Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:10]=1>O1CCCC1>[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17]([OH:30])([CH3:1])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])[CH:10]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-n2cccn2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyllithium (1.6 M in diethyl ether) (0.327 mL, 0.524 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1H-pyrazol-1-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide (75 mg, 0.175 mmol) in tetrahydrofuran (2 mL). After stirring at −78° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% EtOAc/hexane afforded 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-1-yl)phen yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:20])[CH2:3]1.[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:4](=[O:20])[CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)CC(=O)Nc2c(COC3CCCCO3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(COCC[Si](C)(C)C)c2c(COC3CCCCO3)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g of 4,4-dimethyl-8-(tetrahydropyran-2-yloxymethyl)-3,4-dihydro-1H-quinolin-2-one in 10 ml of N,N-dimethylformamide is admixed at 0° C. with 0.2 g of sodium hydride dispersion (60%). After stirring for 1 hour, 0.94 ml of (2-chloromethoxyethyl)trimethylsilane are added and the reaction mixture is warmed to room temperature. After 17 hours and 22 hours, 0.1 g of sodium hydride dispersion (60%) and 0.5 ml of (2-chloromethoxyethyl)trimethylsilane are again added. After a total of 24 hours, the reaction mixture is admixed with a few drops of water and subsequently partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.37 (2:1 EtOAc-heptane); Rt=6.01.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[O:7])[CH3:6].[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:6][C:5](=[O:7])[CH:4]([CH3:3])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:16]
Reactant: CC(=O)C(C)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (0.3965 g, 16.52 mmol) was added slowly to a NaCl ice bath containing EtOH (5.6 mL, 2.6 M) stirring under N2. 59 (2.2727 g, 14.01 mmol) and diethyloxalate (2.0649 g, 14.13 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 67:30:3 Hexanes: CH2Cl2: 2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 60. 1H (CDCl3, 400 MHz): δ 14.55 (1H, broad s), 7.32-7.12 (5H, m), 6.36 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.05 (1H, dd, J=13.5, 6.8 Hz), 2.84 (1H, app sex, J=7.0 Hz), 2.67 (1H, dd, J=13.5, 7.8 Hz), 1.36 (3H, t, J=7.1 Hz), 2.33 (3H, d, J=7.0 Hz) ppm. 13C (CDCl3, 100 MHz): δ 205.78, 166.96, 161.88, 138.75, 128.80, 128.30, 126.29, 100.75, 62.32, 46.35, 39.10, 16.51, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 16.51, 13.88; CH2 carbons: 62.32, 39.10; CH carbons: 128.80, 128.30, 126.29, 100.75, 46.35 ppm. HPLC: 11.084 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].N[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H][H]>[Rh]>[C:10]1([NH:2][CH2:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1cccnc1
Reactant: [H][H]
Agent: [Rh]
Product: c1ccc(NCc2cccnc2)cc1
Reaction time: 13 h

Procedure:
A mixture of 3-cyanopyridine (10.4 g), aniline (101.8 g) and a 5% rhodium on carbon catalyst (1.0 g) was treated with hydrogen at 60 psig 30 deg C. for 13 hours in a rocking autoclave. The catalyst was removed by filtration and the filtrate analyzed by glc to show 3.7 g of N-phenyl-N-(3-pyridylmethyl)amine.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.O1CCCC1.C(N(CC)CC)C>O>[CH3:11][N:12]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10]
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
1.2 mL (7.43 mmol, 2 eq) of heptyl isocyanate are added to a solution of 1.0 g (3.7 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (obtained as in 4c) in 15 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 hours at 40° C. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.15 g of methyl 3-[3′-(1-methyl-3-heptyl-ureido)biphenyl-4-yl]propanoate are obtained. Yield=76%
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[CH3:39][C:40]([CH3:48])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[NH2:41]>>[CH3:39][C:40]([NH:41][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[CH3:48]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCOC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([P:17](=[O:22])([O:20]C)[O:18]C)/[CH:3]=[C:4](\[CH3:16])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C>ClCCl.C1(C)C=CC=CC=1>[OH:1][CH:2]([P:17](=[O:18])([OH:22])[OH:20])/[CH:3]=[C:4](\[CH3:16])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14]
Reactant: COP(=O)(OC)C(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: C[Si](C)(C)Br
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C(O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl [1-hydroxy-(E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]phosphonate (67 mg, 0.203 mmol) and 2,4,6-collidine (0.107 ml, 0.81 mmol)in dichloromethane (3 ml) under argon at 0° C., was added trimethylsilyl bromide (0.107 ml, 0.8 mmol) and the resulting mixture stirred at 0° C. for 30 min and then at r.t. for 5 hrs. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo, the resulting white solid was dissolved in ethylacetate and water and the pH was adjusted to pH=3 by the addition of 1M HCl solution. The organic layer was separated, dried (MgSO4) and evaporated to afford a pale yellow solid. The-solid was washed with dichloromethane (2×5 ml) and the white solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16]N=O)(C)([CH3:14])[CH3:13].N[C:20]1[CH:25]=CC=C[CH:21]=1>N1C=CC=CC=1.[Fe]>[O:16]([N:7]1[C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([CH3:10])[CH3:9])[C:12]1[CH:14]=[CH:25][CH:20]=[CH:21][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CC(C)(C)ON=O
Agent: [Fe]
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of 1.95 g (12.5 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl, 3.09 g (30.0 mmol) of tert-butylnitrite and 378 mg (˜0.125 mmol) of iron polyoxometallate (K7PFeW11O39•H2O) in 100 mL of pyridine at 70° C. under a nitrogen atmosphere is added dropwise over 5 minutes 2.32 g (25 mmol) of aniline in 5 mL of pyridine. Evolution of gas is observed during the addition of aniline. The dark red reaction mixture is kept at 70° C. until evolution of gas subsided. Upon cooling to ambient temperature, the reaction mixture is then concentrated to an thick oil. The residue is purified by vacuum flash chromatography (heptane) to give 2.10 g of a colorless oil in 72.2% yield: 1H NMR (CDCL3) (300.08 MHz) d 1.42, 1.29, 1.12 (overlapping m, CH2, 6 H), 1.16 (s, CH3, 6 H), 1.017 (s, CH3, 6 H), 7.25 (d, CH, 2H, 3JHH′=8.2 Hz), 7.12 (dd, CH, 2H, 3JHH′=8.3 Hz, 3JHH′=8.2 Hz), 6.78 (tt, CH, 1 H, 3JHH′=7.2 Hz, 4JHH″=1.2 Hz); MS [M+1]234.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH2:27])[C:21]2=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH:27][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:21]2=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 57.8 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.36 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.36 mmol), DIPEA (158 mg, 4.07 mmol) and HATU (1.63 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 15 hours. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), washed with water (3×15 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is recrystallized from EtOAc to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (285 mg) as a solid. MS: 363 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.35 (s, 3H), 2.87 (s, 3H), 6.92 (d, H), 7.51 (s, H), 7.60 (t, H), 7.97 (t, H), 8.05 (t, H), 8.65 (d, H), 8.78 (d, H), 9.23 (s, H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:3][CH2:4][CH2:5][C@H:6]([CH2:8][CH2:9][CH2:10][C@@:11]1([CH3:22])[O:16][C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[CH2:13][CH2:12]1)[CH3:7].C(O)=[O:30]>>[C:15]1([CH:17]=[CH:18][C:19]([OH:21])=[CH:20][CH:14]=1)[OH:16].[CH3:27][CH:26]([CH2:25][CH2:24][CH2:23][C@H:2]([CH2:3][CH2:4][CH2:5][C@H:6]([CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]/[CH2:13][OH:30])/[CH3:22])[CH3:7])[CH3:1])[CH3:28]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@]1(C)CCc2cc(O)ccc2O1
Reactant: O=CO
Product: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: Oc1ccc(O)cc1

Procedure:
Tocol (2-methyl-2-(4,8,12-trimethyltridecyl)-6-chromanol) and its derivatives are noted for antioxidant activity. Merck 9th Ed. at page 1221, which is hereby incorporated by reference. Tocol is a colorless viscous oil having a molecular weight of about 388.61 and a boiling point of about 165° C. to about 175° C. at 0.001 atm. Merck 9th Ed. at page 1221. The structural formula of tocol is given in formula (X) below: ##STR7## Tocol can be produced by condensation of hydroquinone and phytol in the presence of anhydrous formic acid. Merck 9th Ed. at page 1221.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:53]=[N:54][CH:55]=[C:56]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:57]=1>CN(C=O)C.O>[Cl:51][C:52]1[CH:57]=[C:56]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)[CH:55]=[N:54][CH:53]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1cncc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 12.71 %

Procedure:
DIPEA (387 mg, 3.0 mmol) was added a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (247 mg, 1.0 mmol) in DMF (2 mL) followed by HOBt (162 mg, 1.2 mmol) and EDCI.HCl (229 mg, 1.2 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 56 mg (12.71% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 95.7%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (m, 2H), 8.0 (m, 1H), 7.8 (m, 3H), 7.4 (m, 4H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])[N:6]=[C:5]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21]3[C@H:29]([C:30]([F:33])([F:32])[F:31])[CH2:28][C:27](=[O:34])[NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH3:42][S:43]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][C:10]([F:12])([F:11])[F:13])[N:6]=[C:5]1[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[C:21]3[C@H:29]([C:30]([F:33])([F:32])[F:31])[CH2:28][C:27](=[O:34])[NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:18][CH2:19]1)(=[O:45])=[O:44]
Reactant: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCO)CC2)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1cc(CC(F)(F)F)nc1C1CCN(c2ncnc3c2[C@H](C(F)(F)F)CC(=O)N3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Combine (R)-4-(4-(1-(2-hydroxyethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 1.88 mmol), dichloromethane (14 mL), and triethylamine (0.79 mL, 3.0 eq). Place under nitrogen and cool to 0° C. Add methanesulfonyl chloride (0.17 mL, 1.2 eq) dropwise. After 30 minutes, dilute with dichloromethane and quench with saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give (R)-2-(2-(1-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethyl methanesulfonate as a yellow solid (1.07 g, 96%). MS (ES) m/z=571 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH:17]1(/[CH:23]=[CH:24]/[C:25]([Cl:27])=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:27].[CH:17]1(/[CH:23]=[CH:24]/[C:25]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [C:1]([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14](Br)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([C:30]4[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCCCCCCCn1c2c(c3cc(Br)ccc31)CN(C(=O)OCC)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCn1c2c(c3cc(-c4cccc(C)c4)ccc31)CN(C(=O)OCC)CC2
Yield: 60.4 %

Procedure:
To the mixture of 2-Carbethoxy-8-bromo-5-n-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (4b, 1 equiv.), m-tolylboronic acid (1.1 equiv.) and Pd(PPh3)4 (0.05 equiv.) in 12 mL 1,4-dioxane was added 4 mL aqueous solution of K2CO3 (3 equiv.). The mixture was refluxed under N2 atmosphere for about 10 h. On cooling, the solvent was evaporated and the resulting residue was extracted with DCM (20 mL×3), the DCM layer was washed with brine, dried (Na2SO4) and filtered. The residue obtained on removal of the solvent was purified by column chromatography on silica gel with EtOAc/hexane as eluting solvents to give the target compound 2-carbethoxy-8-m-tolyl-5-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (7). Yield: 60.4%. 1H NMR (300 Hz, CDCl3) δ 7.67 (br, 1H), 7.48-7.43 (m, 3H), 7.35-7.31 (m, 2H), 7.15-7.12 (m, 1H), 4.76 (s, 2H), 4.22 (q, 2H, J=7.2 Hz), 4.03 (t, 2H, J=7.2 Hz), 3.91 (br, 2H), 2.84 (br, 2H), 2.45 (s, 3H), 1.77-1.73 (m, 2H), 1.35-1.27 (m, 13H), 0.89 (t, 3H, J=6.5 Hz). 13C NMR (75 Hz, CDCl3) δ 156.09, 142.48, 138.10, 135.83, 132.72, 128.50, 128.09, 126.98, 125.57, 124.39, 120.83, 118.99, 116.15, 109.29, 106.70, 61.49, 60.36, 43.21, 41.31, 31.75, 30.38, 29.28, 29.13, 27.04, 22.57, 21.56, 14.73, 14.16, 14.03.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:8])[CH2:6][SH:7])[CH2:3][CH2:2]1.C[O-].[Na+].Cl[C:13]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[C:17]([CH3:24])[C:14]=1[C:15]#[N:16].O>CO>[CH:1]1([NH:4][C:5]([C:6]2[S:7][C:13]3=[N:20][C:19]([O:21][CH3:22])=[C:18]([Cl:23])[C:17]([CH3:24])=[C:14]3[C:15]=2[NH2:16])=[O:8])[CH2:3][CH2:2]1
Reactant: COc1nc(Cl)c(C#N)c(C)c1Cl
Reactant: O=C(CS)NC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-cyclopropyl-2-mercapto-acetamide (6.65 g, 50.68 mmol) in MeOH (100 ml), is added sodium methoxide solution (25% wt. in MeOH)(11.59 ml, 50.68 mmol). The resulting solution is stirred at room temperature for 10 minutes, and then treated with 2,5-dichloro-6-methoxy-4-methyl-nicotinonitrile (10.0 g, 46.07 mmol). The reaction vessel is sealed and heated at 100° C. for 2 hours. The reaction mixture is cooled to room temperature and poured over 500 ml of cold water. A thick white precipitate is formed. The mixture is stirred at 0° C. for 10 minutes, then the solid is collected by filtration. The fluffy white solid (title compound) is placed in the vacuum oven at 60° C. to dry overnight (7.74 g, 54%). Mass (m/z): 312.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:1].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[C:4]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 138.1 %

Procedure:
A solution of (R)-tert-butyl 1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (462 mg, 1.06 mmol) in neat TFA (4 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue obtained was dissolved in CH2Cl2 (1 mL) and treated with 2M HCl in ether (4 mL). The resulting precipitate was evaporated from CH3CN (4×10 mL) to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (271 mg, 63% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.79 (d, 1H), 9.65 (s, 1H), 8.25 (br s, 3H), 8.11 (s, 1H), 7.48 (d, 1H), 3.53-3.48 (m, 1H), 3.44-3.31 (m, 2H), 3.23-3.11 (m, 2H), 2.13-2.08 (m, 1H), 1.89-1.80 (m, 2H), 1.75-1.70 (m, 1H), 1.54-1.45 (m, 1H0, 0.82 (d, 4H). LCMS (APCI+) m/z 334 (M+H)+.