Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[CH3:24]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:23][C:20]1[C:19]([CH3:24])=[C:18]([NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:2][CH:3]=2)(=[O:9])=[O:8])[O:22][N:21]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1noc(N)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
The 4-biphenylsulfonyl chloride from step (a) was added to a solution of 5-amino-3,4-dimethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1 N HCl (2×25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue that, after purification by column chromatography over silica gel (1% methanol in chloroform as eluent), yielded 337 mg (45%) of a white solid. Recrystallization from ethyl acetate/hexanes gave white crystals, m.p. 154-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47]O)([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:43][C:44]([NH:45][CH2:46][CH2:47][O:23][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:26][CH:25]=1)=[O:49])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 48.3 %

Procedure:
[4-(4-Benzyloxycarbonylaminobutyl)phenoxy]acetic acid 48 (240 mg, 0.67 mmol) was dissolved in anhydrous CH2Cl2 (6 mL). To the solution was added DMAP (98 mg, 0.80 mmol), followed by EDC-HCl (154 mg, 0.81 mmol). The reaction mixture was stirred at room temperature for 15 min. (2-Hydroxyethyl)carbamic acid tert-butyl ester (0.21 mL, 1.34 mmol) was then added and the stirring was continued for 16 h. Solvent was removed by rotary evaporation. The residue was subjected to flash silica gel column chromatography eluting with ethyl acetate/dichloromethane (1:20, 1:15, and 1:10, v/v) to give the desired ester 44a as a colorless oil (162 mg, 48% yield). 1H NMR (300 MHz, CDCl3) δ 1.35-1.65 (m, 4H), 1.44 (s, 9H), 2.45-2.58 (m, 2H), 3.10-3.22 (m, 2H), 3.25-3.42 (m, 2H), 4.18-4.28 (m, 2H), 4.62 (s, 2H), 4.70 (br s, 1H), 4.84 (br s, 1H), 5.08 (s, 2H), 6.81 (d, 2H), 7.07 (d, 2H), 7.25-7.38 (m, 5H). m/z (ESI) 501 [C27H36N2O7+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: ClCCCI
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (2 g, 10.41 mmol) at 0° C. under argon was added sodium hydride, 60% (0.624 g, 15.61 mmol). The mixture was stirred at 0° C. until bubbling ceased, approximately 30 min. To this mixture was then added 1-chloro-3-iodopropane (3.29 ml, 31.2 mmol). The mixture was then allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were then washed with a 1:1 mixture of water and brine (3×) then brine (1×). The organic phase was then dried, filtered and concentrated on to silica gel, then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.05 g, 7.63 mmol, 73.3% yield) as a yellow solid. 1H NMR (DMSO-d6) δ 8.15 (m, 1H), 8.13 (dd, J=9, 2.7 Hz, 1H), 7.36 (d, J=9 Hz, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.5 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.99 (quint, J=7.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo [d][1,3]oxazin-2-one and 1-bromo-3-chloro-4-fluorobenzene according to Procedure A. White solid: mp 211-212° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.92 (dd, 1H, J=7.13, 2.19 Hz), 7.71-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.49 (t, 1H, J=8.95 Hz), 6.96 (d, 1H, J=8.01 Hz), 1.67 (s, 6H); MS (EI) m/z 305 ([M+H]+, 20%); Anal. Calc. For C16H13CIFNO2: C, 62.86; H, 4.29; N, 4.58. Found: C, 62.52; H, 4.45; N, 4.42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=O)[C:6]=2[CH:16]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH:8]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]3)[C:6]=2[CH:16]=1
Reactant: CCN1CCNCC1
Reactant: O=C1Cn2cccc2Sc2ccc(Cl)cc21
Product: CCN1CCN(C2=Cn3cccc3Sc3ccc(Cl)cc32)CC1

Procedure:
Starting from 7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.19 g, 0.76 mmol) and N-ethylpiperazine (0.70 mL, 6.13 mmol), the title compound was obtained following the above described procedure for (1). After purification, 0.19 g of the desired product were obtained as a white solid (yield 74%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:43][CH2:44][CH:45]([OH:52])[CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH3:49]>CN(C=O)C>[CH2:48]([N:47]([CH2:50][CH3:51])[CH2:46][CH:45]([OH:52])[CH2:44][NH:43][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:49]
Reactant: CCN(CC)CC(O)CN
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)CNC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol), HOBt 0.16 g (1.2 mmol), EDCI 0.24 g (1.2 mmol) and triethylamine 0.2 g (2.0 mmol) in 10 ml DMF was stirred at room temperature for 20 min, then 1-amino-3-(diethylamino)propan-2-ol 0.31 g (2.1 mmol) was added. After stirred at room temperature for 24 hours, the mixture was poured into the ice water and extracted with CH2Cl2. The organic layer separated was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column, eluted with CH2Cl2/MeOH (3:1), to give 0.26 g (81%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(C)(=O)=O
Yield: 48.2 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with methanesulfonyl chloride (260 μL, 3.26 mmol) to provide 0.70 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide as a tan powder, m.p. 121-124° C. Analysis: Calculated for C23H35N5O3S: %C, 61.99: %H, 7.92; %N, 15.72; Found: %C, 62.01; %H, 7.97; %N, 15.75.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2ccc(N)cc21
Reaction time: 0.25 h

Procedure:
To a stirring solution of 1-Boc-6-nitroindole (250 mg, 0.95 mmol) in THF (5 mL) and MeOH (10 mL) at 0° C., was added Ni(OAc)2.4H2O (473 mg, 1.9 mmol). After complete dissolution, NaBH4 (143 mg, 3.8 mmol) was added slowly. Upon addition of the NaBH4, the reaction mixture turned black and vigorous gas evolution was observed. After 15 min, the solvents were removed in vacuo and the residue was dissolved in a stirring mixture of ethyl acetate (100 mL), conc NH4OH (10 mL) and water (20 mL). The layers were separated and the organic phase was washed again with 33% conc NH4OH in water and then washed twice with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[C:22]12([C:32](O)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)/[C:4](=[N:8]/[C:32]([C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[O:33])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Reactant: BrCCc1cccc2ccccc12
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCc2cccc3ccccc23)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, 1-(2-bromo-ethyl)-naphthalene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.61-1.80 (m, 6H) 1.82-1.93 (m, 6H) 1.95-2.05 (m, 3H) 2.13 (d, J=4.06 Hz, 6H) 3.40-3.56 (m, 2H) 4.26-4.52 (m, 2H) 7.34-7.41 (m, 1H) 7.41-7.46 (m, 1H) 7.51-7.60 (m, 2H) 7.78-7.92 (m, 1H) 7.92-8.02 (m, 1H) 8.27-8.44 (m, 1H); MS (ESI) m/z 445 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:29]([NH:31][NH2:32])[CH3:30].CCN(CC)CC>CCO>[CH2:29]([N:31]1[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:32]1)[CH3:30]
Reactant: CCNN
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Yield: 25.9 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (1.0 g, 3.39 mmol), ethyl hydrazine oxalate (763 mg, 5.08 mmol) and Et3N (709 □L, 5.08 mmol) in EtOH (50 mL) was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The organics were separated, washed with brine (50 mL), concentrated under reduced pressure, and the residue purified by column chromatography on silica eluting with 40% EtOAc/iso-hexanes to yield first 3-{1-ethyl-5-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-3-yl}-benzonitrile (280 mg, 26%) (by-product) and then 3-{1-ethyl-3-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-5-yl}-benzonitrile (380 mg, 35%).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([OH:26])=O)[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[CH:48]=1>C(Cl)Cl>[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:56])([F:57])[F:58])[CH:48]=4)=[O:26])[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Nc1ccc(CO)c(C(F)(F)F)c1
Reactant: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)O)[C@@H]1c1ccc(NC2CCCC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
Step b) Methanesulfonyl chloride (378 mg, 3.3 mmol) was added to a solution of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid prepared above (1.4 g, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) in dry CH2Cl2 (25 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred for an additional 15 minutes, then [4-amino-2-(trifluoromethyl)phenyl]methanol (631 mg, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) were added sequentially. The reaction mixture was allowed to attain room temperature over a period of 30 minutes. When TLC and LCMS indicated completion of the reaction, excess solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in dichloromethane) to get the desired compound (1.2 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.50 (bs, 0.6H), 9.38 (bs, 0.4H), 7.75-7.70 (m, 1H), 7.50-7.33 (m, 3H), 7.24-7.19 (m, 2H), 7.06-6.90 (m, 2H), 6.67-6.55 (m, 3H), 4.77-4.76 (m, 2H), 3.78-3.66 (m, 1H), 3.32-3.00 (m, 3H), 2.44-1.45 (m, 17H). MS: (ES) m/z 598 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:21][CH3:22])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>[Pd]>[CH2:19]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7].[CH3:2][CH2:22][O:21][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCC(=O)OC
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 140 °C

Procedure:
A stirred autoclave was charged, at room temperature, with 67 g (728 mmol) of glycerol, 8.2 g (36 mmol) of methyl tridecylate, 0.82 g (10 wt %) of camphosulfonic acid and 0.74 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 140° C. for 24 h, stirring vigorously. After 24 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was then filtered on a MILLIPORE® filter (a membrane filter) (0.45 μm) and was rinsed with absolute ethanol. The solvents were then evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×20 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was analyzed by GC/MS. 1-O-tridecyl-glycerol ether was obtained at 16% GC yield.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[N:73]1[CH:78]=[CH:77][N:76]=[C:75]2[NH:79][CH:80]=[CH:81][C:74]=12>>[N:73]1[CH:78]=[CH:77][N:76]=[C:75]2[NH:79][CH:80]=[C:81]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)[C:74]=12
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Reactant: c1cnc2[nH]ccc2n1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3nccnc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide) using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 5H-Pyrrolo[2,3-b]pyrazine as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.269 (s, 1H) 10.059 (t, J=5.8 Hz, 1H) 8.472 (d, J=2.5 Hz, 1H) 8.404 (dd, J=7.2, 2.2 Hz, 1H) 8.299 (d, J=2.8 Hz, 1H) 8.256-8.214 (m, 2H) 7.497 (d, J=3.6 Hz, 1H) 7.471-7.347 (m, 2H) 7.182-7.127 (m, 1H) 6.993 (d, J=3.6 Hz, 1H) 6.598 (t, J=6.7 Hz, 1H) 5.193 (s, 2H) 4.678 (d, J=5.8 Hz, 2H; MS m/z=478.09 M+H.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28]([C:34](OC)=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18].CCO>C1COCC1>[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28]([CH:34]=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18]
Reactant: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C)c2C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(C)c2C)c1
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
1M DIBAL in toluene (8.7 mL, 8.7 mmol) was added dropwise over 12 minutes to a stirred solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carboxylate (which may be prepared as described in Description 52) (1.32 g, 4.35 mmol) in dry THF (25 mL) at −75° C. The reaction was stirred at this temp for 2.5 h then EtOH (0.2 ml) was added to quench. After 1 minute the reaction was poured into saturated Rochelle salt solution (200 ml). The mixture was extracted with EtOAc (100 ml) then DCM (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated to a white solid, which was dried at RT under vacuum for 16 h to afford 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carbaldehyde (D53) (1.17 g);
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[CH2:2].[C:13](#N)C.[Cl:16][C:17]([F:21])=[C:18]([F:20])[F:19]>C([O-])([O-])=O.[Cs+].[Cs+].O>[Cl:16][C:17]([F:21])([CH3:13])[C:18]([F:20])([F:19])[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH:1]=[CH2:2])[CH2:6][CH2:7]1
Reactant: FC(F)=C(F)Cl
Reactant: CC#N
Reactant: C=COCC1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: C=COCC1CCC(COC(F)(F)C(C)(F)Cl)CC1
Temperature: 30 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Into a 450 mL capacity PARR® reactor, 1,4-cyclohexanedimethanol vinyl ether (50 g, 294 mmol), acetonitrile (100 mL), and Cs2CO3 (2 g, 6 mmol) were added. The PARR® reactor was cooled to ˜30° C., partially evacuated and chlorotrifluoroethylene (34 g, 294 mmol) was condensed and the resultant mixture was heated at ˜50-60° C. with stirring for 3 hours. After this, the PARR® reactor was cooled to room temperature, vented in the fume hood and the reaction mixture was poured into ˜150 mL water and the lower layer containing the crude product separated, and was concentrated under reduced pressure 0.05 mmHg) at 25-30° C. to afford the desired product as a colorless viscous liquid (49 g, 58% yield) which is a mixture of cis/trans isomers in the ratio 73:18; refractive index of 1.415 at 23.7° C,; GC/MS (EI mode): m/z at 286 for M+; 19F and 1H NMR spectral data are consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:39])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1
Reactant: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 26.4 %

Procedure:
A solution of 97.0 mg (0.170 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-methylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (30 mL) was treated with MeOH (1 mL) and TFA (10 mL) at RT for 1 h. MeOH (10 mL) was added and the solvents were removed in vacuo. The residue was purified by RP-HPLC (C18) with 40-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 19.8 mg (26%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 9.41 (s, 1H), 8.24 (d, 1H, J=8.0 Hz), 7.91 (s, 1H), 7.22 (dd, 1H, J=8.0, 2.0 Hz), 5.79-5.74 (m, 1H), 5.08-5.00 (m, 1H), 3.34-3.27 (m, 2H), 3.06-2.99 (m, 2H), 2.70 (d, 3H, J=5.2 Hz), 2.35-2.28 (m, 2H), 2.10-2.05 (m, 2H), 1.59 (t, 2H, J=6.4 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O3S, 442.2 (M+H). found 442.1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(Cc1ccccc1CN)S(C)(=O)=O
Product: CN(Cc1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
156 c) N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-benzyl}-N-methyl-methanesulfonamide was prepared 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-aminomethyl-benzyl)-N-methyl-methanesulfonamide (540.0 mg, 2.365 mmol) in a manner analogous to Example 2d. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.7 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-7.30 (m, 3H), 6.88 (t, J=7.6 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.25-5.19 (m, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.40 (s, 2H), 2.87 (s, 3H), 2.73 (s, 3H). MS=380 (MH)+.