Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.ClCCCl.[CH3:38][C:39]([CH3:41])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@H:6]4[C@H:7]([O:8][C:9]([CH3:12])([CH3:11])[O:10]4)[C@@H:3]([CH2:2][NH:1][CH:39]([CH3:41])[CH3:38])[CH2:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 7((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7.50 g, 16.5 mmol) in 1,2-Dichloroethane (140 mL, 1800 mmol) was treated with Acetone (1.34 mL, 18.2 mmol;) and Acetic acid (0.94 mL, 16 mmol) dropwise followed by Sodium triacetoxyborohydride (4.20 g, 19.8 mmol) and the mixture was stirred at RT for 4 h. HPLC analysis indicated the reaction was complete. The reaction mixture was diluted with 200 mL CH2Cl2 and washed with 150 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a an oil that produced a stiff foam when placed under high vac. The crude material (9.3 g) was carried on directly to the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[CH:10][N:9]=1)(C)(C)C.Cl.CO>O1CCOCC1>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([CH2:14][N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CC[C@@H](O)C2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(CN2CC[C@@H](O)C2)cn1
Yield: 89.8 %

Procedure:
A mixture of [5-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]carbamic acid tert-butyl ester (Step 100.2) (210 mg, 0.72 mmol), a 4 N solution of HCl in dioxane (2 mL), and MeOH (2 mL) was stirred for 16 h at rt and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 89:10:1) to afford 125 mg of the title compound as a yellow oil. Title compound: ESI-MS: 194.1 [M+H]+; TLC: Rf=0.05 (DCM/MeOH, 9:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[O:35][CH:36]=[CH:37][N:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:44]>Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:39]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH:22]=1)[CH2:40][CH2:41][CH3:42]
Reactant: ClCCl
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[6-Butyl-5-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.13 mmol) in DCM, 2.0 mL of 4.0 M HCl in dioxane was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to get 3-butyl-4-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride salt (60 mg)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnn1)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (170 mg, 0.629 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (150 mg, 0.572 mmol) and diisopropylethylamine (0.199 ml, 1.14 mmol) in dimethylsulfoxide (2.0 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (127 mg, 58.0%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]3)[C:16]([C:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)(O)[CH3:19])=[N:17][C:4]=2[CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]3)[C:16]([C:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH2:19])=[N:17][C:4]=2[CH:3]=1
Reactant: CC(O)(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1RS)-1-{6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}-1-(3-fluoropyridin-2-yl)ethanol (Example 8.6/8.7, Step 3; 1.2 g, 2.33 mmol) and pyridine (1.88 mL, 23.3 mmol) in dichloromethane (20 mL) was added thionyl chloride (0.85 mL, 11.67 mmol) dropwise at 0° C., and the reaction was stirred at 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane (2×25 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (eluting with 40-60% EtOAc/petroleum ether) to afford 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ES/APCl calcd. for C26H24Cl2FN5 [M+H]+ 496. found 496.
Reaction SMILES: [CH2:1](SCC=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(=[O:14])C.C(NC=CSCC1C=CC=CC=1)(=O)C.[CH3:30][C@@H:31]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]([OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C@@H:31]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]1
Reactant: O=CCSCc1ccccc1
Reactant: CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)NC=CSCc1ccccc1
Agent: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Solvent: C1CCOC1
Product: OCc1ccccc1
Temperature: 250 °C

Procedure:
0.10 mol of 2-(benzylthio)acetaldehyde and 0.20 mol of acetamide are heated together at 100° C. with stirring, and the product solid is heated in a sublimator at 250° C. and 1 mm Hg until formation of the enamide 1-acetamido-2-benzylthioethene is complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), D-menthol (0.5 mmol), (PPh3)2PdCl2 (36 mg, 0.05 mmol), and 1-acetamido-2-benzylthioethene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a mixture of two diastereomeric cysteine derivatives, N-acetyl-L-benzylcysteine D-menthyl ester and N-acetyl-D-benzylcysteine D-menthyl ester. These diastereomers are separated by column chromatography on silica gel with benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100° C. in 1N HCl for 2 hours to give pure L- and D-cysteine, benzyl alcohol, acetic acid, and D-menthol, which is thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH:17]([C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH3:18]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:17]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH3:18])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Product: CCOC(=O)CCc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give [rac]-3-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:25][CH3:24])=[CH:13][C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(CNC)ccc1Oc1cc(Cl)ccc1C#N
Yield: 74.2 %

Procedure:
4-Chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 2.2 mmol), methylamine (2M in methanol, 3.5 mL, 7.0 mmol) and sodium cyanoborohydride (0.16 g, 2.5 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (65 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.26 g, 2.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[2-ethoxy-4-(methylaminomethyl)phenoxy]benzonitrile fumarate (707 mg, 74%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1[Cl:20].[F:21][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[NH2:1][C:2]1[C:7]([F:21])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1[Cl:20]
Reactant: Nc1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(=O)O)c1Cl
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Nc1c(F)c(Oc2ccc(Cl)c(Cl)c2)nc(C(=O)O)c1Cl

Procedure:
4-Amino-3-chloro-6-(3,4-dichlorophenoxy)pyridine-2-carboxylic acid was fluorinated with [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate)] (F-TEDA) in refluxing acetonitrile; mp 156-160° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3)ccn2c1=O
Yield: 102.1 %

Procedure:
Methyl 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 4-hydroxy-phenyl-boronic acid (283 mg, 2.06 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (610 mg, 100%). ESI-MS m/z: 388 (M+K)+, 372 (M+Na)+, 350 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:40])[NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:26]([Cl:39])[CH:25]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:26]([Cl:39])[CH:25]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Yield: 98.6 %

Procedure:
0.76 g of the compound obtained in Example 86 dissolved in 22 ml of methylene chloride and 22 ml of trifluoroacetic acid was stirred at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 5 ml of methylene chloride while adding 50 ml of saturated aqueous sodium bicarbonate slowly, and filtered under a reduced pressure to obtain the title compound as solid (0.62 g, 99%).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Reactant: Fc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=S)N2CCN(c3ccccc3F)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCc2ccccc21
Product: c1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-aminoindane by Procedure A (15 min at 200° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 195.5-197° C.). MS(ES+) m/z 250 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.90 (m, 1 H), 2.55 (m, 1 H), 2.83 (m, 1 H), 2.95 (m, 1 H), 5.36 (m, 1 H), 6.82-6.97 (m, 3H), 7.11-7.31 (m, 6H), 10.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 mmol) in THF (10 ml) was added Et3N (0.13 ml, 0.90 mmol) at room temperature. After 6 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 104-106° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J=7.6 Hz, 1H), 7.08 (br, 1H), 7.16-7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1](=[N:4][NH2:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:12](Cl)(=[N:19][OH:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH3:2][C:1]1([CH3:3])[O:20][N:19]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]1[NH2:5]
Reactant: ON=C(Cl)c1ccccc1
Reactant: CC(C)=NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)ON=C(c2ccccc2)N1N
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 38.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-isobutyl-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)=[O:15])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 71 but using 3-(piperidin-1-ylsulfonyl)benzoic acid (100 mg) and 4-aminobenzotrifluoride (59 mg) as the starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][CH:19]([C:30]([O:32][CH3:33])=[O:31])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[C:19]([C:30]([O:32][CH3:33])=[O:31])[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C2CCN(C(=O)OCc3ccccc3)CC2)oc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 1 liter round bottom flask fitted with a condenser, nitrogen inlet, and magnetic stir bar is added 4-[2-(2,4-Difluoro-phenyl)-1-methoxycarbonyl-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester, (32 g, 67.4 mmol), and 120 mL of thionyl chloride. The mixture is immersed in an oil bath preheated to 70° C. and stirred for 10 minutes. The reaction is removed, cooled to room temperature and concentrated to an amber oil. The amber oil is carefully treated with about 50 g of ice, and 350 mL of saturated sodium bicarbonate. The resulting mixture is extracted with 3×100 mL of diethyl ether. The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick amber paste to yield the title compound.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C1C=CC=CC=1.[Al].CCOCC.CO>[CH3:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CN=C1CCc2ccccc21
Agent: [Al]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CO
Product: CNC1CCc2ccccc21
Reaction time: 20 h
Yield: 88 %

Procedure:
(R,R)-Ethylene-1,2-bis(η5 -4,5,6,7-tetrahydroindenyl) titanium (R)-1,1'-binaphth-2,2'-diolate (30 mg, 0.050 mmol) was dissolved in 4 mL of dry benzene in a Schlenk tube under a nitrogen atmosphere. The tube was wrapped in aluminum foil. A solution of n-butyllithium (41 μL, 0.065 mmol, 1.6M in hexane) was added and the mixture was shaken until it turned a dark red brown color. After 5 min. phenylsilane, (93 μL, 0.75 mmol) was added and the reaction mixture turned blue, then brown, in color. After 10 min. indanone N-methyl imine (72.6 mg, 0.50 mmol) was added. The tube was shaken and left for about 20 hours at room temperature. The resulting solution was diluted with 15 mL of ether and 3 mL of methanol and allowed to stir for 2 hours. The reaction mixture was then washed with 20 mL of water and extracted with 1M HCl (2×20 mL). The aqueous layer was separated, basified with 5 M NaOH (until strongly basic to pH paper), and extracted with ether (2×50 mL). The ether solution was dried over anhydrous sodium sulfate and concentrated to yield 65 mg (0.44 mmol, 88% yield) of N-methyl-1-indanamine as a yellow oil.