36]([O:32][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:1]#[N:2])[CH:5]=4)(=[O:11])=[O:12])[C:18]=3[CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:38]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NC(=O)c1cccc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C#N)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=500.0 (M+H+.), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-cyano-benzenesulfonyl chloride and yielded 4-{[4-(3-cyano-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8 at both the carboxylic acid ester and the cyano position.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: Cc1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: Cc1ccccc1-n1ccc2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH:9]([NH:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.[Cl-].[Mn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH:9]([NH:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCc1cccs1)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: [Mn+2]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: O=C(CCCc1cccs1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide (300 mg, 0.65 mmol) in methanol (30 ml) was added manganese (II) chloride (163 mg, 1.30 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added sodium borohydride (49 mg, 1.30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the obtained crude crystal was washed with a mixed solvent of hexane:ethyl acetate=10:1 to give the title compound ((1RS,2SR) form: (1RS,2RS) form=1:1, 204 mg, 68%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([CH2:16][O:17][CH2:18][CH3:19])[NH:13][C:12](=[O:20])[C:11]=1[N:21]=O.[CH:23]([CH:25]=O)=O>O>[CH2:18]([O:17][CH2:16][C:14]1[NH:13][C:12](=[O:20])[C:11]2[C:10](=[N:9][CH:23]=[CH:25][N:21]=2)[N:15]=1)[CH3:19]
Reactant: CCOCc1nc(N)c(N=O)c(=O)[nH]1
Reactant: O=CC=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOCc1nc2nccnc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.1 g (0.11 mole) of sodium dithionite in 88 ml of water is added dropwise to a suspension, maintained at 20° C., of 10.0 g (0.050 mole) of 6-amino-2-(ethoxymethyl)-5-nitroso-4(3H)-pyrimidinone in 50 ml of water. After being stirred for 30 minutes at room temperature, the reaction mixture, still maintained at 20° C., is treated with 47.9 g (0.33 mole) of a 40% aqueous solution of glyoxal. Stirring is continued for 20 hours at room temperature. The solution obtained is then extracted with dichloromethane. These organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from methanol in the presence of Norit. Yld: 6.5 g (63%), m.p. 168°-169° C. The product is identical to that obtained in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[H-].[Na+].[O:13]1[CH:15]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14]1>>[OH:13][CH:15]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14][O:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCc1cccnc1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCOCC(O)COCCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To 3-pyridinepropanol (41.9 g), 60% oily sodium hydride (0.74 g) was added, followed by stirring at room temperature for 15 minutes. Crude 1,2-epoxy-3-octadecyloxypropane (10 g), an intermediate in Reference Example 1, was then added, followed by stirring at room temperature for 67 hours. The excess portion of the 3-pyridinepropanol was distilled off under reduced pressure. After adding a small volume of water to the residue, extraction was conducted with a mixture of hexane and ethyl acetate (1:1, 300 ml). After the extract was washed with water and dried, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (carrier, 250 g; developing solvent, hexane:ethyl acetate:acetone=4:1:0→3:1:1) to yield the desired compound (5.79 g).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])([O-:3])=[O:2].[CH2:18]([O:21][CH2:22]Cl)[CH2:19][CH3:20]>C(Cl)Cl>[Cl:9][CH2:8][C:7]([N:6]([CH2:22][O:21][CH2:18][CH2:19][CH3:20])[C:5]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: O=C(CCl)Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCOCCl
Solvent: ClCCl
Product: CCCOCN(C(=O)CCl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Yield: 93 %

Procedure:
2.5 g. of 2',6'dinitro-2-chloroacetanilide, 3.0 ml. of chloromethyl n-propyl ether, 150 ml of methylene chloride and 1.1 gr. of phase transfer catalyst were charged to a round-bottom flask fitted with a mechanical stirrer. To the mixture was added 100 ml. of saturated NA2CO3 in one portion. The resulting mixture was stirred for three-quarter hour at which time GLC showed no starting material indicating the reaction was complete. The product, 2-chloro-2',6'-dinitro-N-(n-propoxymethyl)acetanilide was obtained as a yellow oil, (3.1 g., yield 93%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 2-nitrophenylacetic acid (300 g, 1.66 mol) and sulfuric acid (d=1.84 g/ml, 6 ml) in methanol (61) was heated under reflux for 21 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane (21). The dichloromethane solution was then washed with saturated aqueous sodium carbonate solution (600 ml), brine (500 ml), dried (MgSO4), filtered and then evaporated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]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>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[CH:25]=[CH:26]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Reactant: Cn1ccc2cc(B(O)O)ccc21
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (500 mg, 1.77 mmol) in dioxane (15.0 mL) and water (5.0 mL) were added K2CO3 (730 mg, 5.31 mmol) and N-methylindole-5-boronic acid (140 mg, 1.95 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (100 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude title compound. Crude product was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.C(OCC)(OCC)O[CH2:22][CH3:23].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)c1ccc2c(c1)CCc1ccccc1C2=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 93.9 %

Procedure:
[step 1] 5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (JP-B-2526005, 19.9 g, 79 mmol) and triethyl orthoformate (17.0 mL, 102 mmol) were dissolved in ethanol (130 mL), followed by adding concentrated sulfuric acid (1.68 mL, 32 mmol) and the mixture was stirred under reflux for 12 hr. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to give ethyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylate (20.8 g, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[C@@H:10]([CH3:22])[CH2:9]2)=[C:4]2[CH:23]=[N:24][CH:25]=[CH:26][C:3]=12.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.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>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])[C@@H:10]([CH3:22])[CH2:9]3)=[C:4]3[CH:23]=[N:24][CH:25]=[CH:26][C:3]=23)=[CH:31][CH:30]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
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+]
Product: C[C@H]1CN(c2nnc(-c3ccc(CO)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1

Procedure:
Using methods described in Example 1, and starting with (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7 (200 mg, 534 μmol), tetrakis(triphenylphosphine)palladium (31 mg, 27 μmol), 4-(hydroxymethyl)phenylboronic acid (122 mg, 800 μmol) and 2 M sodium carbonate (534 μl, 1067 μmol), (S)-(4-(1-(4-(hydroxymethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 9 was obtained. MS 446.2 (calc'd) 447.3 (M+H, found).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31].CO>O>[CH:33]([NH:32][C:30](=[O:31])[CH2:29][N:2]1[CH2:3][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH:13]=[C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)[N:11]=4)[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH2:5]1)([CH3:35])[CH3:34]
Reactant: CC(C)NC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N-isopropyl acetamide. The crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 0 to 70% MeOH in H2O+0.1% HCO2H) to give 200 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.28 Hz), 7.85 (1H, s), 7.63 (1H, s), 7.05 (1H, dd, J=8.32, 1.82 Hz), 6.94-6.92 (1H, m), 6.00-5.90 (1H, m), 4.49-4.40 (4H, m), 4.12-4.02 (1H, m), 3.88 (2H, t, J=7.51 Hz), 3.82-3.71 (1H, m), 3.41 (2H, t, J=7.23 Hz), 3.23 (2H, s), 1.56 (6H, d, J=6.63 Hz), 1.16 (6H, d, J=6.57 Hz). 1 Exchangeable proton not seen. LCMS: RT=6.8 min, M+H+=450
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].Cl>C(O)C.[Zn]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][C:37]([C@H:39]1[CH2:44][NH:43][CH2:42][CH2:41][NH:40]1)=[O:38]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:43]4[CH2:42][CH2:41][NH:40][C@@H:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:44]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC(=O)[C@H]1CNCCN1
Product: CNC(=O)[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
(2R)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)-piperazine-2-carboxylic acid methylamide following General Procedure C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:7]1)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C>[CH:18]1([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]([CH2:32][C:33]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[C:12](=[O:13])[N:6]([CH2:5][C:4]([OH:3])=[O:24])[N:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2NC1=O
Reactant: O=C(CCl)C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester (50 g, 151.7 mmol) in DMF (250 mL) was added potassium carbonate (325 mesh, 102 g, 738 mmol) and tetrabutylammonium iodide (46.0 g, 124.5 mmol). The resulting mixture was heated to about 50-55° C. and while at this temperature, 2-chloro-1-cyclopentylethanone (57.0 g, 373.5 mmol) was added drop-wise over a period of about 1 hr. The reaction mixture was then aged for 1 hr, cooled to ambient temperature and diluted with MTBE (50 mL). The inorganic solids were removed by filtration and rinsed with additional MTBE (50 mL). To the combined filtrates was added DMF (50 mL) and the resulting mixture was treated with 3N NaOH (150 mL), then stirred at −30° C. for about 1 hr. The reaction mixture was then again diluted with MTBE (100 mL) and the layers were separated. The aqueous layer was poured slowly under vigorous agitation, into another flask containing cold 2N HCl solution (400 mL) which was maintained at ˜5° C. Isopropyl acetate (300 mL) was added to the reaction mixture and the layers were separated. The organic layer was rinsed with water (300 mL) and then diluted with n-heptane (300 mL), at which point a solid was observed to precipitate. The precipitate was filtered and dried under vacuum to constant weight to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14](=O)[C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14](=[S:28])[C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:4][CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CCN(CC(=O)N2c3ccccc3NC(=O)c3cccnc32)CC1
Solvent: c1ccncc1
Product: CN1CCN(CC(=O)N2c3ccccc3NC(=S)c3cccnc32)CC1

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-[(4-methylpiperazino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-[(4-methylpiperazino)-acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][C:31]=1[CH:42]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:42][C:31]3[CH:32]=[C:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:34]=[CH:35][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(-c2ccccc2)ccc1F
Product: Fc1ccc(-c2ccccc2)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-fluoro-biphenyl-3-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 563.0.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[H-].[Na+].[CH2:13](Br)[CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16]>C1COCC1>[C:2]([CH:3]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[CH2:13][CH:14]=[C:15]([CH3:16])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])(=[O:1])[CH3:10]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Dimethyl 2-oxopropylphosphonate (560 μL, 4.0 mmol) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension, prewashed with hexane) (210 mg, 4.8 mmol) in anhydrous THF (15 mL) at 20° C. under an Argon atmosphere. The resulting slurry was stirred at 20° C. for 2 hours to allow for complete formation of the sodio derivative and then treated dropwise with farnesyl bromide (1.14 mL, 4.2 mmol). The cloudy yellow mixture was stirred at 20° C. for 2 hours and then quenched with saturated NH4Cl solution. The resulting mixture was washed with water, dried, filtered and evaporated to give the crude product which was purified by flash chromatography on a silica gel column. Elution of the column with hexane:ethyl acetate:methanol (40:10:1, v:v:v) gave the title compound as gum.