Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][C:38](=[O:39])[O:40][CH3:41])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Yield: 11.2 %

Procedure:
Prepared using General Procedure 15: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (20.0 mg, 0.05 mmol) in DMF (1 mL) was added DIEA (19.4 mg, 0.15 mmol) and methyl chloroformate (9.5 mg, 0.1 mmol) for 4 h at room temperature. The solvent was evaporated and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to afford 2.35 mg (11%) of (R)-methyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 149. LCMS-ESI (m/z) calculated for C23H22N4O4: 418.2. found 419.1 [M+H]+, tR=3.85 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.54-7.44 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.43-5.18 (m, 1H), 5.03 (d, J=8.6 Hz, 1H), 4.90-4.63 (m, 1H), 3.77 (d, J=27.4 Hz, 3H), 3.59-3.35 (m, 1H), 3.27-3.01 (m, 1H), 2.68 (ddd, J=12.7, 8.2, 4.7 Hz, 1H), 2.05-1.75 (m, 1H), 1.47 (t, J=5.6 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 167.82, 163.56, 157.51, 151.63, 139.77, 137.77, 128.85, 128.63, 123.19, 122.08, 121.53, 117.97, 111.55, 110.03, 108.32, 98.67, 51.00, 46.99, 28.68, 26.28, 24.46, 16.50.
Reaction SMILES: [CH3:1]I.[K].[CH3:4][S:5][C:6]1[C:11]([F:12])=[CH:10][NH:9][C:8](=[O:13])[N:7]=1>CN(C)C=O>[CH3:1][N:9]1[CH:10]=[C:11]([F:12])[C:6]([S:5][CH3:4])=[N:7][C:8]1=[O:13]
Reactant: CSc1nc(=O)[nH]cc1F
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nc(=O)n(C)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Methyl iodide (0.017 mol) was added to the potassium salt of 4-methylthio-5-fluoropyrimid-2-one (0.012 mol) in dimethylformamide (50 ml) and the reaction mixture was stirred at room temperature for 24 h before evaporation at reduced pressure (1 mm Hg). The residue was extracted with chloroform and the solution was washed with aqueous 2 N NaOH, with water and was dried (MgSO4) before evaporation. The product was recrystallized from EtOAc/ligroin; yield 76%, m.p. 154° C. (Found: C, 41.48; H, 4.10. Calc. for C6H7FN2OS: C, 41.37; H, 4.05).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][O:31][C:32]1[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[C:33]=1[CH:39]=O>>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:28]=[CH:29][C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:39][C:33]3[C:34]([CH3:38])=[N:35][N:36]([CH3:37])[C:32]=3[O:31][CH3:30])[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: COc1c(C=O)c(C)nn1C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Product: COc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)CC2)c(C)nn1C
Yield: 30.8 %

Procedure:
Using an analogous procedure to that described in Example 3, tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) was reacted with 5-methoxy-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (92.6 mg, 0.60 mmol) to give the title compound (68 mg, 36%); NMR Spectrum: (DMSO d6) δ 1.63 (m, 2H), 1.78 (m, 2H), 2.00 (m, 2H), 2.06 (s, 3H), 2.57 (m, 1H), 2.94 (m, 2H), 3.25 (s, 2H), 3.50 (s, 3H), 3.99 (s, 3H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+434.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(C)(C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(C)(C)N1CC(C)C

Procedure:
Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to method B1c, Step 1. The ester was reduced to 3-hydroxy-2-methyl-2-propylamine according to Method B1c, Step 2. The 2-hydroxyethylamine was treated with SOCl2 according to Method B7b, followed by 2-methyl-3-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:16])[NH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>O.S(=O)(=O)(O)O.O>[OH:2][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:16])[NH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(=O)[nH]cnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]cnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of sodium nitrite (1.40 g, 20.32 mmol) in water (17 mL) was added dropwise to a cooled suspension of 7-aminoquinazolin-4-one (712 mg, 4.42 mmol) in sulfuric acid/water (4.4 mL, 18 mL), keeping the temperature at approx. 0° C. The mixture was stirred at room temperature for 2 hours, diluted with water (15 mL) and heated at reflux for 15 minutes. The cooled mixture was neutralized and the precipitate was collected via filtration, and purified by column chromatography (silica) using 10% methanol/ethyl acetate as the eluent. The combined fractions gave an orange solid (541 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:9]=1)[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4N[C@H](C)CO)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and (R)-2-aminopropan-1-ol.
Reaction SMILES: [CH:1]([N:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:12])[CH2:7][CH2:6]1)[CH3:4])=[O:2].[OH-].[Na+]>O1CCCC1.CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)=[O:28])=[C:14]([NH:13][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([N:3]([CH:1]=[O:2])[CH3:4])[CH2:6][CH2:7]3)=[O:12])[C:18]=2[CH:19]=1)([OH:25])=[O:24]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C=O)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.90 g) obtained in Example 234 is suspended in tetrahydrofuran/methanol (1:1, 50 ml), and thereto is added 4N aqueous sodium hydroxide solution (5 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for 17 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured ice-water, and the mixture is neutralized with 10% hydrochloric acid. The precipitates are collected by filtration, washed successively with water and tetrahydrofuran, and dried to give the title compound (1.59 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:24])=[O:23])=[O:27])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine, 25 ml of anhydrous methylene chloride and 2.4 g of 2-methoxycarbonylbenzenesulfonyl isocyanate was stirred at ambient temperature for 16 hours. It was then filtered to remove unreacted amine and the filtrate evaporated at temperatures up to 40° under reduced pressure. The residue was triturated with butyl chloride and filtered to yield the desired compound which melted above 170° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[ClH:1].[CH3:54][N:51]1[CH2:52][CH2:53][N:48]([C:46](=[O:47])[CH2:45][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:49][CH2:50]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(=O)N2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 154.1 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), 2-chloro-1-(4-methylpiperazin-1-yl)ethanone, hydrochloride (34.6 mg, 162 μmol) and cesium carbonate (111 mg, 341 μmol) were combined with dry dimethyl formamide (2 mL) to give a white suspension. The tube was capped and heated at 50° C. with stirring. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with methylene chloride (2×). The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (24 g pre-packed silica gel column, eluted with methanol in methylene chloride) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl ester, hydrochloride as an off-white solid (99 mg, 81% yield). The product was mixed with acetonitrile (2 mL) to form a suspension. A few drops of 1N aqueous hydrochloric acid were added to the mixture. The suspension became clear solution. It was frozen and lyophilized to give an off-white solid as hydrochloride salt. LCMS (ES+) m/z calcd. for C38H42Cl2F2N5O5 [(M+H)+]: 756. found: 756.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:16].[K+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([NH2:15])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: NC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 82 °C

Procedure:
Propan-2-ol (100 ml), tetrahydro-4-(3-bromophenyl)-2H-pyran-4-nitrile (20.0 g, 0.075 mole, 1 eq.), potassium hydroxide (13.74 g, 0.245 mole, 3.26 eq.) were added to a reaction flask set for boiling at reflux under a nitrogen atmosphere, and the reaction mixture was heated with stirring at reflux, about 82° C. for 5-6 hours under nitrogen. After reaction completion, the mixture was cooled (<30° C.) and quenched with water (100 ml). The resultant slurry was filtered and the product residue, washed with water (30 ml), and dried under vacuum at 45-50° C. to yield a white solid. Yield 19.05 g, 89.2%. mp 245-247° C.; m/z 285 (m+1); 1H NMR (300 MHz, DMSO) δ 7.43 (m, 5H), 7.14 (s, 1H), 3.76 (d, 2H), 3.47 (t, 2H), 2.44 (d, 2H), 1.79 (m, 2H).; IR (drifts) vmax 3363, 3174, 3062, 2973, 2935, 2879, 2828, 1685, 1631, 1588.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].OC1C=CC([C:22]([NH:28]C)(C)C(OC)=O)=CC=1>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:2]([NH:28][CH3:22])[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CNC(C)(C(=O)OC)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Product: CNC(C(=O)OC)c1cccc(OC)c1

Procedure:
Starting from 14.5 g of methyl 2-bromo-2-(3-methoxyphenyl)acetate, 7.5 g of product are prepared by the process used above when preparing methyl 2-(4-hydroxyphenyl)-2-methylaminopropionate (yellow oil; Yd=65%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C[Si](Cl)(C)C.[SH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH:5]([C:4]1[CH:3]=[C:2]([CH:1]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Reactant: COC(=O)CCS
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of isophthalaldehyde (5.4 g) in CHCl3 (50 ml) and methyl 3-mercaptopropanoate (9.2 ml) was added dropwise trimethylsilylchloride (6.5 ml). The reaction mixture was stirred 1 hour at room temperature, quenched with aqueous NH4OAc (25%), and extracted with ethylacetate. Flash chromatography of the residue using 1:1 ethylacetate hexane afforded the title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([NH:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[CH3:23])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[N:19][C:18]=1[CH3:23])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)C1CC1
Product: Cc1nc(NC(=O)C2CC2)sc1C(=O)NCc1ccccc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 87% yield; m. p. 241-243° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.5 (s, 1H), 8.49 (t, J=6.0 Hz, 1H), 7.31-7.17 (m, 5H), 4.34 (d, J=6.0 Hz, 2H), 1.94-1.84 (m, 1H), 1.15-1.08 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ 172.7, 162.2, 157.3, 151.0, 140.1, 128.7, 127.6, 127.1, 118.8, 43.0, 17.4, 14.1, 9.0; MS (ES+) m/z 316.3 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[S:73](Cl)(=[O:75])=[O:74])([O-:66])=[O:65]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][S:73]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N+:64]([O-:66])=[O:65])(=[O:74])=[O:75])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in dry methylene chloride (20 ml) was added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution was stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer was washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent was removed in vacuo. Chromatography on silica gel (2:1 ethyl acetate/hexane) gave 70 mg of the title compound A and 60 mg of the title compound B (Mass, 1H and 13C NMR data were consistent with the structures).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.877 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassium hydroxide (0.2 g, 3.5 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyridine (0.104 g, 0.877 mmol) was added and stirred for further at 120 deg C. for 20 h. Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (5% Me OH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) and further purified with preparative TLC to provide the desired compound as brown oil (0.045 g, 15% yield). 8-Isopropyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.045 g, 0.129 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.016 g, 0.129 mmol) in THF (2 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.045 g, 80% yield).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([F:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([F:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-fluoro-piperidin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.59 g, 2.26 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4-fluoropiperidine as a pale yellow oil (0.263 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 4.60 (m, 1H); 3.64-3.52 (m, 4H); 3.26-3.18 (m, 1H); 2.45-2.38 (m, 2H); 2.28-2.17 (m, 2H); 1.96-1.81 (m, 4H)