Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[C:4](=[N:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].Cl.CO.C(=O)([O-])O.[Na+]>CO.O1CCCC1.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.O>[CH2:1]1[CH:10]2[CH:4]([NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2N=C2CCCC12
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2NC2CCCC12
Temperature: 0 °C
Yield: 100187.5 %

Procedure:
2,3,9,10a-Tetrahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one (38.3 g, 0.19 mmol) and bromocresol green (30 mg) were suspended in a mixture of methanol (200 mL) and tetrahydrofuran (200 mL), which was cooled to 0° C. To the suspension was added, at the same temperature, sodium cyanoborohydride (13.2 g, 0.21 mmol), to which was then added dropwise gradually a 10% hydrogen chloride-methanol solution until no more color change of the reaction system was observed. To the reaction mixture was added water (500 mL), which was made alkaline with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform three times. Organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure to give 38.5 g (yield 99%) of the titled compound. The sample for analytical use was prepared by recrystallization from ethanol as a cis-trans mixture (1:1). m.p. 191°-212° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:10]=[C:11]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:12]3[N:18]=[C:17]([CH2:19][CH:20]4[CH2:23][N:22](C(OCCCC)=O)[CH2:21]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[NH:22]1[CH2:23][CH:20]([CH2:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:9]([N:8]4[C:7]5[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=5[N:5]=[C:4]4[CH:1]([CH3:3])[CH3:2])[N:10]=[C:11]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:12]=3[N:18]=2)[CH2:21]1
Reactant: CCCCOC(=O)N1CC(Cc2ccc3nc(-n4c(C(C)C)nc5ccccc54)nc(N4CCOCC4)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)ccc2n1

Procedure:
tent-Butyl 3-((2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidine-1-carboxylate (0.2 g) was deprotected with 4N HCl in dioxane (0.9 mL) at room temperature over 1 hour. The reaction was concentrated to dryness to afford crude 4-(6-(azetidin-3-ylmethyl)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine which was reacted with methyl 2-bromo-2-methylpropanoate (3 eq) and potassium carbonate (6 eq) at 75° C. for 3 hours. The reaction mixture loaded onto a Biotage isolute cartridge, eluted with 2M NH3 in MeOH then purified by reverse phase HPLC to yield 17.9 mg of 117. MS (Q1) 544.3 (M)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:13]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A suspension of 25.0 g (147.8 mmol) 1-methylsulfanyl-4-nitro-benzene and 0.69 g (4.2 mmol) iron(III) chloride (anhydrous) in 120 ml acetonitrile is treated with 36.0 g (158.1 mmol) periodic acid and stirred at room temperature. At the start of heat evolution, the mixture is transiently cooled with an ice-bath, so that the temperature does not rise above 30° C. After the heat evolution has subsided, the mixture is stirred at room temperature for a further 10 mins. The mixture is poured into a solution of 150 g sodium thiosulphate in 1000 ml ice-water and then extracted with DCM. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated. The remaining residue is recrystallised from toluene. 23.6 g (128.0 mmol, corresponding to 86% of theor.) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(CC2(c3cccc(OC)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-methoxybenzyl bromide (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-methoxy-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as orange plates. (Yield 0.19 g, 80.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]>CN(C)C=O.[C].[Pd]>[NH2:11][C:9]1[C:8]([OH:14])=[C:7]2[C:3]([CH2:4][CH2:5][C:6]2=[O:15])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(N)c(O)c2c1CCC2=O
Yield: 77.8 %

Procedure:
Into a solution of 26.0 g of 4-methyl-6-nitro-7-hydroxy-1-indanone in 50 ml of dimethylformamide was added 2.6 g of 10% palladium carbon, then the mixture was subjected to a catalytic hydrogenation under an atmospheric pressure at 0° C. to a room temperature. The catalyst was removed by filtration and the solvent was removed by evaporation to obtain 17.3 g of 6-amino-4-methyl-7-hydroxy-1-indanone.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[N:22]1[C:30](N)=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][NH:26]2)(=[O:3])[CH3:2]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncnc3[nH]cnc23)c1=O
Yield: 1.3 %

Procedure:
To a stirred solution of 250 mg (0.870 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (12 mL), adenine (235 mg, 1.740 mmol) was added. The resulting mixture was stirred and refluxed during two days. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 95:5) and preparative HPLC/MS to yield the title compound (4.4 mg, 1.4% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:23])[C:14](=[O:22])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][CH2:8][S:7][C:6]=2[CH:24]=1.I.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](SC)=[NH:32]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:23][N:13]([CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:24]=[C:2]([NH:1][C:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)=[NH:32])[CH:3]=[CH:4][C:5]1=2)[C:14](=[O:22])[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(CCN1CCSc2cc(N)ccc21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a stirred solution of phenyl 2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (80 mg, 0.233 mmol) in ethanol (5 mL) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (133 mg, 0.466 mmol). The mixture was then stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and then extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, yielding the desired product (72 mg, 68%). 1H NMR (DMSO-d6) δ 7.74-7.69 (m, 1H), 7.58-7.56 (m, 1H), 7.42-7.34 (m, 2H), 7.25-7.17 (m, 1H), 7.14-7.05 (m, 3H), 6.83-6.80 (m, 1H), 6.53-6.44 (m, 2H), 6.36 (brs, 2H), 3.63-3.55 (m, 4H), 3.49-3.45 (m, 2H), 3.11, 2.98 (2s, 3H), 3.06-3.01 (m, 2H); MS-EI: (m/z, %) 452 (M+, 97), 288 (100).
Reaction SMILES: C([O:5][C:6]([C:8]([NH2:21])([C:12]1[C:20]2[CH2:19][S:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)C(O)=O)=[O:7])(C)(C)C.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[NH2:21][CH:8]([C:12]1[C:20]2[CH2:19][S:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C(N)(C(=O)O)c1cccc2c1CSC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: NC(C(=O)O)c1cccc2c1CSC2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
α-(tert-Butoxycarbonyl)amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid (0.05 m) is added to chloroform and the mixture cooled to about 0° C. Over a period of about 2.5 hours, 0.12 moles of m-chloroperbenzoic acid dissolved in chloroform is added to the mixture maintained at 0° C. When the addition of the m-chloroperbenzoic acid is complete, the temperature of the mixture is raised to about 20° to 25° C. from about 0° C. and stirred for about 18 hours, chilled to 0° C. to precipitate the m-chlorobenzoic acid which is filtered from the solution. Removal of a portion of the chloroform results in the precipitation of Amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid, 2-oxide
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:26])[C:23]=3[F:25])[C:18]([S:27][C:28]3[C:29]([F:39])=[C:30]([CH:36]=[CH:37][CH:38]=3)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:17]2[CH:40]2[CH2:42][CH2:41]2)[CH:13]=[N:12]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:26])[C:23]=3[F:25])[C:18]([S:27][C:28]3[C:29]([F:39])=[C:30]([CH:36]=[CH:37][CH:38]=3)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:17]2[CH:40]2[CH2:42][CH2:41]2)[CH:13]=[N:12]1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCNC(=O)OC(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCN)c3)c3c(F)c(Cl)ccc23)c1F
Yield: 78.6 %

Procedure:
A solution of compound 3 (200 mg, 0.32 mmol) in 4.0 M HCl in 1,4-dioxane (5 mL) under inert atmosphere was stirred at 0° C.-RT for 2 h. The volatiles were removed under reduced pressure. The residue was diluted with water (5 mL), basified with aq. NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 4 (130 mg, 81%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.82 (s, 1H), 7.60 (t, J=6.8 Hz, 1H), 7.22-7.11 (m, 3H), 6.84 (t, J=6.8 Hz, 1H), 4.33 (q, 2H), 4.17 (t, J=6.0 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H), 1.84-1.80 (m, 3H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.84-0.82 (m, 2H); MS: m/z 517.6 (M+H+).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]1)[CH2:10][CH2:9]2.[B].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]1)[CH2:10][CH2:9]2
Reactant: COc1cccc2c1CC(N1CCN(c3ncccn3)CC1)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [B]
Solvent: ClCCl
Product: Oc1cccc2c1CC(N1CCN(c3ncccn3)CC1)CC2
Temperature: -78 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
2-(4-(1,2,3,4-Tetrahydro-8-methoxy-2-naphthalenyl)-1-piperazinyl]-pyrimidine hydrochloride (1.62 g, 5.0 mmole) was dissolved in 185 ml of methylene chloride and cooled to -78° C. in a dry ice/acetone bath. A mixture of 15 ml of 1 M boron triboromide and 15 ml of methylene chloride was added. The reaction mixture was allowed to come to room temperature and it was then stirred for three days. The reaction was then poured into a saturated NaHCO3 solution and the product extracted with 600 ml of chloroform. This solution was dried over MgSO4, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel with 5% methanol/chloroform and the crude title compound thus obtained was crystallized from isopropanol with addition of 4 N isopropanolic HCl and recrystallized from acetone to give 1.1 g of the title compound as the hydrochloride, monohydrate, m.p.>300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Mg].[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A three neck flask (2 L) under an atmosphere of nitrogen with Mg turnings (9.8 g) was stirred for 15 min and tetrahydrofuran (90 mL) was added and stirring continued for an additional 15 min. 1-Bromo-2,4,5-trifluorobenzene (85 g) was dissolved in tetrahydrofuran (340 mL). A portion of this solution (75 mL) was added to the stirred magnesium turnings and then heated to 50° C. The rest of the solution was added and stirring continued at the same temperature for an additional 1 h. The reaction mixture was cooled to 40° C., a solution of 1,4-dioxaspiro[4.5]decan-8-one (57.3 g) in tetrahydrofuran (275 mL) was added, and stirring continued for 10 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (970 mL) and extracted with toluene (700 mL). The organic layer was washed with water (3×700 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a red-orange oil which was used in the next step without further purification.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(CC)(C)C.Br[C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=[C:44]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:66](=[N:79][NH2:80])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:66](=[N:79][NH:80][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=[C:44]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=1)([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Solvent: COCCOC
Product: CC(C)(C)c1cc(NN=C(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Palladium acetate (8.4 mg, 0.037 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (X-PHOS) (35.6 mg, 0.074 mmol) were dissolved in tert-amyl alcohol (10 μl, 0.093 mmol) and anhydrous ethylene glycol dimethyl ether (0.25 ml). The mixture was heated and stirred at 60° C. for five minutes under a nitrogen atmosphere to prepare a catalyst. In a separate reaction container under a nitrogen atmosphere, 1-bromo-3,5-di-t-butyl benzene (501 mg, 1.9 mmol), lithium bis(trimethylsilyl) amide (475 mg, 2.8 mmol), and benzophenone hydrazone (401 mg, 2.0 mmol) were dissolved in anhydrous ethylene glycol dimethyl ether (2.5 ml). Then, a solution containing the prepared catalyst was added thereto. After deaeration, this was heated and stirred at 90° C. for two hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/5). Thus, N-benzhydrylidene-N′-(3,5-di-tert-butyl-phenyl)-hydrazine was obtained as a yellow amorphous material (699 mg, 97.7%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 1 h

Procedure:
20 mg of Pd/C (10%) is prehydrogenated for 20 minutes in 2 ml of absolute methanol. To it are added 200 mg (0.53 mmole) of the compound from Example 1 in a mixture of 2 ml of absolute methanol and 0.8 ml of ethyl acetate, and the mixture is hydrogenated for 1 hour at 20° C. The catalyst is filtered off, and the solvent is evaporated under vacuum in a rotary evaporator. The residue is pure in TLC and crystallizes upon drying under high vacuum.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][C:10]=1[F:25])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH:16]2[CH2:18][CH:17]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[C:10]([F:25])[C:9]=1[OH:8]
Reactant: CCOC(=O)CC1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CC1c1cc(F)c(O)c(F)c1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 2-(2-(4-(benzyloxy)-3,5-difluorophenyl)cyclopropyl)acetate (505) (0.782 g, 2.25 mmol) in EtOAc/EtOH (5 mL/10 mL) was added 159 mg of 10% Pd/C, and the mixture was stirred under a hydrogen balloon overnight. After filtration through celite and washing with EtOH, the filtrate was concentrated in vacuo to afford 0.508 g of desired product (506) as a pale-yellow liquid. The product was sufficiently pure to be used directly in subsequent couplings. 1H NMR (400 MHz, CDCl3) δ: 6.67 (d, J=8.4 Hz, 2H), 4.96 (br, 1H), 4.23-4.05 (m, 2H), 2.50-2.26 (m, 2H), 1.70-1.66 (m, 1H), 1.33-1.19 (m, 4H), 0.97-0.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[NH:9][C:10](=O)[CH3:11])=[N:4][CH:5]=[CH:6][N:7]=1>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH3:11])=[N:9][C:8]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 80 °C

Procedure:
N-[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-acetamide (273.0 mg, 0.702 mmol) was dissolved in 20 mL of POCl3. The reaction was heated to 80° C. for 24 h. The excess POCl3 was removed in vacuo. The residue was worked up by basifying with cold 2.0 M NH3 in IPA followed by the addition of CH2Cl2 and water. The aqueous layer was washed with CH2Cl2 (2×). The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo to yield a light brown oil; 1H NMR (400 MHz, CDCl3) δ 2.77 (s, 3H), 7.41-7.59 (m, 4H), 7.70-7.72 (m, 1H), 7.88-7.93 (m, 3H), 8.19-8.28 (brm, 3H), 8.55 (brs, 1H); MS (ES+): 370.96 (M+1), 372.97 (M+3), 373.98 (M+4).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:12]Br.[OH-].[K+]>OS(O)(=O)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:12][C:10]1[CH:9]=[CH:8][C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][NH:1][C:2]=2[CH:11]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCCCN2
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Brc1ccc2c(c1)NCCCC2
Temperature: 20 °C
Yield: 74.5 %

Procedure:
To 2,3,4,5-tetrahydro-1H-benzo[b]azepine (410 mg, 2.78 mmol; from Preparation 41) in conc. H2SO4 (5 mL) was added Ag2 SO4 (438 mg, 1.41 mmol). The mixture was stirred until the silver sulfate had dissolved and then Br2(l) (145 μL, 2.80 mmol) was added at 0°-5° C. over 15 minutes. The mixture was stirred in the dark and allowed to warm to 20° C. After 4 hours the mixture was poured into ice/H2O (50 mL), the pH was adjusted to 12-14 by the careful addition of 6N KOH with cooling, and then filtered through a pad of Celite. The pad was washed with CH3CN, CHCl3, and Et2 O. The aqueous phase was extracted with EtOAc and the organic extracts and washes were combined, dried over MgSO4(s), filtered and concentrated in vacuo to afford 468 mg of a waxy yellow solid. The 6-bromo (48 mg) and 8-bromo isomers (492 mg; GC-MS: 226, 228 (M+)) were separated by flash chromatography on silica (10% EtOAc/hexanes) and/or recrystallization (Et2O/Hexanes).
Reaction SMILES: II.C(O)(=O)C.P(=O)(O)(O)O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=O)=[C:15]([Cl:28])[CH:14]=1>C(OCC)(=O)C.O>[Cl:28][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH2:19][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[NH2:12]
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: II
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cc2ccc(Cl)cc2)c(Cl)c1
Yield: 98.9 %

Procedure:
Iodine (1 g) and 50 mL of acetic acid were mixed together, 2.53 g of 50% phosphoric acid was added thereto, and the mixture was heated with stirring to reflux. Subsequently, a mixture composed of 3.2 g of (4-amino-2-chlorophenyl)-(4′-chlorophenyl)methanone and 15 mL of acetic acid were added dropwise to the mixed solution. This solution was heated under reflux for 134 hr, was then cooled and was poured into water. Ethyl acetate was added to the mixed solution followed by separation and washing with brine. The ethyl acetate layer was concentrated to give 3.0 g of 3-chloro-4-(4-chlorobenzyl)aniline (yield 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 211 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (350 mg) was obtained.