Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([NH:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([OH:37])[CH:28]=2)=[O:25])=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1.Cl.[N+:50]([CH3:53])([O-:52])=[O:51]>CN(C=O)C.O>[CH2:1]([O:37][C:29]1[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH2:53][N+:50]([O-:52])=[O:51])[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1O
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccc(Cl)cc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Benzyl bromide (0.575 g, 3.36 mmol) and K2CO3 (0.77 g, 5.60 mmol) were added to a stirred solution of 45 (0.9 g, 2.80 mmol) in anhydrous DMF (20 ml) under Ar. The reaction mixture was stirred at room temperature overnight and the mixture was poured in water (20 ml). The product was extracted with ethyl acetate (2×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure. The resultant crude 46 was stirred in the microwave reactor in presence of DBU (0.468 g, 3.08 mmol), and nitromethane (10 mL in the microwave), at 100° C. for 15 min. After cooling to room temperature, the reaction mixture was poured into HCl 1M (15 ml). The product was extracted with ethyl acetate (2×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure. Chromatography on silica gel (80:20, hexanes/ethyl acetate) afforded 50 (0.521 g, 1.10 mmol, 40%) as a white solid, mp 81-83° C. 1H NMR (400 MHz, CDCl3) δ 2.75 (1H, dd, J 6.6, 15.4 Hz), 2.85 (1H, dd, J 7.6, 15.6 Hz), 3.87 (3H, s), 4.07 (1H, quint, J 6.8 Hz), 4.70 (1H, dd, J 7.8, 13.0 Hz), 4.83 (1H, dd, J 6.4, 12.8 Hz), 5.17 (2H, s), 6.77 (1H, dd, J 2.0, 8.4 Hz), 7.19 (3H, d, J 8.0 Hz), 7.32 (3H, d, J 8.8 Hz), 7.39 (2H, t, J 8.0 Hz), 7.51 (2H, d, J 7.2 Hz), 7.55 (1H, bs), 7.82 (1H, d, J 8.0 Hz). 13C NMR (100 MHz, CDCl3) δ39.89, 40.59, 52.18, 70.79, 79.25, 104.96, 111.08, 116.14, 127.20, 128.11, 128.76, 128.92, 129.61, 133.17, 134.28, 136.56, 137.04, 142.50, 159.65, 166.36, 168.17. νmax (pure sample)/(cm−1) 3329, 1695, 1591, 1549, 1530, 1245, 1090. MS (API-ES): m/z 483 [M+H]+ (100%), HRMS (API-ES) m/z found 483.1236 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]([O:19]CC)=[O:18])[CH2:15][C:14]2([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:31][C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][C:14]2([CH2:13][N:12]([C:10](=[O:11])[C@H:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:16]([C:17]([OH:19])=[O:18])[CH2:15]2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])[CH3:32]
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)CC1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a solution of 8-(1,1-dimethylethyl) 3-ethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (132) (125 mg, 0.27 mmol) in THF/water/MeOH (1.2 mL/0.6 mL/0.6 mL) was added lithium hydroxide monohydrate (22 mg, 0.53 mmol) and the reaction stirred at room temperature for 1.5 h. The reaction was treated with 1N HCl (0.5 mL) and partitioned between EtOAc and 0.1 N HCl (10 mL each) and the aqueous layer extracted with EtOAc (10 mL). The organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (107 mg, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29-12.54 (m, 1H) 7.08-7.44 (m, 1H) 4.47 (t, J=5.4 Hz, 1H) 4.13-4.30 (m, 1H) 3.86-4.13 (m, 3H) 3.45-3.58 (m, 3H) 3.16-3.27 (m, 2H) 2.64 (br. s., 1 H) 2.15-2.31 (m, 1H) 1.81-1.95 (m, 1H) 1.43-1.67 (m, 3H) 1.29-1.43 (m, 11H) 0.69-1.03 (m, 6H). LC-MS ESI (M−H)−=440.59.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][NH2:22].ClC1C=CC=CC=1Cl>O>[C:2]1([C:1]23[NH:23][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[C:11](=[O:13])[C:10]2[C:9]3=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: NCCCCN
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=C1c2ccccc2C2(c3ccccc3)NCCCCN12

Procedure:
22.6 Parts of o-benzoyl-benzoic acid and 10.1 parts of 1,4-butanediamine in 100 parts by volume of o-dichlorobenzene are heated within 2 hours to 179° whereby reaction water and a little dichlorobenzene azeotropically distill off. The solvent is then distilled off in vacuo whereupon an oil remains which spontaneously crystallises after some time. On recrystallising from benzene, the pure 11b-phenyl-1,2,3,4,5,11b-hexahydro-7H-[1,3]-diazepino[2,1-a]isoindol-7-one is obtained of the formula ##STR21## It melts at 180°-181°. On using o-(p'-chlorobenzoyl)-benzoic acid, 11b-(p-chlorophenyl)-1,2,3,4,5,11b-hexahydro-7H-[1,3]diazepino[2,1-a]isoindol-7-one is obtained in the same manner. It melts at 134°-135°.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N+:6]([O-])[CH:5]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][N:6]=1
Reactant: [O-][n+]1cc(C2CC2)c2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc(C2CC2)c2ccccc12
Yield: 5.76 %

Procedure:
A solution of 4-cyclopropylisoquinoline-2-oxide (0.3 g, 1.620 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get the desired compound (0.02 g, 5.76%) as oil. 1H NMR (400 MHz, CDCl3): δ ppm 8.37-8.35 (d, J=8 Hz, 2H), 8.08 (s, 1H), 7.81 (t, J=8 Hz, 1H), 7.70 (t, J=4 Hz, 1H), 2.18 (m, 1H), 1.11 (t, J=4 Hz, 2H), 0.80 (t, J=8 Hz, 2H); MS: MS m/z 204.28 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH4+:17].[OH-]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([NH2:17])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)benzoyl chloride (1.8 g, 7.10 mmol) in THF (20 mL) was added NH4OH (2.96 mL, 21.30 mmol) at 20° C. The mixture was stirred at 20° C. for 12 h. LCMS showed the reaction was finished. The mixture was extracted with EA, washed with water, and concentrated to give 3-nitro-5-(trifluoromethyl)benzamide (1.5 g, 5.86 mmol, 83% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.62 (br.s, 2H), 8.53 (s, 1H), 7.93 (s., 1H). ES-LCMS m/z 235 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1.[C:20]([O-:23])([O-])=O.[Na+].[Na+]>CN(C=O)C>[O:23]([C:16]1[CH:17]=[CH:18][C:13]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[N:14][CH:15]=1)[C:20]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OC1CN2CCC1CC2
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OC3CN4CCC3CC4)nc2)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol)) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. 2-Chloro-5-bromopyridine (7.1 g, 30 mmol) was added and the mixture was stirred at 100° C. for 6 hours. The mixture was allowed to cool to room temperature, treated with Na2CO3 (2M, 10 mL) at 10° C., and extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46–1.58 (m, 1H), 1.60–1.88 (m, 2H), 1.96–2.10 (m, 1H), 2.24–2.30 (m, 1H), 2.72–2.98 (m, 5H), 3.42–3.46 (m, 1H), 5.00–5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65](O)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1>CN(C=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1
Reactant: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: C1COCCN1
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: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HATU (0.38 g, 0.99 mmol), diisopropylethylamine (0.41 mL, 2.48 mmol) and morpholine (0.08 mL, 0.99 mmol) were added at 0° C. to a solution of 300b) (0.35, 0.83 mmol) in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 6 h and then quenched with ice-cold water. The mixture was extracted with dichloromethane (2×50 mL), the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The remnant was purified by flash column chromatography [silica, dichloromethane with 1.5% methanol]. White solid. Yield: 0.32 g (80% of theory)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@@H](F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 91.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (235 mg, 0.389 mmol) prepared in Example 106e, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (162 mg, 92%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.[Li]C(C)(C)C.C(=O)=O.[C:20](OC)(=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:25]
Reactant: Cn1ccc2cccc(Br)c21
Reactant: COC(=O)C(=O)OC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1cccc2ccn(C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
A solution of 1-methyl-7-bromoindole (1.53 g, 7.29 mmol) in THF (50 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (10 mL, 17 mmol) added dropwise over 10 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (2.13 g., 18.1 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into EtOAc and the EtOAc washed with pH 7.0 buffer, saturated aq NaHCO3, brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (896 mg, 57%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.48 (d, J=3 Hz, 1H), 7.20 (dd, J=8 Hz, 1H), 6.66 (d, J=3 Hz, 1H), 3.95 (s, 3H), 3.79 (s, 3H). 13C (75.5 MHz, DMSO-d6) 185.80, 164.31, 133.64, 133.02, 131.23, 128.07, 127.04, 118.77, 118.25, 102.15, 53.01, 37.49. IR (CHCl3, cm−1) 1739, 1678. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.48; H, 5.23; N, 6.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]=O)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2].[NH2:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][NH:27][CH:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(C=O)c2)c(Cl)c1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(CNC3CCc4ccccc43)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-[3,5-dichloro-4-(3-formyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester (30 mg, 0.08 mmol) and aminoindan (10 mg, 0.08 mmol) in dichloroethane (1.0 mL) was added sodium triacetoxyborohydride (22.4 mg, 0.11 mmol) and acetic acid (4.5 mg, 0.08 mmol) in single portions. After stirring at RT for 3 h, the solution became clear and yellow. The solution was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated to give the crude product as a yellow glass. The crude product was purified by preparative TLC (5% Et2O in CH2Cl2) to afford the title compound as an off-white solid. NMR (400 MHz, CDCl3) d 8.94 (s, 1H), 7.74 (s, 2H), 7.36-7.37 (d, 1H), 7.19-7.25 (m, 4H), 6.75-6.77 (d, 1H), 6.61-6.64 (dd, 1H), 6.54-6.55 (d, 1H), 4.40-4.46 (q, 2H), 4,30-4.33 (t, 1H), 4.05-4.08 (d, 1H), 3.95-3.98 (d, 1H), 2.98-3.06 (m, 1H), 2.81-2.88 (m, 1H), 2.42-2.51 (m, 1H), 1.88-1.96 (m, 1H), 1.41-1.45 (t, 3H). MS Calc.: 514.20, Found: 513.1 (M−1).
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:24])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)C.Cl.O1CCOCC1>CCO>[NH2:6][CH:7]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:24])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate (1.060 g; 2.84 mmol) in EtOH (15 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (1.5 ml; 6.00 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 30 min. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate. LC-MS (conditions A): tR=0.50 min. and [M+H]+: 270.33 g/mol.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)N(NCCCCCC(O)=[O:28])C(=O)C=C1>CN(C=O)C>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)CCCCCNN1C(=O)C=CC1=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One equivalent (2.24 g, 0.01 mole) of HNSA was mixed together - with one equivalent (2.06 g, 0.01 mole) of dicyclohexylcarbodiimide and one equivalent (2.10 g, 0.01 mole) of N-maleimido-6-aminocaproic acid in 25 ml of DMF at room temperature overnight. A white precipitate of dicyclohexyl urea was formed. The precipitate was filtered and 300 ml diethyl ether was added to the mother liquor. After about 10 minutes to four hours a gummy solid that precipitated from the mother liquor was formed. This solid was found to contain 58% of active HNSA ester and 42% of free HNSA by the analysis described above. The product was positively identified as mal-sac-HNSA ester by its reactivity with amines. The yield of the pure ester was estimated to be approximately 30% of theoretical; the purified material consisted of 99% ester.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>ClCCl>[CH3:34][O:33][C:31]1[CH:30]=[C:27]([CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:26]=[C:25]([O:24][CH3:23])[CH:32]=1
Reactant: OCCO
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: COc1cc(OC)cc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
4.2 ml of ethylene glycol, 4.1 ml of trimethyl orthoformate and 5 mg of p-toluenesulfonic acid are added to a solution of 5 g of 3,5 dimethoxy benzaldehyde in 100 ml of dichloromethane. It is allowed to stir for 20 more hours at 25° C. Then, it is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 5.67 g of product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C@H:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 68.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide (78 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylic acid (100 mg), (R)-(−)-1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.86-7.65 (m, 2H), 7.48 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (bs, 3H), 3.26-3.19 (m, 2H), 1.09 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30](O)=[O:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=2)[CH2:16][CH2:15]1.O.O[N:35]1[C:39]2C=CC=[CH:43][C:38]=2N=N1.Cl.C(/N=N/CCCN(C)C)C.N1CCC1>C(Cl)Cl>[N:35]1([C:30](=[O:31])[CH2:29][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:18][CH2:19]3)=[C:2]([F:1])[CH:3]=2)[CH2:43][CH2:38][CH2:39]1
Reactant: On1nnc2ccccc21
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)O)cc3F)CC2)nc1
Agent: C1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)N4CCC4)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
2-(3-Fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetic acid (Step D product, 70 mg, 0.158 mmol), 1-HYDROXYBENZOTRIAZOLE HYDRATE (36.3 mg, 0.237 mmol) and (E)-3-(ETHYLDIAZENYL)-N,N-DIMETHYLPROPAN-1-AMINE HYDROCHLORIDE (42.5 mg, 0.237 mmol) were dissolved in CH2Cl2 (3 ml). The mixture was stirred at RT for 10 min., to which was added AZETIDINE (0.016 ml, 0.237 mmol). The reaction mixture was stirred at RT overnight. TLC and LC-MS showed the SM was completely consumed. The mixture was diluted with DCM, washed with water, dried over MgSO4, and evaporated to dryness. The crude product was purified by prep TLC (pure EtOAc) to afford 58.2 mg (76%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (S, 2H), 7.38 (m, 1H), 7.05 (m, 2H), 4.70 (m, 2H), 4.60-4.50 (m, 2H), 4.25 (s, 2H), 4.10˜4.00 (m, 4H), 3.70 (m, 1H), 3.40 (m, 3H), 3.32 (s, 3H), 2.83 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H), 1.82 (m, 1H), 1.40-1.20 (m, 3H), 1.05 (m, 1H), 0.70 (m, 2H), 0.40 (m, 1H). LC/MS (m/z): 483 (M+H)+, GPR119 Human EC50: 5.16 nM.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1.[C:18]([O:23][C@@H:24]([C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(O)(C)C>[C:18]([O:23][C@@H:24]([C:26]1[N:27]=[C:28]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][C:2]([CH3:1])=[N:7][C:6]=3[CH2:8]2)[CH:29]=[CH:30][N:31]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: Cc1nc2c(c(-c3ccccc3)n1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(nc(C)nc3-c3ccccc3)C2)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (prepared according to the method of Example 86, Step D, 6.8 g, 30.0 mmol) in isopropanol (125 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 30 mmol) followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at reflux for 8 h, cooled to room temperature overnight, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/ethyl acetate) to give 11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.62-7.40 (c, 5H), 6.45 (d, 1H), 5.69 (q, 1H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H), 1.77-1.63 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 418 (MH+).