Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][N:55](C)C=O.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:54]#[N:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), zinc cyanide (142 mg) and N,N-dimethylformamide (10 ml) is stirred at 95° C. under nitrogen flow for 8 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (572 mg). MS (m/z): 664 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)(=O)C>O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])[NH2:12]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N)cc1F
Temperature: 95 °C
Yield: 89.8 %

Procedure:
A mixture of 3-fluoro-4-(methylsulfonyl)nitrobenzene (8 g, 36.5 mmol), iron powder (22 g, 394 mmol), and acetic acid (0.3 mL) in water (200 mL) was heated at 95° C. for 3 hours. After cooling, insolubles were filtered off by Celite. The filtrate was extracted with ethyl acetate (200 mL×2), the combined organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with ethyl acetate/hexane (1/1) provided the subtitle compound (6.2 g, 90% yield).
Reaction SMILES: C[O-].[Na+].[CH2:4]=[C:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7](=[O:13])[O:6]1>CS(C)=O.O>[CH:11]12[CH2:12][CH:8]([CH2:9][CH2:10]1)[C:7](=[O:13])[CH2:4][C:5]2=[O:6]
Reactant: C=C1OC(=O)C2CCC1C2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CC(=O)C2CCC1C2
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
4.27 g (79 mmol) of sodium methanolate in 40 ml of dimethyl sulfoxide are used as initial charge in a reaction vessel. A solution of 7.2 g (52 mmol) of 4-methylene-3-oxa-bicyclo(3.2.1]octan-2-one in 20 ml of dimethyl sulfoxide is fed into that solution in the course of 2.5 hours at a temperature of from 25 to 35° C., with stirring. After a further 0.5 hours, the reaction mixture is diluted with 200 ml of water and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water. The aqueous phases are then combined, adjusted to pH 3 using approximately 35 ml of 2N hydrochloric acid, and extracted four times using 400 ml of ethyl acetate each time. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The brown solid remaining is filtered over silica gel and yields 6.3 g (46 mmol) of bicyclo[3.2.1]octane-2,4-dione with a content of 93%, corresponding to a yield of 81.4%, and a melting point of 129-130° C.
Reaction SMILES: B#B.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7][CH2:6][C:5]1=O.Cl.N>O1CCCC1.O>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:7][CH2:6][CH2:5]1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: B#B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CN1CCNC(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 7.5 h
Yield: 94.9 %

Procedure:
To a solution of 50 ml of 1.07 M diborane in tetrahydrofuran was added with stirring 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one at room temperature, and the mixture was refluxed with stirring for 7.5 hours. After having been left standing overnight, 5 ml of water followed by 5 ml concentrated hydrochloric acid was added to decompose the excess diborane, and the mixture was refluxed for one hour. After cooling, the solution was neutralized with concentrated ammonia, and extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was ramoved under reduced pressure. The residue was recrystallized from n-pentane to obtain 1.30 g of 1-methyl-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, melting at 66° to 68° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([NH2:20])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])([OH:4])([OH:3])=[O:2].[N:22]([O-])=O.[Na+]>>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH2:19][C:18](=[N+:20]=[N-:22])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])([OH:3])([OH:4])=[O:2]
Reactant: O=N[O-]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: [Na+]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)C(=O)NC1=O

Procedure:
acidifying said 5-amino-2'-deoxyuridine-5'-monophosphate and reacting the acidified product with sodium nitrite to produce 5-diazo-2'-deoxyuridine-5'-monophosphate; and
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.CC(O)=O.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)cn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
(S)-2-fluoro-4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)morpholino)pyrimidin-5-yl)benzaldehyde (41 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and then AcOH (0.006 mL, 0.10 mmol) and 1-methylpiperazine (0.02 mL, 0.17 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then NaBH(OAC)3 (28 mg, 0.13 mmol) was added, followed by stirring at room temperature for 13 hours. When the reaction was completed, the reaction mixture was adjusted to pH 8 with 5% K2CO3, followed by extraction with dichloromethane and water two times or more. The organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. PLC using 10% dichloromethane/methanol gave (S)-4-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (20 mg, 0.034 mmol) with a yield of 46%.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:21])[CH3:20]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
1.0 G of 3-phenylindoline was dissolved in 10 ml of acetic anhydride at room temperature. After 10 minutes, the reaction mixture was poured into 100 ml of water, slightly basified with aqueous sodium hydroxide and extracted with methylene chloride. After removal of the methylenechloride, the residue was recrystallized from cyclohexane to give 1.15 g of the desired N-acetyl-3-phenylindoline which was found to have a 106°-7° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:13]
Reactant: O=C=NCCCCl
Reactant: O=C1CCCN1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)NCCCCl
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of 17.1 g (201 mmol) of 2-oxopyrrolidine and 20 g (167 mmol) of chloropropyl isocyanate was heated with stirring at 95°-105° C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting product obtained from the eluate with toluene-ethyl acetate (20/1-10/1 v/v) was washed with ether-n-hexane and then collected by filtration, whereby 27.87 g of the objective compound 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) melting at 57.0°-58.0° C. was obtained as crystals. Yield: 81.0%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(=O)=O.[OH-].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (500 mg, 2.3 mmol) in dry CH3CN (40 mL) was added 2-amino-N-methylbenzamide (350 mg, 2.3 mmol) at room temperature. The reaction mixture was cooled to −30° C. using dry ice. Powdered KOH (1.0 g, 17.8 mmol) was added and the reaction mixture was stirred at −30° C. for 1 h, and then warmed to −10° C. to −5° C. and stirred for another 2 h, then quenched with water (200 mL). The mixture was extracted with EtOAc (3×100 mL), the combined organic layer was dried over MgSO4, concentrated, and residue was purified by column chromatography to give 213 mg of the title compound (yield: 28%). 1H NMR (DMSO, 400 MHz): δ=2.75 (d, J=4.4 Hz, 3 H), 7.20-7.24 (m, 1 H), 7.53-7.58 (m, 1 H), 7.74 (dd, J=2.0, 8.0 Hz, 1 H), 8.33 (dd, J=1.2, 8.4 Hz, 1 H), 8.85 (s, br, 1 H), 12.0 (s, br, 1 H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1>CCCCCC>[Br:1][CH2:14][C:10]1[C:9]([OH:15])=[C:8]([CH3:16])[C:7]([CH3:17])=[C:6]2[C:11]=1[CH2:12][CH2:13][C:4]([CH3:18])([CH3:3])[O:5]2
Reactant: BrBr
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(CBr)c1O)CCC(C)(C)O2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of Br2 (0.540 mL, 10.5 mmol) in hexane (70 mL) was quickly added to the round bottom flask equipped with a CaCl2 drying tube and containing a stirred solution of 2,2,5,7,8-pentamethyl-6-chromanol (2.20 g, 10.0 mmol) in hexane (340 mL). After stirring the reaction mixture for 2 h the solvents were evaporated yielding of 5-bromomethyl-2,2,7,8-tetramethyl-chroman-6-ol as a pale yellow solid (3.0 g), which was immediately used in the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ (ppm): 4.68 (s, 2H), 2.81 (t, J=7, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 1.84 (t, J=7, 2H), 1.32 (s, 6H). MS (ESI-Pos) m/z 219.2 (M-Br+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)C(C)(C)c1ccc(CN)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-aminomethylphenyl)-2-methylpropionate (29.4 g) and triethylamine (23.8 ml) indichloroethane (300 ml) was added dropwise acetyl chloride (11.1 ml) at 5° C. over 30 min. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=3:1, ethyl acetate) to give the title compound (23.47 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])(C)(C)C.S(C)C.C1C[O:22]CC1>CCCCC>[OH:22][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10]
Reactant: C1CCOC1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CSC
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (7.07 g, 36.1 mmol) in 225 mL of THF at -78° C. is added a 1.7 M solution of tert-butyl lithium (45.6 mL, 77.6 mmol) in pentane. After 5 minutes, CuBr.SMe2 (15.9 g, 77.6 mmol) is added. The resulting solution is stirred for 10 minutes, then O2 is slowly bubbled through the reaction mixture for 30 minutes. After this time, the solution is allowed to warm to ambient temperatures. The solution is stirred for 16 hours. The solution is then poured into 100 mL of H2O. The solution is diluted with EtOAc. The layers are separated. The organic layer is washed with saturated (NH4)2SO4 solution. The organic layer is then extracted with 10 N NaOH. The collected aqueous basic layers are acidified to pH=6 with 6N HCl. The solution is then extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The title compound is obtained as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1cccs1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-thiophenecarbonyl chloride (0.28 g, 1.9 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.23 g, 83%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13][N:12]([C:22](=[O:24])[CH3:23])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (4-phenylpiperidin-4-ylmethyl) carbamic acid tert-butyl ester (2.1 mmol) in CH2Cl2 is added acetic anhydride (3.1 mmol) and triethylamine (3.1 mmol) at 0° C. The reaction mixture is stirred at room temperature for 2.5 h then the bulk of solvent is concentrated in vacuo. After the residue is suspended in AcOEt, the mixture is washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give (1-acetyl-4-phenylpiperidin-4-ylmethyl)carbamic acid tert-butyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH:23]1([N:29]([CH3:37])[CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][N:29]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH3:37])[CH2:32][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(CC1CCNCC1)C1CCCCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and cyclohexyl-methyl-piperidine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (43%, white crystals). HPLC-MS m/z=492.3 (M+1), Rt: 3.22 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)(O)[O-].[Na+].I[CH2:25][CH3:26]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 3-methyl-4-nitrobenzoic acid (1) (362.3 g, 2.0 mol), N,N-dimethylformamide (2000 mL), sodium bicarbonate (200 g, 2.38 mol) and iodoethane (623.9 g, 4.0 mol) was stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature and poured into water (2000 mL. The resulting solid was collected by filtration, washed with water and dried. The solid was washed further with hexane and dried to provide the title product (382.1 g, 91%) as an off-white solid: mp 51°-52.5° C.; 1H NMR (CDCl3) δ 8.04-7.98 (m, 3H), 4.42 (q, 2H), 2.63 (s, 3H), 1.42 (t, 3H); Mass spectrum (NH3 --CI) m/z 210 (100%, M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>ClCCl>[Cl:15][C:3]1[C:2]([Cl:1])=[CH:7][N+:6]([O-:8])=[C:5]([CH3:9])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Cl)c[n+]1[O-]

Procedure:
To a stirred and cooled solution of 5-chloro-4-nitro-2-methyl-pyridine-N-oxide (9.7 g) in dichloromethane (100 ml) at 5°-10°, a solution of phosphoryl chloride (14.7 ml) in dichloromethane (100 ml) was added. The solution was heated under reflux for 4.5 hours, poured on ice-water and basified (NaOH) to pH 8-9. The dichloromethane was separated, dried (K2CO3), stripped and the residue triturated with ether filtered, washed and dried to give 4,5-dichloro-2-methylpyridine-N-oxide, (7.69 g). m.p.120°-123°
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:71]([CH3:73])[CH3:72]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:71]([CH3:73])[CH3:72])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CNC
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CN(C)C)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (166 mg, 0.23 mmol, see Ex. 25) in dichloroethane (4 mL) and HOAc (10 mg) was added NaBH(OAc)3 (242 mg, 1.15 mmol) and Me2NH (2M in THF, 0.58 mL, 1.15 mmol). The reaction mixture was stirred at RT for 20 h then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by reverse phase HPLC (MeOH/H2O/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 38 °C

Procedure:
To a solution of trans-4-cyanocyclohexanecarboxylic acid (1.29 g, 8.42 mmol) in dichloromethane (7.7 mL) was added thionyl chloride (2.0 M in dichloromethane, 10.11 mL, 20.21 mmol) and the reaction was heated at 38° C. overnight. Then, the reaction was concentrated to afford trans-4-cyanocyclohexanecarbonyl chloride that was used in the next step without further purification.