Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][Si:4]([Cl:8])(Cl)[CH2:3][CH2:2]1.NC(N)=O.[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH2:14][OH:15]>C1COCC1>[Cl:8][Si:4]1([O:15][CH2:14][C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1
Reactant: Cl[Si]1(Cl)CCCCC1
Reactant: O=C(CO)OCc1ccccc1
Agent: NC(N)=O
Solvent: C1CCOC1
Product: O=C(CO[Si]1(Cl)CCCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of cyclopentamethylenedichlorosilane (0.5 mL; 3.42 mmol) in dry THF (10 mL) was added urea (0.246 g; 4.10 mmol). The mixture was then cooled to 0° C. and benzyl glycolate (0.48 mL; 3.42 mmol) was added dropwise over a 15 minute span. The mixture was then taken off the ice bath and allowed to stir at room temperature for 40 minutes. The mixture was then concentrated under high vacuum and diluted with chloroform. The aqueous layer was soaked up with excess Na2SO4 and the mixture was filtered. The filtrate was concentrated to a light yellow crude liquid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[N:4][O:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[C:16]([O:15][C:14]([NH:13][C@@H:11]([CH3:12])[CH2:10][O:9][C:3]1[C:2]([F:1])=[C:6]([C:7]([OH:22])=[O:8])[O:5][N:4]=1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@@H](COc1noc(C=O)c1F)NC(=O)OC(C)(C)C
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](COc1noc(C(=O)O)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of tert-butyl {(1S)-2-[(4-fluoro-5-formylisoxazol-3-yl)oxy]-1-methylethyl}carbamate (244 mg), sodium dihydrogen phosphate (305 mg), 2-methylbut-2-ene (449 mL), 2-methylpropan-2-ol (5 mL) and water (1 mL) was added sodium chlorite (115 mg) at room temperature, and the obtained mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/2-propanol (volume ratio 3/1). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white powder (256 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][C:15]([P:18]([CH2:23][CH2:24][CH3:25])(=[O:22])[O:19]CC)=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[N:3]=1.[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[CH:13]=[CH:14][C:15]([P:18]([CH2:23][CH2:24][CH3:25])(=[O:19])[OH:22])=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[N:3]=1
Reactant: CCCP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCP(=O)(O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl 4-((4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(propyl)phosphinate, 16-f, (2.1 g, 4.16 mmol) in dioxane (30 ml) was added 2N NaOH (0.83 g, 20.8 mmol). The mixture was stirred at 85° C. for 6-8 hours, then evaporated the solvent and the residue was added water (20 ml) and extracted with ethyl acetate (30 ml) twice. The aqueous phase was adjusted to pH=1˜2 with conc. HCl, then filtered, and the filtered solid was washed with water, dried to give the title compound, 16-1, (crude product), which was further purified by prep_HPLC to give pure 16-1 (400 mg). 1H NMR (300 MHz, DMSO-d6): δ 10.38 (s, 1H), 8.61 (d, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.34 (m, 9H), 6.72 (s, 1H), 6.32 (d, 1H), 1.75 (m, 2H), 1.41 (m, 2H), 0.95 (t, 3H). (M+H)+=478.2.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][NH2:23])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH3:1][NH:2][C:3](=[S:4])[NH:23][NH:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:24]=[CH:25][CH:26]=[C:12]([CH2:11][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:13]=1)=[O:21]
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.5 g (6.6 mmol) of methylisothiocyanate are added to 1.0 g (3.3 mmol) of N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide in 20 ml of THF and the mixture is stirred at room temperature for 12 hours. The precipitate obtained is filtered off and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[Cl:23])C1C=CC=CC=1.CS(O)(=O)=O>>[Cl:23][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:16]([C:19]([F:20])([F:21])[F:22])=[N:17][N:18]=2)[C:10]=1[CH2:9][OH:8]
Reactant: FC(F)(F)c1nnc2ccc(Cl)c(COCc3ccccc3)n12
Agent: CS(=O)(=O)O
Product: OCc1c(Cl)ccc2nnc(C(F)(F)F)n12

Procedure:
To a solution of 5-(benzyloxymethyl)-6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine, prepared as described in Step 4 (700 mg, 2.1 mmol) was added methanesulfonic acid (2 mL, 70% in water) and the reaction was heated to reflux overnight. The reaction was concentrated and the residue purified by flash chromatography to yield (6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-5-yl)methanol.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH2:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 155.0-156.0° C.; 1H NMR (250 MHz) δ 9.17 (s, 2H), 3.50 (s, 1H), 3.25 (s, 1H), 1.94-1.15 (m, 16H), 0.82 (d, 6H); 13C NMR (62.7 MHz) δ 51.7 (s), 47.9 (s), 38.4 (s), 30.9 (s), 28.8 (s), 27.8 (s), 26.1 (s), 23.5 (s), 22.5 (s), 22.3 (s), 17.3 (s), 16.8 (s) ppm. FT-IR (neat): 3430, 2948, 1615, 1589, 1557, 1472, 1436, 1418, 1362, 1102, 895. Elemental Analysis for C12H26NCl: C, 65.56%; H, 11.95%; N, 6.37%. Found: C, 64.90%; H, 11.89%; N, 6.26%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[C:23]5[C:19]([CH:20]=[CH:21][N:22]5[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:18][CH:17]=4)[CH2:12][C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:4]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[C:23]5[C:19]([CH:20]=[CH:21][N:22]5[CH2:25][C:26]([OH:28])=[O:27])=[CH:18][CH:17]=4)[CH2:12][C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c2c(c3c(Cl)cccc31)C(=O)N(c1ccc3ccn(CC(=O)OC(C)(C)C)c3c1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c3c(Cl)cccc31)C(=O)N(c1ccc3ccn(CC(=O)O)c3c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-(6-(8-chloro-4-methyl-1-oxopyrrolo[3,4-b]indol-2(1H,3H,4H)-yl)-1H-indol-1-yl)acetate (1.6 mmol, 1 equiv.) was dissolved in DCM (40 ml); TFA (16 ml) was added and the mixture was stirred for 2 h at 25° C. The solvent was reduced under reduced pressure, dichloromethane was added 2× to the residue, and in each case concentration to dryness again was carried out. The residue was used in the next step without being purified further.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 4-fluorobenzonitrile (303 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was used in the next step without further purification. Isolated 642 mg (2.13 mmol, 85% yield).
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([NH:5][NH2:6])=O.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>Cl.CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:5]([C:3]([C:2]([F:17])([F:1])[C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[N:13]=[CH:12][CH:11]=[CH:10]4)=[N:20][N:21]=2)[N:6]=1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: CO
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Temperature: 90 °C

Procedure:
A suspension of 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide (2000 mg, 8432 μmol) and 3,6-dichloropyridazine (3768 mg, 25295 μmol) in 1.25 M HCl in MeOH (20 mL) was heated to 90° C. with microwaves for 50 min. The solvents were then removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (60 mL) and 1 M NaOH (20 mL). The organic phase then dried over MgSO4, concentrated, then purified on silica (120 g) eluting with 1>2.5% of 2 M NH3 in MeOH/DCM to provide product isolated as a dark tan solid. MS (ESI pos. ion) m/z: 332 (MH+). Calc'd exact mass for C15H8ClF2N5: 331.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12])[CH2:8][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-4-methyl-1-trifluoromethylbenzene 26 (0.20 g, 1 mmol), N-bromosuccinimide (0.17 g, 1 mmol) and benzoyl peroxide (7.4 mg, 0.03 mmol) in carbon tetrachloride (2 mL) was heated to reflux for 2 hours. Another portion of benzoyl peroxide (20 mg, 0.08 mmol) was added. The mixture was heated to reflux for another 0.5 hours. The reaction mixture was further stirred at room temperature for 16 hours. The solid was removed by filtration. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica, using petroleum ether as eluent, to give 0.22 g (80%) of Compound 27.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43]>ClCCl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:6][N:7]([C:42]([O:44][CH3:45])=[O:43])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 100B) (420 mg, 0.75 mmol) and pyridine (148 mg, 1.88 mmol) were dissolved in anhydrous dichloromethane (15 mL) and cooled to 0° C. Methyl chloroformate (142 mg, 1.5 mmol) was added over 1 min. The reaction was stirred at 0° C. for 1 h, then at room temperature for 24 h. The reaction mixture was then diluted with 50 mL of dichloromethane, and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title product (400 mg) which was used without further purification. MS m/z 618.8 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([CH:12]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=[N:22]2)=[CH:20][CH:21]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(C(C=O)C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
To a solution of 2-(4-methoxyphenyl)malondialdehyde (797 mg, 4.48 mmol, 1 eq) in 20 ml of ethanol are added m-anisidine (551 mg, 4.48 mmol, 1 eq) and 10 ml of conc. HCl. The reaction mixture is stirred at 80° C. for 3 days, and after cooling to RT, the reaction is stopped by adding a 10% sodium carbonate solution. The mixture is extracted with dichloromethane, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. After purification by column chromatography with hexane/ethyl acetate as the eluent, the product was obtained in a yield of 19% (221 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: CCCOC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOC(=O)CCc1ccc(OCC2CO2)cc1
Yield: 28.4 %

Procedure:
A mixture of 9 g (0.04 mole) of n-propyl 3-(4-hydroxyphenyl)propionate, 10 g (0.08 mole) of K2CO3 and 12 mL (0.15 mole) of epichlorohydrin in 150 mL of acetone was stirred and heated to reflux for 20 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was taken up in 100 mL toluene and washed consecutively with 50 mL water 2×50 mL of 1N NaOH and 2×50 mL of water. The toluene phase was then dried over MgSO4 and evaporated under reduced pressure to provide 3 g (30%) of a clear oil which was used directly in the next step without additional purification. The IR and NMR spectra of the reaction product were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:33]([O:35]CC)=[O:34])=[CH:24][C:25]=2[NH:26]3)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:33]([OH:35])=[O:34])=[CH:24][C:25]=2[NH:26]3)[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N2CCC[C@@H](NC(=O)OCc3ccccc3)C2)c2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 20.6 %

Procedure:
Step 3 A solution of (R)-ethyl 5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylate (0.67 g, 1.349 mmol) and potassium hydroxide (0.379 g, 6.75 mmol) in 10:1 ethanol-water (33 mL) was heated at 85° C. for 2 h. The mixture was cooled to rt and the precipitate was collected by filtration, washed with ethanol and dried to afford (R)-5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylic acid as a yellow solid (130 mg, 21%). Mass spectrum m/z 469.1 (M+H)+. (R)-5-(3-aminopiperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylic acid was also isolated from filtrates (150 mg, 33%). Mass spectrum m/z 335.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=3)=[CH:11][C:10]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(Cl)cc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(C(F)(F)F)c3)n(-c3ccc(Cl)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 104A in analogy to the synthesis of the compound of Example 1. 34 mg (92% of theory) of the title compound are obtained.
Reaction SMILES: C(O)C.[N:4]1[CH:5]=[CH:6][N:7]2[CH:12]=[C:11]([C:13]3[C:17]4[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:16]=4[NH:15][N:14]=3)[CH:10]=[CH:9][C:8]=12.Cl>O1CCOCC1>[N:4]1[CH:5]=[CH:6][N:7]2[CH:12]=[C:11]([C:13]3[C:17]4[CH2:18][NH:19][CH2:20][CH2:21][C:16]=4[NH:15][N:14]=3)[CH:10]=[CH:9][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: c1cn2cc(-c3n[nH]c4c3CNCC4)ccc2n1
Reaction time: 0.5 h

Procedure:
In a flask, ethanol (1 mL) was added to tert-butyl 3-(imidazo[1,2-a]pyridin-6-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.750 g, 0.0022 mol). Hydrochloric acid in dioxane (4 M, 8 mL) was added to the reaction and was stirred for 30 minutes. Ethanol (5 mL) was added to the reaction, and the resulting solution was concentrated in vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:26](#[N:29])[CH:27]=[CH2:28].CCOC(C)=O>C1COCC1>[C:26]([CH2:27][CH2:28][N:23]1[CH2:22][CH2:21][CH:20]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:25][CH2:24]1)#[N:29]
Reactant: C=CC#N
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(CCC#N)CC2)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.) in THF (0.70 mL) was treated with acrylonitrile (55 μL, 0.84 mmol, 4.2 equiv.). After being stirred for 24 h at 50° C., the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2, gradient elution) gave the title compound as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 4.16-4.09 (m, 1H), 3.02-2.98 (m, 2H), 2.75-2.70 (m, 3H), 2.57-2.54 (m, 3H), 2.26-2.20 (m, 2H), 2.15-2.08 (m, 2H), 1.92-1.87 (m, 2H), 1.78 (s, 3H), 0.58-0.53 (m, 2H), 0.46-0.42 (m, 2H); MS(ESI) 410 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCOCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (100.4 mg, 0.169 mmol) in N,N-dimethylformamide (1.5 mL) was added morpholine (73.6 μL, 0.844 mmol). The reaction mixture was stirred at 80° C. for 1.5 hrs. The starting material wasn't consumed completely. To the mixture was added morpholine (73.6 μL, 0.844 mmol). The reaction mixture was stirred at 80° C. for 3.5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (74.6 mg, 0.140 mmol, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]Br)[CH2:25][CH2:24]1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC[C@H]1CC[C@H](CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)cc2)nc1

Procedure:
A mixture of 11 g of a 2-p-hydroxyphenyl-5-n-hexylpyrimidine, 7.8 g of trans-4-n-propyl-1-bromomethylcyclohexane, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is warmed at 90° for 10 hours. Customary working up gives 4-(5-n-hexylpyrimidin-2-yl)-phenyl trans-4-n-propylcyclohexylmethyl ether.