Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[N:10]([C:14]([F:17])([F:16])[F:15])[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1SC.ClC1C=C(F)C(C2N(C(F)(F)F)N=NC=2)=CC=1S>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[N:10]([C:14]([F:16])([F:17])[F:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CSc1cc(-c2cnnn2C(F)(F)F)c(F)cc1Cl
Agent: Fc1cc(Cl)c(S)cc1-c1cnnn1C(F)(F)F
Product: Fc1cc(Cl)ccc1-c1cnnn1C(F)(F)F
Yield: 85.7 %

Procedure:
2.2 g (7.1 mmol) of [2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)phenyl]methyl sulfide was converted to 2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)thiophenol in the same manner as in Reference Example 1 and then to 1.8 g of 1,1′-thiodi-[2-chloro-4-fluoro-5-(3-trifluoromethyltriazolyl]benzene (yield 85.7%) in the same manner as in Reference Example 5 (1), which was used in Example 2 (4) as the starting material.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.O[C@H]1CCNC1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([C:24]([NH:26][CH2:27][C@:28]3([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]3)=[O:25])=[C:19]([Cl:36])[CH:18]=[CH:17][C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:36][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)[CH:23]=[CH:22][C:21]=2[C:20]=1[C:24]([NH:26][CH2:27][C@:28]1([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]1)=[O:25]
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: O[C@@H]1CCNC1
Agent: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](O)C4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting (R)-3-hydroxypyrrolidine (80 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.2 g) and diisopropylethylamine (300 μl) in acetonitrile (3 ml) to afford the title compound as a cream solid (190 mg). m.p. 222-223° C. (acetonitrile).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.O>CN1CCCC1=O.CCCCCC>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Yield: 82.5 %

Procedure:
4-Chloro-6-(4-nitrophenoxy)pyrimidine (508 mg, 2.00 mmol) and aniline (559 mg, 6.00 mmol) were heated and stirred in 1-methylpyrrolidone (5 ml) at 90° C. for 3 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=1:3), and the fraction containing the target substance was concentrated to obtain the title compound (508 mg, 1.65 mmol, 82%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11](=[O:21])[CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11](=[O:21])[CH:12]([P:13]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])=[O:14])[CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:22][CH:23]=1
Reactant: BrCC1CC1
Reactant: CCOP(=O)(CC(=O)OCc1ccc(OC)cc1)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(CC1CC1)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (0.840 g, 21.0 mmol) in DMF (100 mL) was added a solution of 2-(diethoxyphosphoryl)acetic acid para-methoxybenzyl ester (6.04 g, 19.1 mmol) from Step A in DMF (10 mL). The reaction mixture was stirred for 30 min at room temperature. Bromomethylcyclopropane (2.4 mL, 24.8 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with diethyl ether, poured into saturated sodium bicarbonate, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfate, and filtered. The volatiles were removed in vacuo and the residue was purified by FC (40% ethyl acetate in hexanes) to afford 4.31 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:35][N:36](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN>ClCCl.O1CCCC1>[OH:19][C@H:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][N:8]([CH:20]1[CH2:21][CH2:22][CH2:23][C:24]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH:36][CH3:35])=[CH:27][C:25]=2[CH2:26]1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(C(=O)O)cc2C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a mixture of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (0.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 1-hydroxybenzotriazole (0.11 g) in dichloromethane (6 ml) was added a solution of methylamine in tetrahydrofuran (2.0M, 0.40 ml). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (100:1 to 10:1) to afford N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.13 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.O>C1COCC1>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:22][C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[N:11]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Yield: 33.3 %

Procedure:
A solution of methyl 2,6-dichloro-4-cyanonicotinate (455 mg, 1.97 mmol), triethylamine (0.549 mL, 3.94 mmol) and m-toluidine (0.32 mL, 2.95 mmol) in THF (10 mL) was stirred at RT for 3 days. Water was added to the resulting mixture, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a yellow solid (198 mg, 33.3%). 1H NMR (500 MHz, CDCl3) δ ppm 2.40 (s, 3 H), 3.99 (s, 3H), 6.92 (s, 1H), 7.05-7.14 (m, 4H), 7.33 (t, J=7.81 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:33])[C:28]1[O:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:33][CH2:27][C:28]3[O:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[N:6]=1
Reactant: NCc1ccco1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CNCc3ccco3)c2)N=C1N
Yield: 71.2 %

Procedure:
A small vial (2 ml) was charged with 3-[2-amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (110 mg, 306 μmol). To this was added furfurylamine (30 mg, 308 μmol) in methanol (1 ml). After stirring overnight at room temperature sodium borohydride (29 mg) was added, then after another 90 minutes 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 96 mg (71%) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (s, 3H) 3.56 (br. s., 4H) 6.15 (d, J=3.2 Hz, 1H) 6.68 (br. s., 1H) 6.34 (t, J=2.4 Hz, 1H) 6.64 (s, 2H) 7.06 (d, J=8.8 Hz, 2H) 7.13 (t, J=74.18 Hz, 1H) 7.15-7.28 (m, 3H) 7.37 (s, 1H) 7.43 (d, J=8.8 Hz 2H) 7.51 (t, J=1.4 Hz, 1H); MS (ES) m/z 439.2 [M−H]−
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25]>CCCCCC.O.O1CCCC1>[Br:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:22]=2[F:21])[OH:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: Clc1ccc(Br)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: OC(c1cc(F)ccc1F)c1cc(Br)ncc1Cl
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 88 ml, 138 mmol) was added to a tetrahydrofuran (200 ml) solution of diisopropylamine (21 ml, 150 mmol) at −78° C. The resulting mixture was stirred for 1 hour. To the reaction mixture was added dropwise a tetrahydrofuran (100 ml) solution of 2-bromo-5-chloropyridine (19 g, 98.7 mmol). The resulting mixture was stirred for 1.5 hours. To the reaction mixture was added dropwise 2,5-difluorobenzaldehyde (16 ml, 148 mmol), followed by stirring for 2 hours. After addition of water, the resulting mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=6:1 eluate was concentrated under reduced pressure to give the title compound (24.8 g, 74.1 mmol, 75%) as a pale yellow powder.
Reaction SMILES: [OH-].[Li+:2].[SH:3]([O:6][C:7]([F:10])([F:9])[F:8])(=[O:5])=[O:4]>>[Li:2][S:3]([O:6][C:7]([F:10])([F:9])[F:8])(=[O:5])=[O:4]
Reactant: [Li+]
Reactant: O=[SH](=O)OC(F)(F)F
Agent: [OH-]
Product: [Li]S(=O)(=O)OC(F)(F)F

Procedure:
To a lithium hydroxide (LiOH.2H2O, 4.20 g, 0.10 mol) aqueous solution, HSO3CF3 (15.01 g, 0.10 mol) was added dropwise. Water was evaporated from the resulting solution in a rotavapor, the residue was recrystallized in ethyl cyanide/toluene to yield LiSO3CF3. The LiSO3CF3 obtained was then dried under vaccum at 140° C. for 24 hr.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:38][CH3:39])=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)C1C=CC=CC=1>CO.[Pd]>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:21])([C:32]3[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=3)[C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[CH:16]=2)[N:11]=[C:10]([O:38][CH3:39])[C:9]=1[OH:8]
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1O
Reaction time: 1.5 h

Procedure:
To a solution of (3-(benzyloxy)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (2.56 g, 4.61 mmol, Intermediate 11: step e) in MeOH (97 mL) was added 10% Pd/C (246 mg, 0.23 mmol). The reaction vessel was evacuated and then placed under an atmosphere of hydrogen for 1.5 hours. The mixture was then flushed with N2 and filtered through a pad of Celite®. The filtrate was concentrated to dryness, then DCM was added and the solution concentrated to dryness. The resulting solid was dried in the oven. The solid was then purified by FCC (15% MeOH/DCM) to provide the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH:11]([OH:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].O>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH:11]([OH:21])[CH2:12][O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2RS,3RS)-4-(benzylamino)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)butan-2-ol (6.40 g) and triethylamine (2.16 mL) in THF (50 mL) was added dropwise chloroacetyl chloride (1.23 mL) at 0° C. The mixture was stirred at 0° C. for 20 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-30%)) to give the title compound (6.83 g) as a pale-yellow oil.
Reaction SMILES: C=O.C[C:4](C)(O)[C:5]#[N:6].[C:9]([NH:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)(=[O:11])[CH3:10].[OH-].[Na+]>>[C:9]([NH:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH2:4][C:5]#[N:6])[C:15]([CH3:21])([CH3:22])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)C1(NC(C)=O)CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(O)C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1(NC(C)=O)CC(C)(C)N(CC#N)C(C)(C)C1
Temperature: 25 °C

Procedure:
0.9 g of 37% formalin solution and 2 ml of acetone cyanohydrin were added to 1 g of 4-acetamido-4-ethoxycarbonyl-2,2,6,6-tetramethylpiperidine obtained by the procedure of Example 2. The resulting mixture was stirred at room temperature, 0.4 ml of 0.1 N-sodium hydroxide solution was added to it, and the mixture was then stirred at room temperature for 3 hours.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([OH:33])=O)[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH2:72][CH2:71][CH:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31]([N:76]3[CH2:75][CH2:74][CH:73]([CH:70]4[CH2:69][CH2:68][N:67]([CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH2:72][CH2:71]4)[CH2:78][CH2:77]3)=[O:33])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 350 mg (0.69 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 244 mg (0.76 mmol) TBTU and 138 μL (1.04 mmol) triethylamine in 15 mL THF was stirred for 1 h at RT. Then 175 mg (0.69 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added. The reaction mixture was stirred for 4 h at RT. The solvent was eliminated i.vac., the residue was taken up in 30 mL EtOAc, the organic phase was washed with 30 mL 5% NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient DCM/EtOH 19:1 to DCM/EtOH 9:1). The fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[C:12](O)(=[O:14])C>C[O-].[Na+]>[CH3:12][O:14][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1nc(N)nc2[nH]ncc12
Temperature: 25 °C
Yield: 99 %

Procedure:
Compound 3 (70.4 g, 0.416 mol) was refluxed in methanolic sodium methoxide solution (25 g sodium dissolved in 1 L methanol) for 2 h. The reaction mixture was cooled to room temperature and neutralized by addition of acetic acid (75 ml). The mixture was evaporated to dryness and the solid was triturated in 600 ml of water, filtered and dried to provide 67.5 g (99% yield) of 4-methoxy-6-aminopyrazolo[3,4-d]pyrimidine (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]([CH3:22])([CH2:20][OH:21])[C:17](O)=[O:18].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]([CH2:20][OH:21])([CH3:22])[NH:15][C:9]2=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(N)(CO)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CO)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 41.4 %

Procedure:
1-Chloro-4-isocyanato-2-trifluoromethyl-benzene (4.40 g, 20 mmoL) and 2-amino-3-hydroxy-2-methyl-propionic acid (2.38 g, 20 mmoL) in dioxane (100 mL) was heated at 80° C. for 6 hrs. The reaction was cooled to room temperature and concentrated HCl (2 mL) was added and the reaction mixture was heated to refluxed for 4 hrs. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated, then recrystallization was conducted using ethyl acetate as solvent to afford the title compound as a white solid (2.65 g, yield 41%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])CCc1ccc(Cc2ccccc2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Temperature: 0 °C
Yield: 63 %

Procedure:
To 2-benzyl-5-(2-nitro-ethyl)-pyridine (260 mg, 1.1 mmol) described in Manufacturing Example 210-1-6 and methanol (5 mL) was added lithium methoxide (81 mg, 2.1 mmol), which was concentrated under a reduced pressure. Titanium(IV) tetrachloride (0.38 mL, 3.4 mmol) was added dropwise at −76° C. to a suspension of the residue in methylene chloride (5 mL) and tetrahydrofuran (2.5 mL), which was stirred for 20 minutes at room temperature. This reaction solution was added to ice water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again (four times). The organic layers were combined, washed with aqueous sodium chloride (one time), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and tetrahydrofuran was added to the residue. The insolubles thus produced were filtered out. The filtrate was concentrated under a reduced pressure to obtain the title compound (180 mg, 63%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16](=O)[C:15](=O)[C:14]=2[C:13]1=[O:24]>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[C:13](=[O:24])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: O=c1ccc2c(=O)n(CCO)c(=O)c=2c1=O
Reactant: Oc1cccc(I)c1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(I)c1

Procedure:
Alkylation of 3-iodophenol with 2-(2-hydroxyethyl)isoindoline-1,3-dione dione following method used in Example 31 gave 2-(2-(3-iodophenoxyl)ethyl)isoindoline-1,3-dione. Yield (2.8 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (m, 2H), 7.71-7.73 (m, 2H), 7.22-7.26 (m, 3H), 6.94 (t, J=8.4 Hz, 1H), 6.81:6.84 (m, 1H), 4.19 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+:13].[Na]>CO>[CH3:1][C:2]1([C:8]([O-:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Na+:13]
Reactant: CC1(C(=O)O)CCCCC1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC1(C(=O)[O-])CCCCC1
Temperature: 50 °C

Procedure:
0.1 mole of 1-methyl-1-cyclohexyl-carboxylic acid prepared by a method similar to that used in example 7, dissolved in methanol was added to a solution of sodium methylate in dry methanol, prepared using 0.095 mole of sodium and 40 cm3 of methanol as the starting materials. The mixture was heated at 50° C. for 10 minutes and the methanol was then evaporated off in vacuo. The colourless crystals of sodium 1-methyl-1-cyclohexyl-carboxylate were washed with ether, filtered off and dried.
Reaction SMILES: [C:1]1(/[C:7](/[C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[N:8]\[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][O:9]/[N:8]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28]
Reactant: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
(E)-Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone oxime (Example 37, 0.070 g, 0.18 mmol) was taken into DMF (3 mL). Then NaH (0.014 g, 0.36 mmol) was added and stirred for 20 minutes, followed by addition of iodomethane (0.05 mL, 0.72 mmol) and stirring over the weekend. The reaction was quenched with water and extracted with ether. The combined organics were washed with water and dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to afford 0.063 g (86%) of desired product as a white solid. MS (ESI) m/z 407 ([M+H]+); Anal. Calcd for C24H17F3N2O: C, 70.93; H, 4.22; N, 6.89. Found: C, 70.92; H, 4.19; N, 6.68.