Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S([Cl:28])(=O)=O)=CC=1>O1CCCC1>[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([Cl:28])[C:13]1=[O:18])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C1CCCC(Cl)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
N-butyl lithium is added dropwise to a solution, cooled to 0° C., of diisopropylamine (5.5 mmol) in dry tetrahydrofuran. After the addition is complete the mixture is cooled to −78° C., and a solution of 2-tert-butylcyclohexanone (5 mmol) in dry tetrahydrofuran (50 ml) is introduced, followed by the addition of p-toluenesulphonyl chloride (5 mmol), also dissolved in dry tetrahydrofuran (50 ml). The reaction mixture is heated to room temperature and after stirring for 30 mins over silica gel filtered with ether as eluant. After concentration by evaporation in a vacuum 2-tert-butyl-6-chlorcyclohexanone (760 mg) is obtained in a yield of 81% (Tet. Lett. 1999, 40(12), 2231-2234).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].O>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1C=CC=CC=1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:14])[CH2:11][O:12][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:24]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(CO)c1ccc(OC(F)F)cc1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Yield: 81 %

Procedure:
2.0 g of 2-(4-difluoromethoxyphenyl)-2-methylpropyl alcohol, 2.0 g of m-phenoxybenzyl chloride, 20 g of 50% NaOH and 0.3 g of triethylbenzyl ammonium bromide were stirred at 50° C. for 2 hours. Then, H2O and benzene were added to the reaction mixture, and the mixture was sufficiently shaken and the benzene layer was separated, washed with water, dried over Na2SO4, and evaporated under reduced pressure, and the obtained crude ether was purified by column chromatography on 130 g of silica gel (2:3 mixed solvent of toluene and hexane was used as eluent) to give 3.0 g of the desired ether (the yield was 81% of the theoretical yield).
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35]NCC1>>[O:38]=[S:31]1(=[O:39])[CH2:37][CH2:36][CH2:35][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: O=S1(=O)CCCNCC1
Product: O=S1(=O)CCCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 275 is synthesized from Intermediate C and [1,4]thiazepane 1,1-dioxide according to General Method H. (LC/MS method 16: ES+ m/z 375.4 [M+H]+, Rt=2.51 min)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[NH2:20][C@@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH2:14][NH:20][C@H:21]([CH:22]([CH3:24])[CH3:23])[CH2:25][OH:26])[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of Example 267A (0.500 g, 1.86 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.20 mL, 1.9 mmol) and acetic acid (0.40 mL, 7.4 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1M NaOH. The organic extract was concentrated and purified by chromatography to provide 390 mg (59%) of the title compound. MS (DCI+) m/z 270 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J=6.8, 2.0 Hz, 1H), 8.24-8.15 (m, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.34-7.25 (m, 2H), 4.04 (q, J=14.5 Hz, 2H), 3.70 (dd, J=10.9, 4.0 Hz, 1H), 3.49 (dd, J=10.8, 6.9 Hz, 1H), 2.53 (td, J=6.7, 4.1 Hz, 1H), 1.97-1.85 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([N:15]=[C:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[C:18]1([NH:17][C:16]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(N=C(NNc2ccccc2)Nc2ccccc2)cc1
Yield: 60.5 %

Procedure:
To 300 ml of benzene was added 10 g of phenylhydrazine and the mixture was stirred under ice-cooling. To the solution thus formed was added dropwise 17 g of diphenylcarbodiimide and the mixture was stirred for 5 hours as it was to precipitate crystals, which were recovered by suction filtration to provide 16 g of 1,2-diphenyl-3-anilinoguanidine. Then, 5.8 g of the compound thus obtained and 3.4 g of benzoyl chloride were heat refluxed in 100 ml of toluene for 6 hours; after the reaction was over, toluene was distilled off under reduced pressure, and the oily material thus obtained was dissolved in 80 ml of ethanol. After adding 10 ml of aqueous ammonia to the solution, water was gradually added to the mixture, whereby Compound (1) was obtained as light yellow crystals. The yield for the product was 62.1% and the melting point was 226° to 227.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[Cl:11][CH2:12][C:13](Cl)=[O:14]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[CH2:12][Cl:11]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 9.42 g. (0.1 mole) of 2-aminopyridine in 50 ml. of methylene chloride was added dropwise 4.0 ml. (0.05 mole) of chloroacetyl chloride in 20 ml. of the same solvent, keeping the reaction temperature at -20° to -10° C. for one hour. After stirring at room temperature for 10 hours, 50 ml. of water was added and the organic layer separated. The organic solution was washed with water and a brine solution and was dried over magnesium sulfate. Removal of the solvent in vacuo gave 6.64 g. (78%), m.p. 114°-117° C., of the desired product.
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:33])[C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cc1C
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2c[nH]c(=O)c(C)c2)c1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (44 mg, 0.09 mmol) in CH3CN (2.0 mL) was added TMSI (27 μL, 0.19 mmol) drop wise. The reaction was stirred at 55° C. for 2 hours and 30 minutes. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (37 mg, 86%). ESI-MS m/z calc. 453.4. found 454.5 (M+1)+. Retention time 1.58 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10](C)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[O:20]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[CH:30]=[N+:31](C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:30]([NH2:31])[C:29]2[CH:34]=[CH:35][CH:36]=[C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:28]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1c(-c2ccc(F)c(Cl)c2)cc2ccccc21
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: NC(c1cccc(Oc2ccccc2)c1)c1c(-c2ccc(F)c(Cl)c2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(3-chloro-4-fluoro-phenyl)-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[OH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:2][C:3]2[N:4]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
A solution of tert-butyl 4-(4-chloromethylthiazol-2-yl)piperazine-1-carboxylate (820 mg, 2.58 mmol) and methyl 4-hydroxybenzoate (395 mg, 2.58 mmol) in DMF was treated with potassium carbonate (360 mg, 2.6 mmol). The mixture was stirred at 70° C. for approximately 12 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the or organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from a mixture of ethyl acetate/hexanes to provide tert-butyl 4-[4-(4-methoxycarbonyl-phenoxymethyl)thiazol-2-yl]piperazine-1-carboxylate (830 mg, 74% yield). HNMR (dmso-d6): HNMR (dmso-d6): 7.91 (2H, d), 7.13 (2H, d), 6.91 (1H, s), 5.00 (2H, s), 3.81 (3H, s), 3.41 (8H, m), 1.41 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: c1ccsc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 58 mL of o-chlorobenzoyl chloride and 24 mL of thiophene in 700 mL of carbon disulfide, cooled to 0° C. under a nitrogen atmosphere, was added 134 g of aluminum trichloride portionwise over a 20-minute period. A delayed exotherm was noted and the resulting deep red mixture was stirred for one hour at room temperature. Reaction mixture was poured into 4.0 kg of ice-water, extracted with methylene chloride and the organic layer washed three times with 1N NaOH followed by a final water wash. The organic layer was dried (MgSO4), filtered and concentrated to a dark oil. Distillation under vacuum provided 55 g of the subject compound as a light green viscous liquid, B.P. 160° C. at 1.6 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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(O)C.O>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=Cc1ccc(Br)cn1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc(F)c2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 5-bromopyridine-2-carbaldehyde, 1.96 g of 3-fluorophenylboronic acid, 11.2 g of K2CO3, 160 ml of toluene, 60 ml of water, 60 ml of ethanol and 0.93 mg of tetrakis(triphenylphosphine)palladium(0) is stirred at 100° C. under argon for 2 hours. The solvents are evaporated and the residue is dispersed in 100 ml of water, and the product is extracted with 2 portions of 30 ml of ethyl acetate. The organic phase is washed with 30 ml of sat. brine, dried over sodium sulfate and concentrated. The resulting residue is recrystallized from 28 ml of isopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[O-:25]Cl=O.[Na+]>C(O)(C)(C)C.O.CC(OC)(C)C>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]([OH:25])=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: COC(C)(C)C
Product: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (132 g, 0.519 mol) and 2-methyl-2-butene (364 g, 5.19 mol) in tert.-butanol (1500 mL), a solution of NaH2PO4 dihydrate (249 g, 2.08 mol) in water (1500 mL) is added. To this mixture, NaClO2 (187.8 g, 2.08 mol) is added in portions. The temperature of the reaction mixture is kept below 30° C., and evolution of gas is observed. Upon completion of the addition, the orange bi-phasic mixture is stirred well for 3 h before it is diluted with TBME (1500 mL). The org. layer is separated and washed with 20% aq. NaHS solution (1500 mL) and water (500 mL). The org. phase is then extracted three times with 0.5 N aq. NaOH (1000 mL), the aq. phase is acidified with 25% aq. HCl (500 mL) and extracted twice with TBME (1000 mL). These org. extracts are combined and evaporated to dryness to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.31 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 4.86 (s, 2H), 7.34-7.53 (m, 5H), 7.68 (s, 2H), 12.70 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:23][CH2:22][C:21]2[CH:25]=[CH:4][CH:3]=[CH:2][CH:13]=2)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Reactant: C1CCOC1
Product: O=C(CCc1ccccc1)c1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (10 g) in THF (80 mL) was slowly added phenethyl-MgBr (91.2 mL, 1 M in THF), and the mixture stirred at 0° C. for 30 min, followed by 1 h at RT. The reaction mixture was then quenched with NH4Cl (sat'd aq), extracted with EtOAc, and chromatographed (0-40% EtOAc/DCM) to provide 1-(4-fluoro-2-phenylamino-phenyl)-3-phenyl-propan-1-one (11.34 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17].FC1C=CC(C2N=NC(NNC([O-])=O)=CC=2)=CC=1>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCOC(=O)NN
Agent: O=C([O-])NNc1ccc(-c2ccc(F)cc2)nn1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(F)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-fluorophenyl)-3-chloropyridazine, 5.0 g. of ethyl carbazate and 50 ml. of n-butanol is refluxed for 2 hours. The solvent is removed and the residue washed with water and recrystallized from ethanol to give 1.75 g. of 3-[6-(p-fluorophenyl)-3-pyridazinyl]carbazate as crystals, m.p. 173°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.Cl[C:15]1C(C)=C2C(=CC=1)NC(=O)C=C2.C([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH3:15])[C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1cc2[nH]c(=O)ccc2cc1Cl
Reactant: Cc1c(Cl)ccc2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc(=O)n2C)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-7-methylquinolin-2(1H)-one, 6-chloro-5-methylquinolin-2(1H)-one, Cs2CO3, and iodomethane in DMF was heated in a microwave reactor at 100° C. for 30 min. The mixture was diluted with dichloromethane, washed with water and dried over sodium sulfate. After removing the solvent the crude product (600 mg) was used in the next step without purification. MS (ESI) m/z: Calculated for C11H10ClNO: 207.1. found: 208 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCN(CCC)c1ccc(S(=O)(=O)N2CCCCC2=O)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
5 g of product obtained in Stage A are heated to reflux for 2 hours with 5 g of sodium acetate in 50 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in 50 cm3 of water and dried and 4.4 g of expected product are obtained. M.p. 105°-108° C. after chromatography on silica (eluent: ethyl acetate/n-hexane, 1:1). After crystallization in isopropanol, 3.2 g of pure product are obtained. M.p. 110°-111° C.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:33])[CH3:32]>>[C:31]([NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:13])=[O:12])=[CH:22][CH:21]=1)(=[O:33])[CH3:32]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: CC(=O)Nc1ccccc1N
Product: CC(=O)Nc1ccccc1NC(=O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(2-aminophenyl)acetamide (36 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(2-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as an off-white solid. Yield: 26 mg (24%). 1H-NMR: 10.01 (s, 1H), 9.60 (s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.24-7.16 (m, 3H), 7.11-7.08 (m, 2H), 3.85-3.80 (m, 2H), 2.47 (d, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.69-1.60 (m, 2H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (40 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:19][CH2:20]Br.CCOC(C)=O>O.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][C:10]([C:13]2([C:14]#[N:15])[CH2:20][CH2:19]2)=[CH:9][CH:8]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 65 °C
Yield: 99.4 %

Procedure:
4-phenyl-phenylacetonitrile (VWR scientific, 55.7 g, 289 mmol) was added to a solution of KOH (161.6 g, 2890 mmol) in water (170 mL) and toluene (550 mL) at room temperature. Tetrabutyl ammonium bromide (9.2 g, 29 mmol) followed by 1,2 dibromoethane (64.9 g, 347 mmol) were added and the solution was heated to 65° C. overnight. Reaction complete by TLC (10% EtOAc/hex). The organic layer was extracted 2 times with dilute hydrochloric acid, dried and evaporated to yield 63 g of 1-(biphenyl-4-yl)cyclopropanecarbonitrile.
Reaction SMILES: S(C)C.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](OC)=[O:13])=[CH:7][CH:6]=1.C1(O)C=CC=CC=1.O>O1CCCC1>[OH:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CSC
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: OCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A solution of BH3.(CH3)2S (500 mL, 2M in tetrahydrofuran) was added dropwise to a solution of methyl 4-hydroxyphenylacetate (116 g, 0.70 mole) in 300 mL dry tetrahydrofuran. This solution was heated at reflux for 2 hr and stirred at room temperature for 12 hr. TLC indicated the presence of phenol and another 30 mL of BH3.(CH3)2S solution was added. This solution was refluxed for 1 hr, cooled, and then hydrolyzed by dropwise addition of water. The mixture was concentrated in vacuo and the residue triturated with ethyl ether. The ethyl ether portion was dried (MgSO4) and concentrated in vacuo to give 90 g (93%) of 4-(2-hydroxyethyl)phenol, m.p. 84°-86°.