Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[S:29])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncccc2C(=O)N(C)c2cccnc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCN1c2ncccc2C(=S)N(C)c2cccnc21
Yield: 162.8 %

Procedure:
A mixture of 2.66 g (0.01 mol) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido-[3,2-b:2'3'-e] [1,4]diazepin-6-one and 2.10 g (0.005 mol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in 50 ml of toluene was refluxed for 21/2 h. The solvent was then removed in vacuo and water was added to the residue. The product was extracted with ethyl acetate, dried (anhydrous sodium sulfate), and concentrated in vacuo. Purification was effected on a silica gel column using methylene chloride as the first eluent, followed by ethyl acetate/hexane (1:4). Removal of the solvent in vacuo gave 2.20 g (74% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione as a yellow powder, which was recrystallized from 10% hexane/ethyl acetate to provide 1.1 g of the title compound as yellow needles, m.p. 157°-158° C.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:16][CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])=[CH:18][CH:19]=1)[C:12]#[N:13]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2ccc(C(=O)c3cccs3)cc2)cc1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: N#CC(Sc1nc2ccccc2s1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
1.191 g of O-(p-toluenesulfonyl)-p-(2-thienylcarbonyl)mandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (567 mg) was added, and the mixture was stirred under ice cooling for 45 minutes, and then at room temperature for 30 minutes. Water (30 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 788 mg (yield 67%) of alpha-(2-benzothiazolylthio)[p-(2-thienylcarbonyl)phenyl] acetonitrile as a viscous oil.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:24][Si:25]([CH3:62])([CH2:41][CH2:42][C:43]([F:61])([F:60])[C:44]([F:59])([F:58])[C:45]([F:57])([F:56])[C:46]([F:55])([F:54])[C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])[CH2:26][CH2:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:29][CH2:28][CH2:27][CH2:26][Si:25]([CH3:62])([CH3:24])[CH2:41][CH2:42][C:43]([F:61])([F:60])[C:44]([F:58])([F:59])[C:45]([F:56])([F:57])[C:46]([F:54])([F:55])[C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: Cc1ccc(S(=O)(=O)OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 4-(5-decyl-pyrimidin-2-yl)-phenol (3.744 g, 13.00 mmol), toluene-4-sulfonic acid 4-[dimethyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-octyl)-silanyl]-butyl ester (7.58 g, 13.00 mmol) and cesium carbonate (4.69 g, 14.4 mmol) in DMF (35 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: Br[CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH2:36][CH3:37])([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=3)[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[C:30]([CH3:35])[CH:29]=3)([CH2:36][CH3:37])[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CCC(Br)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 62 h
Yield: 87.6 %

Procedure:
Add 4-bromo-2,2-dimethylhexane-3-one (660 mg, 3.187 mmol) to a mixture of 6-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (1.1 g, 3.035 mmol), and K2CO3 (629 mg, 4.55 mmol) in DMF (10 ml). Maintain the reaction mixture 45° C. for 14 h. Add an additional amount of 4-bromo-2,2-dimethylhexane-3-one (314 mg, 1.52 mmol) and maintain the mixture at 60° C. while stirring for 62 h. Cool the reaction mixture and dilute it with CH2Cl2, filter, and concentrate in vacuo. Chromatograph the resulting residue (CH2Cl2to 1% EtOAc/CH2Cl2) to give the title compound as a colorless viscous oil (1.299 g, 88%). 1NMR (400 MHz, CDCl3) δ ppm: 0.62 (t, J=7.2 Hz, 6H), 1.01 (t, J=7.6 Hz, 3H), 1.16 (s, 9H), 1.88 (m, 2H), 2.16 (m, 4H), 2.19 (s, 3H), 3.97 (s, 3H), 4.86 (dd, J=5.2, 1.6 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.88 (m, 2H), 7.14 (dd, J=7.2, 1.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.04 (dd, J=6.4, 2.0 Hz, 1H), 8.52 (s, 1H). High Res. ES-MS: 511.2824; calc. for C32H40O4+Na: 511.2825.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:20]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C:20]2[C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)=[N:18][CH:19]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC2CCNCC2)cc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Trifluoroacetic acid (0.1 μL, 1.298 μmol) was added to tert-butyl 4-(2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (4 mg, 7.97 μmol) dissolved in dichloromethane (0.45 mL) and the mixture was stirred for 1 hr. The mixture was concentrated and purified by ion exchange on Isolute SCX II acidic resin (1 g), eluting with MeOH then 2M NH3-MeOH. The basic fractions were combined and concentrated. Preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane) gave 5-(5-(4-methoxyphenyl)-4-(piperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (2 mg, 4.98 μmol, 62.5% yield) as a yellow powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[O:7]([C:14]([NH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27]([NH:31][C:32]([C:34]3([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH2:36][CH2:35]3)=[O:33])=[C:26]([F:47])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:47][C:26]1[CH:25]=[C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:4]3[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]3)=[O:7])[CH:22]=2)[C:29]([F:30])=[CH:28][C:27]=1[NH:31][C:32]([C:34]1([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])[CH2:36][CH2:35]1)=[O:33]
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 81 %

Procedure:
(S)-3-Hydroxypyrrolidine (0.0577 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, and the solid was washed with water (20 ml, three times), and the solid was dried by hot air (80° C.) for 1 day to give the title compound (159.0 mg, 81%) as a white solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(C2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2)C(C2CCCCC2)NC(C(=O)O)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 50b (0.69 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.8 g, 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:23]=O>C(O)(=O)C>[F:22][C:2]([F:21])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][C:12]2[N:17]3[C:18](=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:23]1)=[O:4]
Reactant: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)F
Reactant: C=O
Solvent: CC(=O)O
Product: O=C(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3860 mg (12.28 mmol) of 5-[N-(4-trifluoroacetamidobutan-1-yl)aminomethyl]imidazo[1,2-a] pyridine in 15 ml of acetic acid was added 13.8 ml (184.21 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 150 ml of dichloromethane. The organic layer was washed with 200 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2890 mg of the desired compound (72.0%, a white solid).
Reaction SMILES: [CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([SH:10])=[N:8][N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:15]1[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C.C1C=CC=CC=1>[CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([S:10][C:15]2[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1nccnc1Cl
Reactant: CC(C)Sc1nnc(S)n1C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Sc1nnc(Sc2nccnc2C#N)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(isopropylthio)-4-methyl-4H-1,2,4-triazole-3-thiol (379 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)[CH3:3].[BH4-].[Na+].[CH2:28]1COCC1>CCOC(C)=O.CCOCC>[CH3:28][O:1][CH:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)[CH3:3]
Reactant: CC(O)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(C)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
9-(1-hydroxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 47-2. A solution of 47-1 (400 mg, 1.20 mmol) in THF (30 mL) was treated with NaBH4 (23 mg, 0.60 mmol) and the mixture was stirred at RT for 48 h. The mixture was then diluted with AcOEt, and washed with H2O. The org. phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chroatography (SiO2, DCM to DCM/MeOH 95:5) to afford a yellow oil that was suspended in Et2O. The suspension was filtered and the filter cake was dried on vacuo to give the title compound (145 mg) as a light yellow solid. UPLC-MS: MS 337.3 (M+H+); UPLC rt 0.60 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.49 (d, J=6.26 Hz, 3 H); 1.82-1.96 (m, 1 H); 2.86-3.09 (m, 2 H); 3.75-3.99 (m, 2 H); 3.92 (s, 3 H); 4.48 (d, J=12.12 Hz, 2 H); 5.17 (d, J=3.52 Hz, 1 H); 6.82 (br. s., 1 H); 7.19 (s, 1 H); 7.32-7.40 (m, 2 H); 7.61 (d, J=7.82 Hz, 1 H); 7.64 (d, J=7.82 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].NO.CC(O)=O.CO[CH:38](OC)[N:39](C)C>O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]4[O:26][N:39]=[CH:38][N:27]=4)=[CH:28][CH:29]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Reactant: COC(OC)N(C)C
Agent: NO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-c4ncno4)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of step B (80 mg, 0.203 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 120° C. for 4 h. Upon cooling to RT, the solvent was removed under vacuum to leave a residue. The resulting residue was dissolved in 1,4-dioxane (1 mL) followed by the addition of NH2OH (0.016 mL of 50% solution in H2O, 0.243 mmol) and HOAc (0.5 mL). The reaction was stirred at 90° C. for 4 h before being cooled to RT. The reaction was quenched with a saturated aqueous solution of NaHCO3 and the layer was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:ethyl acetate) to give the title compound. MS (ESI) m/z 420 [M+H]+. GPR119 Human EC50: 5.5 nM
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2-propanesulfonyl chloride. Off-white solid. MS (m/z): 519.3 (M+H)+.
Reaction SMILES: COCCO[C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>O1CCOCC1>[N:7]1[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][CH:6]=1
Reactant: COCCOc1cc(C(=O)OC)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccncc1
Temperature: 80 °C
Yield: 139.6 %

Procedure:
Methyl 2-(2-methoxyethoxy)pyridine-4-carboxylate (562 mg, 2.66 mmol), dioxane (6 mL) and NaOH (7.1 mL of 1 M, 7.1 mmol) were combined and the mixture was heated at 80° C. for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl and was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 242-methoxyethoxy)pyridine-4-carboxylic acid (457 mg, 87%) as a white solid. ESI-MS m/z calc. 197.2, found 198.3 (M+1)+; Retention time: 0.66 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.64 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.39 (d, J=5.2 Hz, 1H), 7.18 (s, 1H), 4.51-4.27 (m, 2H), 3.78-3.54 (m, 2H), 3.30 (s, 3H).
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[C:17]1(N)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].O>CO>[NH:5]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=[C:4]1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.32 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (3 g; 19.21 mmol) in 20 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 3.4 g of 1,2-phenylenediamine bishydrochloride, the reaction mixture was stirred further overnight and then added to 100 ml of H2O, and the resulting solid was filtered off and dried in vacuo.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34].Cl>C(#N)C>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH3:34]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 200 °C

Procedure:
A mixture of Example 229A (143 mg, 0.393 mmol), triethylamine (0.165 mL), acetonitrile (1.2 mL), and N,N-diethyl-1,3-propanediamine (0.37 mL, 2.36 mmol) was sealed and heated in microwave for fifteen hundred seconds at 200° C. The solution was cooled and adjusted to pH 5 with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 460 (M+H)+; (ESI(−)) m/e 458 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H), 9.54 (s, 1H), 9.02 (br s, 1H), 7.51 (dd, 1H), 7.41 (dt, 1H), 6.96 (2, 1H), 6.86 (d, 1H), 6.64 (m, 2H), 6.00 (t, 1H), 3.29 (q, 2H), 3.09 (m, 7H), 2.65 (br s, 4H), 1.89 (m, 2H), 1.67 (br s, 4H), 1.14 (t, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[O:46]1[C:50]2[CH:51]=[CH:52][C:53](B(O)O)=[CH:54][C:49]=2[CH2:48][CH2:47]1>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>[O:46]1[C:50]2[CH:51]=[CH:52][C:53]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]5[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]5)=[O:12])[CH:9]=4)[N:4]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:3]=3)=[CH:54][C:49]=2[CH2:48][CH2:47]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccc4c(c2)CCO4)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
(R)-tert-butyl 3-(3-bromo-1-trityl-1H-indazole-5-carboxamido)piperidine-1-carboxylate (650 mg, 1 mmol) was added to a vial containing 2,3-dihydrobenzofuran-5-ylboronic acid (180 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). After purging the vial with nitrogen gas, dioxane (3 mL) and 2M sodium carbonate (1.5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (10 mL) was added and was extracted using dichloromethane (3×25 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using flash chromatography.