Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:18][C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(NC(=O)c2ccncc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
To a mixture of 1.17 g of N-(2-hydroxy-5-methoxyphenyl)isonicotinamide, 1.26 g of triphenylphosphine and 25 ml of tetrahydrofuran, a mixture of 0.85 g diethyl azodicarboxylate and 5 ml of tetrahydrofuran was added dropwise. The mixture was warmed to room temperature and stirred for four hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added thereto, which was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 5-methoxy-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 11”).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3S(C2C=CC=CC=2)(=O)=O)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1.[I-].[Na+].CCN(C(C)C)C(C)C.Cl>CC#N>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([CH2:2][C:3]2[N:8]=[C:7]([C:9]([NH:11][C:12]3[CH:20]=[C:19]([C:21]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:22]=4[CH:23]=[CH:24][NH:25]5)[CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(CN2CCS(=O)(=O)CC2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
6-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide (75 mg), thiomorpholine 1,1-dioxide (25 mg) and sodium iodide (25 mg) were added to a small round-bottomed flask followed by MeCN (2 ml) and DIPEA (0.048 ml). The reaction mixture was heated at 70° C. for 18 h. The reaction was cooled to RT and the solvent was removed under a stream of nitrogen. The residue was suspended in IPA (2 ml) and 2M NaOH (aq) (1 ml) was added. The mixture was stirred at RT for 2 h, heated to 50° C. for 1 h, then cooled to RT to remain stirring overnight. The reaction was heated to 60° C. for 1 h. Then 2M NaOH (aq) (0.5 ml) was added and reaction was stirred at 60° C. for 2 h. The reaction was neutralised with 2M HCl (aq.) and the solvent was removed in vacuo. The residue was dissolved in DMSO (3 ml), filtered and purified by MDAP (method K). The product-containing fractions were evaporated under a stream of nitrogen and the residues were taken up in methanol, combined and blown down to give title compound, 24 mg.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>S(Cl)(Cl)=O.C(Cl)Cl>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acridine-9-carboxylic acid (1 g, 4.1 mmol) was suspended in thionyl chloride (5 mL) and the reaction mixture was refluxed for 3 hours. The solvent was removed under reduced pressure leaving a yellow solid which was dissolved in methylene chloride and pyridine (350 μL) under argon. This solution was cooled in an ice bath and a solution of phenol (0.78 g, 8.2 mmol) in methylene chloride was added dropwise. The reaction mixture was stirred overnight at room temperature. After evaporation of solvent, the residue was redissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to obtain a crudematerial which was chromatographed on silica gel (30% ethyl acetate/hexane)to yield the pure product as a yellow solid. 1H NMR (CDCl3) δ7.35-7.57 (m, 5H), 7.63-8.37 (m, 8H).
Reaction SMILES: C[CH:2]([CH:5]=[CH:6][CH3:7])[CH2:3]O.[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1.CCOCC>[CH2:2](/[C:5](/[CH3:8])=[CH:6]/[CH2:7][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH3:3]
Reactant: C1COCCN1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC=CC(C)CO
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC/C(C)=C/CN1CCOCC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Morpholine 17 was prepared using a modification of the procedure outlined by Froyen and coworkers (Froyen et al. (1995) Tetrahedron Lett. 36:9555). To a solution of 2-methyl-3-penten-1-ol (1.3 g, 13 mmol) and triphenylphosphine (3.6 g, 14 mmol) in THF (10 mL) was added N-bromosuccinimide (2.5 g, 14 mmol). After 15 min, morpholine (2.7 mL, 31 mmol) was added dropwise and the resulting brown solution was heated to 70° C. for 2.5 h. Upon cooling to rt, the reaction mixture was diluted with Et2O (25 mL) and filtered through a pad of Celite©. The filtrate was then extracted with aqueous 1N HCl (100 mL). The product containing aqueous layer was then washed with Et2O (3×100 mL), and then made alkaline by the addition of NaOH (4 g). The aqueous solution was then extracted with Et2O (3×100 mL), the combined organic layers dried (Na2SO4), and then concentrated by rotary evaporation at 0° C. under reduced pressure. The resulting residue was then distilled (110° C., 20 mm) to afford (E)-N-(3-ethyl-3-methyl-2-propenyl)-morpholine (16) as a colorless oil in 49% yield (1.0 g, 6.0 mmol); IR 2968, 1455, 1293, 1116, 1004, 907 cm−1; 1H NMR(400 MHZ) δ5.21-5.25 (m, 1H, CH═CCH3), 3.65-3.77 (m, 4H, O(CH2)2), 2.96 (d, J=7.0 Hz, 2H, CH2C═CH), 2.44 (m, 4H, N(CH2)2), 2.01 (q, J=7.3 Hz, 2H, CH3CH2), 1.63 (s, 3H, CH3C═CH), 0.97-1.04 (m, 3H, CH3CH2); 13C NMR (100 MHZ) δ141.1, 118.7, 67.0, 56.0, 53.5, 32.4, 16.4, 12.5; LRMS (FAB) m/z 169 (M)+; HRMS (FAB) exact mass calcd for (C10H19NO)+ requires m/z 169.1467, found m/z 169.1464. (b) Preparation of (2R*,3R*)-N-(2,3-Dimethyl-3-ethyl4-pentenoyl)-morpholine (18): Prepared according to general procedure B from (E)-N-(3-ethyl-3-methyl-2-propenyl)-morpholine 17 (135 mg, 0.80 mmol), TiCl4.(THF)2, (27 mg, 81 μmol), i-Pr2NEt (0.56 mL, 3.2 mmol), and propionyl chloride (2.4 mL, 1 M solution in CH2Cl2, 2.4 mmol) in CH2Cl2 (2.7 mL) to provide the pure product as a yellow oil in 72% yield (130 mg, 0.58 mmol); >99:1 syn:anti. Syn isomer: IR (CH2Cl2) 2972, 1633, 1459, 1432, 1235 cm−1; 1H NMR (400 MHZ) δ5.88 (dd, J=10.9 Hz, 17.6 Hz, 1H, CH═CH2), 5.03 (dd, J=1.5, 10.9 Hz, 1H, CH═CH2), 4.88 (dd, J=1.4, 17.6 Hz, 1H, CH═CH2), 3.49-3.64 (m, 8H, N(CH2CH2)2), 2.63 (q, J=6.9 Hz, 1H, CHC═O), 1.32-1.49 (m, 2H, CH2CH3), 1.02 (d, J=6.9 Hz, 3H, CH3CHC═O), 0.99 (s, 3H, CHC3C), 0.73 (t, J=7.5 Hz, 3H, CH3CH2); 13C NMR (100 MHZ) δ174.1, 143.8, 67.0, 66.7, 66.6, 46.8, 42.7, 42.2, 41.8, 30.9, 18.7, 13.3, 8.3; LRMS (FAB) m/z 225 (M)+; HRMS (FAB) exact mass calcd for (C13H23NO2)+ requires m/z 225.1710, found m/z 225.1727.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:31])[C@@H:8]([NH:18][C@@H:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH2:9][S:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4]1)#[N:2].[OH:32]OS([O-])=O.[K+].[OH2:38]>CO>[C:1]([C:3]1([NH:6][C:7](=[O:31])[C@@H:8]([NH:18][C@@H:19]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:20]([F:22])([F:23])[F:21])[CH2:9][S:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:32])=[O:38])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H](CSCc2cccnc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2cccnc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)propionamide was dissolved in MeOH (3 mL) and OXONE® (460 mg, 1.5 mmol) in H2O (3 mL) was added. After stirring at rt for 2 h, the solvent was removed and the residue was extracted with ethyl acetate. The organic layer was dried with MgSO4 and the solvent was removed under reduced pressure. The title compound was purified by Prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CC1CCCC1)c1nc2ccccc2nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC1CCCC1)c1nc2ccccc2nc1CBr

Procedure:
A mixture of N-(3-methylquinoxalin-2-yl)-N-(cyclopentylmethyl)ethylamine (160 mg, 0.59 mmol), N-bromosuccinimide (130 mg, 0.73 mmol), and 2,2′-azobisisobtyronitrile (10 mg) in CCl4 is stirred and refluxed for 1 hour. The reaction mixture is purified by silica gel column chromatography to give N-[3-(bromomethyl)quinoxalin-2-yl]-N-(cyclopentylmethyl)ethylamine. 1H-NMR (400 MHz, CDCl3), δ (ppm): 1.10-1.25 (m, 2H), 1.22 (t, 3H), 1.45-1.73 (m, 8H), 2.22 (m, 1H), 3.42 (d, 2H), 3.49 (q, 2H), 4.73 (s, 2H), 7.51 (ddd, 1H), 7.62 (ddd, 1H), 7.81 (dd, 1H), 7.94 (dd, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:30])[F:31])[C:10](=[O:22])[NH:11]2)[C:6]([OH:33])=[C:5]1[C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccccc3C(F)(F)F)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.059 mmol), β-alanine (530 mg, 5.9 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH3:1])[CH:3]=2)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (4.31 g, 13.4 mmol) and phosphoroxychloride (40 mL) according to the general procedure I. Obtained as a light yellow solid (4.47 g, 98%). MS (EI) 340.1 [(M)+]; mp 53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>COC(C)(C)C>[CH2:20]([NH:24][C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:16])=[O:17])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Solvent: COC(C)(C)C
Product: CCCCNC(=O)C1CCCCC1(O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
20.8 g (0.08 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one (example 10) are dissolved in 200 ml of tert-butyl methyl ether. 10.46 g (0.143 mol) of n-butylamine are slowly added to this solution over one hour. The reaction mixture is stirred overnight at room temperature and the solvent is subsequently distilled off under vacuum. The yellowish oil thus obtained crystallizes upon standing and is purified by recrystallization from heptane. 22.5 g (85%) 2-(4-methoxybenzoyl)-2-hydroxy-cyclohexanecarboxylic acid butyl-amide are thus obtained as white solid with a melting point of 94-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].I[C:26]1[CH:27]=[N:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: COc1ccc(Cn2cc(I)cn2)cc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(Cc4ccc(OC)cc4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6]=1[CH2:7][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1c(Br)cnn1Cc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(Br)cnn3Cc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-bromo-1-(4-chlorobenzyl)-1H-pyrazole-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CCCCCCC.CCO>CO>[OH:1][C@@H:2]1[C@@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:3]1
Reactant: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CO
Solvent: CCO
Solvent: CCCCCCC
Product: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Yield: 47.9 %

Procedure:
The racemic mixture of trans-(±)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (14 g) was resolved by using chiral HPLC (Chiralpak AD-H Heptane:EtOH:MeOH, 8:1:1). The desired enantiomerically enriched (3S,4R)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (6.7 min; 6.3 g, >99.5% ee) and undesired (3R,4S)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (9.3 min; 6.7 g, 99.5% ee) were obtained with 92% recovery.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([S:25][CH3:26])[C:3]=1[C:4]#[N:5].[NH2:27][NH2:28].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:27][NH:28]3)=[C:6]([S:25][CH3:26])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
A 2-mL microwave vial was charged with 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (40 mg, 0.107 mmol), hydrazine (0.037 mL, 0.643 mmol), Hunig's base (0.056 mL, 0.321 mmol) and ethanol (1.5 mL). The mixture was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, and then concentrated. The resulting residue was dissolved in DMSO and purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA). The product fractions were pooled, basified with NaHCO3, then extracted into EtOAc. The organic layer was dried, then concentrated to afford the title compound (28 mg) as an off-white solid. LC-MS (ES) m/z=386 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.61 (s, 3H), 2.83 (d, J=4.3 Hz, 3H), 3.04-3.22 (m, 1H), 3.40-3.52 (m, 1H), 3.55-3.66 (m, 1H), 3.67-3.79 (m, 1H), 3.85-3.99 (m, 1H), 4.05-4.23 (m, 1H), 4.44-4.59 (m, 1H), 5.10 (s, 2H), 6.38-6.71 (m, 2H), 7.26-7.49 (m, 1H), 7.66-7.88 (m, 1H), 11.62-11.92 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:19][C:20]2[NH:21][NH:22][C:23](=[O:25])[CH:24]=2)S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.OC1C=CC(C(O)=O)=CC=1.Br>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:19][C:20]2[NH:21][NH:22][C:23](=[O:25])[CH:24]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1cc(CN(c2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)[nH][nH]1
Agent: Br
Agent: O=C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: O=c1cc(CNc2cc(Cl)cc(Cl)c2)[nH][nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
N-(3,5-dichlorophenyl)-N-((5-oxo-2,5-dihydro-1H-pyrazol-3-yl)methyl)benzenesulfonamide (398 mg, 1 mmol) and 4-hydroxybenzoic acid (800 mg, 5.8 mmol, 200% weight) were added to a solution of HBr (48% in H2O, 4 mL) and AcOH (4 mL). After the resulting suspension was stirred at 100° C. for 2 h, the reaction mixture was partitioned between 1N HCl (10 mL) and ethyl acetate (30 mL×2). The collected organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography eluting with a mixture of MeOH and dichloromethane (5% MeOH) to afford 2 (142 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6, 500 MHz): δ=6.65 (t, J=5.5 Hz, 1H), 6.61 (s, 1H), 6.59, (s, 2H), 5.35 (s, 1H), 4.10 (d, J=5.0 Hz, 2H); 13C NMR (DMSO-d6, 125 MHz): δ=150.7, 134.3X2, 114.6, 110.4X2 ppm; MS (ESI): m/z 280.0 [M+Na]+; CHN calculated for C10H9Cl2N3O: C, 46.53; H, 3.51; N, 16.28. found: C, 46.44; H, 3.61; N, 16.36.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:2]1[N:1]([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)OCc1ccccc1

Procedure:
Ethyl indole-2-carboxylate (22 g) was dissolved in dimethylformamide (150 ml), and sodium hydride (including 60% oil, 5.12 g) was gradually added with stirring. Then, benzyl bromoacetate (19.2 ml) was added, and the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The residue thus obtained as a solid was subjected to silica gel column chromatography and eluted with a mixed solvent of ethyl acetate and hexane to give benzyl 2-ethoxycarbonyl-indole-1-acetate (28.9 g) as an oil. This compound (32.5 g) was dissolved in ethanol (350 ml), and hydrogenated in the presence of palladium/carbon (10%) catalyst at 1 atm. The catalyst was filtered off, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 10.22 g of 2-ethoxycarbonyl-indole-1-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[S:22][C:23]([C:32]#[N:33])=[C:24](NC3C=CC=CC=3)[C:13]=2[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:13]3[CH:12]=[CH:11][C:10](=[O:9])[N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[S:22][C:23]=2[C:32]#[N:33])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1cccc(Br)c1

Procedure:
The title compound was prepared from 3-bromoaniline (155 mg, 0.9 mmol) following the method described for the compound of Example 18 to give the product as a pale yellow solid (183 mg). δH (CDCl3) 7.91-7.83 (3H, m), 7.83-7.66 (2H, m), 7.62 (1H, d, J 9.7 Hz), 7.52-7.44 (3H, m), 7.23 (1H, dt, J 7.1, 1.7 Hz), 6.81 (1H, d, J 9.7 Hz), 6.74 (1H, bs). LCMS (ES+) 422 (M+H)+79Br, 424 (M+H)+81Br.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([N:10]1[C:14]([CH:15]=[N:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH3:24])=[CH:13][N:12]=[C:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH3:9].[CH2:31]1COCC1>>[CH2:6]([N:10]1[C:14]([C@@H:15]([NH:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH2:24][CH3:31])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][N:12]=[C:11]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: CCCCn1c(C=NN2CCC[C@@H]2COC)cnc1-c1ccccc1
Product: CCCC[C@H](NN1CCC[C@@H]1COCC)c1cnc(-c2ccccc2)n1CCCC
Temperature: 25 °C

Procedure:
To a solution of BuLi (2.5 M in hexane, 12.5 ml, 31 mmol) under argon in anhydrous THF (15 mL) at −78° C. is slowly added a solution of crude 192 (14 mmol) in TEF (15 mL). The mixture is allowed to warm to room temperature over a period of 15 h and quenched with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate and the combined organic phases were washed with water and dried over sodium sulfate. Removal of solvents under reduced pressure and purification of the residue by column chromatography affords the desired product as a colorless syrup. Yield: 5.1 g; [α]D-72 (c=1.2, CHCl3); LC-MS (MH+): 399.
Reaction SMILES: [CH2:1]1[C:15]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=2)[CH2:5][CH2:4][CH2:3][NH:2]1.[Cl:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[ClH:16].[CH2:20]([O:19][C:17]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[C:15]2[CH2:1]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: c1ccc2nc3c(cc2c1)CNCCC3
Product: CCOC(=O)N1CCCc2nc3ccccc3cc2C1
Product: Cl
Yield: 81 %

Procedure:
2,3,4,5-Tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 63.