Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH2:12]O)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:12][C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][CH:10]=1
Reactant: OCc1cnc(-c2ccccc2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cnc(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
(2-phenylthiazol-5-yl)methanol (390 mg, 2.03 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled to 0° C. Triphenyl phosphine (800 mg, 3.05 mmol) was then added, followed by carbon tetrabromide (1.35 g, 4.07 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 5% EtOAc in petroleum ether) to get 5-(bromomethyl)-2-phenylthiazole (250 mg, yield 48%) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.80 (s, 1H), 7.46-7.45 (m, 3H), 4.77 (s, 2H). MS (ESI) m/z: Calculated for C10H8BrNS: 254.95. found: 256.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CN1CCC[C@H]1CO
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1O[C@H]1CCCN1C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A solution of 2-methoxy-5-nitrophenol (5.58 g; 0.033 mol), (S)-1-methyl-2-hydroxymethylpyrrolidine (3.45 g; 0.03 mol) and triphenylphosphine (8.65 g; 0.033 mol) in dry THF (80 ml) was cooled to 50 and treated with DEAD (5.2 ml; 0.033 mol) over 15 min. The reaction mixture was allowed to stand at RT for 16 h, then evaporated in vacuo and partitioned 5% NaOH(aq)/Et2O. The organic phase was separated and extracted with 10% HCl(aq). The aqueous extract was washed with Et2O, basified with 40% NaOH(aq) and extracted with Et2O. The organic extracts were washed with H2O, dried over Na2SO4 and evaporated in vacuo to yield the title compound (D43) (6.79 g; 85%) MH+=267.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[CH:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:39]=[CH:40][C:35]([O:34][CH:31]([CH3:33])[CH3:32])=[CH:36][CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 4-isopropoxyphenylboronic acid (130 mg, 0.74 mmol). Yield 100 mg (50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([CH2:20][C:21](=[O:22])[NH:23][CH:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:7]2[CH2:6][C:5]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: COC(=O)CBr
Product: COC(=O)COc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with methyl bromoacetate
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][OH:18])[C:10]=3[OH:19])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:18][CH2:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(F)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(F)cc3n2)c1O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
The esterification was carried out using the product. In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 5.06 g (17.5 mmol) 2-(5-fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 60 ml anhydrous THF. Triethylamine (8.7 ml, 62 mmol)) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (2.26 g, 21.6 mmol) was added dropwise and the mixture was stirred for 1 hr at −10° C. followed by 20 hours at ambient temperature. The salts were filtered and rinsed with 100 ml THF (≧99.9%, anhydrous containing inhibitor, Aldrich). Diethyl ether (100 ml) was added to the filtrate, which was washed with 1N HCl and water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the desired product, which was recrystallized in ethanol to give 2.5 g (40%) of a yellow solid. 1H NMR (CDCl3) delta: 11.03 (s, 1H, phenol OH), 7.94 (m, 1H, Ar—H benzotriazole ring), 7.87 (s, 1H, Ar—H phenol ring), 7.53 (m, 1H, Ar—H benzotriazole ring), 7.29 (m, 1H, Ar—H benzotriazole ring), 7.05 (s, 1H, Ar—H phenol ring), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15](CO)[O:14][CH:12]([OH:13])[C@H:11]([CH2:18][OH:19])[C@H:10]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[CH2:1]([O:8][C@H:9]([CH:15]=[O:14])[C@H:10]([OH:20])[C@@H:11]([CH2:18][OH:19])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1OC(O)[C@H](CO)[C@@H](O)[C@@H]1OCc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C[C@H](CO)[C@@H](O)[C@@H](C=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-gluco-pyranose (1.41 g, 5.0 mmol) in methanol (15 ml), a solution of sodium periodate (5.35 g, 25.0 mmol) in water (50 ml) was added dropwise over 15 minutes. Further, methanol (25 ml) was added. The mixture was stirred at 45° C. for 3 hours. The precipitated iodate was filtered off, and the mixture was concentrated. By resolution of the residue in ethyl acetate/ethanol (1:1; 80 ml), more iodate was precipitated and filtered off. The mother liquour was concentrated and the residue (2.07 g) was flash chromatographed using ethyl acetate as eluent. The purified product was obtained as a yellow sirup in 87% (1.09 g) yield and 9% of unreacted starting material (0.13 g) was isolated. The purified product was used imidiately in the next reaction.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:48])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1c(F)ccc(F)c1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)ccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 260. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.85 (s, 1H), 7.65-7.52 (m, 3H), 7.39-7.27 (m, 1H), 5.03-4.83 (m, 2H), 4.16-3.90 (m, 2H), 3.73 (s, 3H), 3.39 (dd, J=7.1, 4.6 Hz, 1H), 2.18 (ddd, J=15.1, 6.7, 3.5 Hz, 1H), 1.87 (dt, J=14.1, 10.3 Hz, 1H), 1.69 (dtd, J=18.1, 13.8, 11.5, 7.4 Hz, 2H). LCMS (ES+) m/z 485 (M+1).
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]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:3]=1[C:4]#[N:5].[NH2:30][NH2:31].CCN(C(C)C)C(C)C>C(O)C>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:6]1[CH:7]=[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:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:30][NH:31]2
Reactant: CNc1nc(-c2cc(F)c(C#N)c(-c3ccco3)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2cc(-c3ccco3)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.7 %

Procedure:
To a 2-mL microwave vial was added 2-fluoro-6-(2-furanyl)-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (50 mg, 0.127 mmol), hydrazine (0.044 mL, 0.763 mmol), Hunig's base (0.067 mL, 0.381 mmol) and ethanol (1 mL). The reaction was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, then was concentrated in vacuo, and the residue was purified by flash chromatography (0-10% CH3OH in CH2Cl2) to afford the title compound (35 mg, 0.086 mmol) as a yellow solid. LC-MS (ES) m/z=406 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J=6.6 Hz, 3H), 2.75-2.94 (m, 3H), 3.05-3.21 (m, 1H), 3.41-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.68-3.80 (m, 1H), 3.87-4.00 (m, 1H), 4.06-4.21 (m, 1H), 4.45-4.62 (m, 1H), 5.11 (s, 2H), 6.46-6.68 (m, 2H), 6.68-6.74 (m, 1H), 6.97-7.16 (m, 1H), 7.74-7.82 (m, 1H), 7.89-7.95 (m, 1H), 7.97-8.07 (m, 1H), 11.95 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH2:24])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)[CH3:3].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH:24][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:14]=3[N:15]=2)[CH2:8][CH2:9]1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCN)Cc4ccccc4)c3n2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCNC(=O)c4ccccc4)Cc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.75 g of 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-aminopropyl)-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 8 ml of methylene chloride and mixed with 0.24 g of benzoyl chloride and 0.3 g of triethylamine in 2 ml of methylene chloride. The reaction mixture is stirred for 12 hours at ambient temperature and then extracted three times with water. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed over a silica gel column using methylene chloride/methanol=7:3. Yield: 0.7 g (77% of theory) Oil C34H43N9O2 (609.78)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH:9]([C:15](OCC)=[O:16])[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH:9]([CH2:15][OH:16])[CH2:10][OH:11])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(CCOc1ccc(Br)cc1)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC(CO)CCOc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-(2-(4-bromophenoxy)ethyl)malonate (2.50 g, 6.96 mmol) in anhydrous MeOH (15 mL) was added sodium borohydride (1.32 g, 34.8 mmol) in portions at 0° C. The reaction mixture was stirred for 30 minutes at this temperature. The reaction mixture was then carefully quenched with water and extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (ethyl acetate:petroleum ether) to deliver the title compound (1.0 g, 52%) as a white solid.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29](O)=[O:30])[C:20]3=[O:32])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.[ClH:51].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[ClH:51].[ClH:51].[CH:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[O:30])[C:20]3=[O:32])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Cn2c(=O)n(C3CCN(C4Cc5cccc6cccc4c56)CC3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
(RS)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetic acid (0.85 g, 2 mmol) was dissolved in DMF (10 ml). 1-Methylpiperazine (0.2 g, 2 mmol), WSC.HCl (0.46 g, 2.4 mmol), HOBt (0.37 g, 2.4 mmol) and triethylamine (0.53 ml, 3.8 mmol) were added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) and hydrochloric acid/ethanol was added to give the title compound (0.73 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.7 g, 25.0 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (25 ml, 50.0 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (6.7 g, 74%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.Cl[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>O1CCCC1>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)=[O:7]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
(S)-methyl azetidine-2-carboxylate hydrochloride (1 g, 6.60 mmol) was diluted with Tetrahydrofuran (Volume: 20 ml) and treated with TRIETHYLAMINE (0.919 ml, 6.60 mmol). The reaction mixture was stirred vigorously and sonicated periodically, until a fine suspension resulted. This was stirred for 1 h and filtered through a small plug of celite. The plug was washed well with THF (20 mL) and the combined filtrate and washes were treated with methyl 6-chloro-5-nitronicotinate (0.714 g, 3.30 mmol). The reaction mixture was concentrated in vacuo and heated briefly (5 min) to 80° C. LCMS showed complete conversion. The reaction mixture was diluted with DCM (10 mL) and purified using flash column chromatography on silica gel (80 g SiO2, 20-30% ethyl acetate in hexanes) to afford the title compound (S)-methyl 6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90 g, 3.05 mmol, 92% yield) as a yellow oil. [M+H] calc'd for C12H13N3O6, 295; found, 295.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:5][CH2:4][O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:14]=[C:12]([NH2:13])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])c(N)c2)CCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc(N)c(N)c2)CCO1
Yield: 85.8 %

Procedure:
5-(2-Methylmorpholino)-2-nitroaniline (200 mg, 0.843 mmol) was added to the 10% Pd/C (25 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for overnight at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (150 mg). 1H NMR: (400 MHz, DMSO-d6): δ 6.38 (d, 1H, J=8.0 Hz), 6.18 (d, 1H, J=2.4 Hz), 5.99 (dd, 1H, J=2.8 and 8.0 Hz), 4.34 (bs, 2H), 3.96 (bs, 2H), 3.82 (m, 1H), 3.57 (m, 2H), 3.19 (d, 1H, J=11.2 Hz), 3.11 (d, 1H, J=11.2 Hz), 2.44 (m, 1H), 2.13 (t, 1H, J=11.2 Hz), 1.08 (d, 3H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].Cl[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: COC(=O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-chloro-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Off-white solid. MS (ESI): 330.1 (M−H)−.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26](=[O:28])=[O:27]>CCCCCC.CCOCC>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([C:26]([OH:28])=[O:27])[C:21]1=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: O=C1CCCN1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)C1CCN(Cc2ccccc2)C1=O

Procedure:
At -60° C., 150 ml of 1.6 molar butyl lithium solution in n-hexane are added to 28.3 g =39.3 ml (0.28 mol) of diisopropylamine in 400 ml of absolute ether, with stirring and under nitrogen. 35.1 g (0.2 mol) of N-benzyl-2-pyrrolidone dissolved in 150 ml of absolute ether are added dropwize thereto at -60° C. The cooling bath is taken away and dry carbon dioxide is introduced for 15 minutes. After stirring for 10 minutes the mixture is poured onto ice, the organic phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid, with cooling. The aqueous phase is extracted twice with methylene chloride and, after the organic phase has been dried over magnesium sulphate, it is concentrated by evaporation in vacuo. Yield: 35 g (79.8% of theory), Rf value: 0.42 (silica gel, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.O[CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42]2[CH:45]=[CH:46][O:47][C:41]=2[C:40]1=[O:48].[N+:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58]([NH:61][CH2:62][CH2:63][CH2:64][O:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][O:67]1)(=[O:60])=[O:59])([O-:51])=[O:50]>O1CCCC1>[N+:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58]([N:61]([CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42]2[CH:45]=[CH:46][O:47][C:41]=2[C:40]1=[O:48])[CH2:62][CH2:63][CH2:64][O:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][O:67]1)(=[O:59])=[O:60])([O-:51])=[O:50]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCOC1CCCCO1
Reactant: O=c1c2occc2ccn1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2occc2ccn1CCN(CCCOC1CCCCO1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Triphenylphosphine (393 mg, 1.5 mmol) and azodicarboxylic acid di-tert-butyl ester (345 mg, 1.5 mmol) were added to a tetrahydrofuran (THF) solution (10 ml) of 6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one (179 mg, 1.0 mmol) and 2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide (413 mg, 1.2 mmol), and stirred overnight. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 286 mg (yield: 57%) of 2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide as a white amorphous solid.