Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][NH2:63])[CH2:56][CH2:55]1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:63][CH2:62][CH2:61][CH2:60][N:57]2[CH2:58][CH2:59][O:54][CH2:55][CH2:56]2)=[O:20])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1ncccc1-c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1ncccc1-c1cc2cc(C(=O)NCCCN3CCOCC3)ccc2[nH]1
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a solution of 2-(2-methoxypyridin-3-yl)-1H-indole-5-carboxylic acid (0.850 g, 0.317 mmol) in dimethylformamide (5 ml) was added HBTU (1.20 g, 0.317 mmol) and N,N-diisopropylethylamine (0.70 ml, 0.519 g, 0.402 mmol). The reaction mixture was allowed to stir for five minutes and 3-morpholinopropan-1-amine (0.59 ml) was added. The reaction was allowed to stir for 2 hours at room temperature. The reaction was quenched by adding water (25 ml), saturated sodium bicarbonate solution (25 ml) and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with brine (1×25 ml), dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (SiO2, 100% EtOAc to 3% MeOH in EtOAc) to give the desired product as a white solid (1.09 g, 87%). M.p.=224-225° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.55 (s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.23 (dd, J=1.6 Hz, 7.6 Hz, 1H), 8.17 (dd, J=2.0 Hz, 5.2 Hz, 1H), 8.11 (s, 1H), 7.65 (dd, J=2 Hz, 8.4 Hz, 1H), 7.47 (d, J=8.4, 1H), 7.18-7.12 (m, 2H), 4.06 (s, 3H), 3.60-3.56 (m, 4H), 3.35-3.27 (m, 2H), 2.38-2.31 (m, 6H), 1.76-1.66 (m, 2H); LCMS: 395 [M+H]. Hydrolysis as described in General Procedure O provides compound 55 in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(F)cnc1=O)c1ccccc1
Yield: 21.1 %

Procedure:
A solution of 5-fluoropyrimidin-2-one (480 mg) and α-bromoacetophenone (843 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 31/2 hours. The resulting suspension was chilled in ice. The solid was collected by filtration, then crystallised twice from ethanol to give the title pyrimidinone (206 mg yield); m.p. 167°-175°, λmaxEtOH 243 nm (ε 15110), 331 nm (ε 3590), λinf 283 nm (ε 1870), 290 nm (ε 1890), 344 nm (ε 2740).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:13]([CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[C:12]2[C:44]([O:46]C)=[O:45])(=[O:8])=[O:7])[CH3:5]>CO.O>[CH3:5][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:13]([CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[C:12]2[C:44]([OH:46])=[O:45])(=[O:8])=[O:7])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Potassium hydroxide (0.665 g, 11.85 mmol) was added to a solution of methyl 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.77 g, 1.185 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight, cooled to room temperature, and diluted with water. The methanol was removed under reduced pressure, and the residue was acidified to about pH 6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed twice with brine, dried over Na2SO4, filtered, and concentrated to afford 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.67 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ8.81 (s, 1H), 8.03 (s, 1H), 7.91 (t, J=6.53 Hz, 2H), 7.76-7.82 (m, 1H), 7.70 (s, 1H), 4.05-4.12 (m, 5H), 3.81 (dt, J=6.87, 13.61 Hz, 1H), 3.57 (br. s., 4H), 3.01 (d, J=9.79 Hz, 2H), 2.41-2.49 (m, 4H), 2.31-2.40 (m, 1H), 1.78 (d, J=11.54 Hz, 2H), 1.24-1.41 (m, 4H), 1.22 (s, 3H), 1.20 (s, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][C:34]=1[C:42]([F:45])([F:44])[F:43].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:33]([Cl:32])=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=2)=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 55.7 %

Procedure:
4-(8-Nitroquinolin-4-yloxy)phenylamine (103 mL, 0.46 mmol), N-hydroxybenzotriazole (HOBt) (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarboimide (EDCl) (102 mg, 0.53 mmol) and 4-chloro-3-trifluoromethylbenzoic acid (103 mg, 0.46 mmol) were dissolved in dimethylformamide (3.6 mL), and to which triethylamine was added dropwise at room temperature, which was then heated and stirred at 80° C. When the reaction was completed, the resultant was extracted with ethyl acetate and saturated sodium bicarbonate, combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=½) to obtain 125 mg of the desired compound as a brown solid (yield 71.2%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.OO.FC(F)(F)C(O)=[O:38].[OH-:42].[Na+]>C(OCC)(=O)C.O>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([S:24]([C:21]2[CH:22]=[C:23]3[C:18]([CH:17]=[CH:16][N:15]=[C:14]3[N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)(=[O:38])=[O:42])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)c(Cl)c4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cl
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)c1ccc2ccnc(N3CCNCC3)c2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[7-(3,4-dichloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (230 mg, 0.47 mmol), H2O2 (30% in water, 0.5 mL), trifluoroacetic acid (1.5 mL) was heated at 50° C., 2 h. The reaction was continued overnight at 35° C. A water solution of NaOH (1N) was added (pH=14), ethyl acetate was added and the organic phase was separated, dried (MgSO4), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO2, dichloromethane:methanol 9:1) The free base was converted into hydrochloride by treatment with HCl in diethyl ether to obtained 45 mg of the title compound. 1H NMR (CH3OH-d4) δ 8.75-8.85 (m, 1H), 8.10-8.30 (m, 4H), 7.90-8.00 (m, 1H), 7.75-7.85 (m, 1H), 7.50-7.60 (m, 1H), 3.85-3.90 (m, 4H), 3.50-3.70 (m, 4H).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]1([C:8]2[NH:7][C:6](=[O:5])[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[CH:9]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(-c2c[nH]c3ncccc23)cc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of EXAMPLE 34D in 1 mL dichloromethane was added 1 mL trifluoroacetic acid. The solution was stirred at room temperature for 25 minutes and the solvent was removed. The crude material was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound. MS (ESI) m/e 287.9 (M+H)+; 1H NMR (DMSO-d6) δ 6.70 (s, 1H), 7.03 (s, 1H), 7.11-7.30 (m, 1H), 7.37-7.64 (m, 3H), 7.76-8.01 (m, 2H), 8.18-8.48 (m, 3H), 11.52 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:57])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:63](=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([O:57][CH3:63])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 25m (0.45 g, 0.57 mmol) in a methanol/tetrahydrofuran mixture (v/v=6/5, 22 mL) was added concentrated sulphuric acid (0.05 mL) at room temperature. The mixture was warmed up to 60° C. and stirred for 14 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 at room temperature and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 25n as a pale yellow solid (0.38 g, 84.4%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.48 (m, 1H), 7.47 (m, 2H), 7.41 (m, 4H), 7.33 (m, 7H), 7.25 (m, 3H), 7.21 (m, 4H), 7.16 (m, 2H), 7.08 (m, 2H), 6.87 (m, 2H), 5.01 (s, 2H), 4.81-4.75 (m, 3H), 4.78 (m, 1H), 4.63 (d, 1H), 4.52 (d, 1H), 4.26 (d, 1H), 4.19 (m, 2H), 4.09 (m, 1H), 4.01 (m, 2H), 3.87 (m, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH:24]=O)([CH3:23])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH2:23][NH:4][CH:1]1[CH2:3][CH2:2]1)([CH3:24])[CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.3 %

Procedure:
Cyclopropylamine (1.00 mL, 14.4 mmol), glacial acetic acid (1.0 mL), and sodium cyanoborohydride (1.82 g, 29.0 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (2.90 g, 14.5 mmol) in ethanol (40 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclopropylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.33 g, 5.51 mmol, 38%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.04 (2H, m), 0.12-0.16 (2H, m), 0.62 (6H, d, J=6.4 Hz), 0.76-0.86 (1H, m), 0.88 (3H, s), 1.00 (3H, t, J=6.9 Hz), 1.12-1.25 (2H, m), 1.30-1.38 (2H, m), 1.82-1.87 (1H, m), 2.38 (1H, d, J=11.7 Hz), 2.67 (1H, d, J=11.9 Hz), 3.86 (2H, q, J=6.9 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:29])=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH3:28])[S:18](=[O:27])(=[O:26])[N:19]([CH2:20][CH:21]4[CH2:23][C:22]4([F:25])[F:24])[C:14]3=[CH:13][CH:12]=2)[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.CCOC(C)=O>[F:25][C:22]1([F:24])[CH2:23][CH:21]1[CH2:20][N:19]1[C:14]2[C:15](=[N:16][C:11]([C:9]3[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[CH:7][C:8]=3[CH3:29])=[CH:12][CH:13]=2)[N:17]([CH3:28])[S:18]1(=[O:26])=[O:27]
Reactant: Cc1ccc(CN=[N+]=[N-])cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(CN)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-[5-(azidomethyl)-2-methylphenyl]-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (44-1) (480 mg, 1.1 mmol, 1.0 eq) in THF (6.7 mL) was added triphenylphosphine (600 mg, 2.3 mmol, 2.0 eq) followed by water (0.31 mL, 17.1 mmol, 15 eq). The reaction mixture stirred at ambient temperature overnight and was then diluted with EtOAc (100 mL), washed with sodium bicarbonate (4×10 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (24 g SiO2, 20-100% EtOAc in hexanes) to afford 1-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanamine (44-2). HRMS m/z (M+H) 395.1348 found, 395.1348 required.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:25]=[N:24][N:23]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH:22]=1
Reactant: Clc1ccccc1-c1cn[nH]c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)n1cc(-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) are dissolved in 30 mL CH2Cl2 and cooled to 0° C. TEA (1.7 mL, 12.0 mmol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25 g) and TEA are added. After 1 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7 g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-1H-pyrazole-1-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[CH:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31]([OH:33])=O)([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[CH:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31]([NH:54][S:51]([CH:48]6[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:33])([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CC2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CC2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A mixture of 9 (50 mg, 0.104 mmol) and CDI (68 mg, 0.418 mmol) in dry THF (5 mL) was heated at reflux for 2 h under nitrogen. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (101 mg, 0.836 mmol) was added. Then, DBU (73 mg, 0.481 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. Solvent was evaporated, and the residue partitioned between AcOEt and acidic water (pH=3). The crude material was purified by column chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1). The residue was crystallized in Et2O, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 1.5 mL of water, filtered, washed with water and dried overnight in the high vacuum pump to give 28 mg (46%) of the target compound as a white powder: m/z=582 (M+H)+.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](C3CCNCC3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrCCCO.C(#N)C>O>[O:8]1[C:4]2[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=2[CH:6]=[N:7]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: c1ccc2oncc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:8]([CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(C)c1
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (5.1 g, 21.96 mmol) in tetrahydrofuran (70 mL) and dimethylsulfoxide (15 mL) cooled in a ice-water bath, NaH (0.96 g, 24.15 mmol) and methyl iodide (1.5 mL, 24.15 mmol) were added. The reaction was continued at room temperature for 12 h, the tetrahydrofuran was removed under vacuo, then dichloromethane (200 mL) were added and the organic phase washed with water (100 mL). The acqueous fraction was extracted with dichloromethane (1×100 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/ethanol 95/5) provided 4.45 g (82%) of the title compound as a pale yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([NH:10][CH2:11]/[CH:12]=[CH:13]\[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([N:24]([C:33]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]2[C:36]([C:37]3[CH:49]=[CH:48][O:47][C:38]=3[CH2:39][O:40]2)=[CH:35][CH:34]=1)COCC[Si](C)(C)C)(=[O:23])=[O:22])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:8]([NH:10][CH2:11]/[CH:12]=[CH:13]\[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:33]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]2[C:36]([C:37]3[CH:49]=[CH:48][O:47][C:38]=3[CH2:39][O:40]2)=[CH:35][CH:34]=1)(=[O:23])=[O:22])[CH3:9]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
TFA (1 mL) was added to a solution of methyl 7-{N-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)-amino}-furo[2,3-c]chromene-6-carboxylate (Intermediate 47, 0.410 g) in DCM (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. Aqueous potassium carbonate was added and the layers were separated. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with DMAW 350, followed by DMAW 240 to give methyl 7-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.096 g) as a yellow gum.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14]2)[N:11]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:9])#[N:2].O.[OH-].[Li+]>O1CCOCC1.O>[C:27]([O:26][C:24]([N:11]1[C@H:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:9])[C@H:15]2[CH2:16][C@@H:12]1[C@H:13]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14]2)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-(2-ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 15-1 (249 mg) in dioxane (3 mL) and water (1 mL), was added lithium hydroxide monohydrate (302 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo. 1N Hydrochloric acid (1.2 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the target compound (261 mg).