Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=C(N)C=1)[N:9]=C(C)C=C2.C[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1>N1C=CC=CC=1>[N+:26]([C:18]1[CH:17]=[CH:16][CH:21]=[CH:20][C:19]=1[S:22]([NH2:9])(=[O:24])=[O:23])([O-:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: COc1cc(N)c2nc(C)ccc2c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.3 %

Procedure:
To a solution of 6-methoxy-2-methylquinolin-8-amine 2a (0.19 g, 1.0 mmol) in pyridine (5 ml) was added 4-methyl-2-nitrobenzenesulfonyl chloride (0.24 g, 1.0 mmol). The mixture was stirred at room temperature overnight and precipitated with H2O. The crude product was filtered and recrystallized from EtOH to afford nitrobenzenesulfonamide (0.31 g, 79%) as red crystal. 1H NMR (300 MHz, CDCl3) δ 10.1 (br, 1H); 8.04 (d, 1H), 7.86 (d, 1H), 7.62 (m, 2H), 7.39 (d, 1H), 7.24 (d, 1H), 6.73 (s, 1H), 3.88 (s, 3H), 2.66 (s, 3H), 2.41 (s, 3H); ESI-MS (M++1): 388.0. To a suspension of above nitro compound (0.20 g, 0.56 mmol) in EtOH (5 ml) was added SnCl2 (0.32 g, 1.7 mmol) slowly. The mixture was refluxed for 2 h. After removal of EtOH, the residue was treated with 1M NaOH. The aqueous solution was extracted with CH2Cl2. The combined organic phases were washed by brine, dried over Na2SO4, and concentrated to yield 9a (0.18 g, 92%) as white solid. 1H NMR (300 MHz, CDCl3) δ 9.42 (br, 1H); 7.83 (d, 1H), 7.65 (d, 1H), 7.30 (s, 1H), 7.23 (d, 1H), 6.64 (s, 1H), 6.48 (d, 1H), 6.42 (s, 1H), 3.80 (s, 3H), 2.61 (s, 3H), 2.17 (s, 3H); ESI-MS (M++1): 358.1.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][C:13]=1[C:14]([F:21])=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>O>[F:21][C:14]([C:13]1[CH:12]=[C:11]([Si:22]([CH3:24])([CH3:25])[CH3:23])[S:10][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7])=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)NS(=O)(=O)c1sc([Si](C)(C)C)cc1C(F)=C(F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[Si](C)(C)c1cc(C(F)=C(F)C(F)(F)F)c(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.5 %

Procedure:
A portion (1.5 g) of the N-tert-butyl-3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide prepared in (2) was reacted with 4 ml of trifluoroacetic acid under stirring at room temperature for 13 hours. After completion of the reaction, the resulting product was poured into water and extracted with methylene chloride. The extracted layer was washed with water and dried. After distilling off methylene chloride under vacuum, the residue was purified by column chromatography on silica gel (eluent: methylene chloride) to provide 0.93 g of 3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide having a melting point of 129° to 140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1I.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18]>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccc(S)c(Br)c1
Reactant: Cc1ccc(I)c(F)c1
Product: Cc1ccc(Sc2ccc(F)cc2Br)c(F)c1

Procedure:
Prepared from 2-fluoro-1-iodo-4-methyl-benzene and 2-bromo-4-fluoro-benzenethiol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]([NH:35][S:36]([C:39]([CH3:42])([CH3:41])[CH3:40])(=O)=[O:37])[C:31]([F:34])([F:33])[F:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:43][Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]([N:35]([CH3:43])[S:36]([C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[C:31]([F:33])([F:34])[F:32])=[N:9][N:10]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)S(=O)(=O)NC(c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)C(F)(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CN(C(c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)C(F)(F)F)S(=O)C(C)(C)C
Temperature: 25 °C
Yield: 49.7 %

Procedure:
N-(1-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfonamide (108 mg, 0.181 mmol) was cooled to 0° C. and charged with lithium bis(trimethylsilyl)amide (0.217 ml, 0.217 mmol) followed by iodomethahe (0.011 ml, 0.181 mmol) (˜2 drops). The reaction was allowed to warm to rt overnight. Quenched excess LiHMDS with methanol and evaporated solvents on the V-10. The residue was purified on silica, 10-50% DCM/EtOAc to provide N-(1-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (53 mg, 0.09 mmol, 48% yield) MS ESI Calc'd for C32H30ClF3N4OS [M+H]+ 611, found 611.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[O:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]2[C@@H:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][B:12]([OH:21])[C:11]=2[CH:22]=1.C1COCC1.[Li+].[OH-].Cl>O.CO>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[O:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]2[C@H:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][B:12]([OH:21])[C:11]=2[CH:22]=1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(Oc3nncs3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1OB(O)c2cc(Oc3nncs3)cc(C)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-ethyl 2-(6-(1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.9 g, 2.69 mmol) in a mixed solution of THF (30 mL) and methanol (4 mL) was added a solution of LiOH. H2O (0.57 g, 13.5 mmol) in water (30 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hrs and then acidified to pH=2 with diluted hydrochloric acid at 0° C. After removal of the volatile organics, the residue was dissolved in EtOAc. The aqueous phase was dried and concentrated in vacuo to give the products.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([N:6]([CH2:22][NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH2:22][NH:23][C:24](=[O:25])[O:26][CH2:27][CH3:28])[C:4](=[O:5])[CH2:3][N:2]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:9]=1
Reactant: CCOC(=O)NCN(C(=O)CN)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)NCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
An aqueous solution of 1 g. of 2-amino-N-[(ethoxycarbonylamino)methyl]-2'-benzoyl-4'-chloroacetanilide hydrochloride is made alkaline with 10% sodium carbonate solution. The base precipitated is extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated. The residue is taken up in ethanol and the solution obtained is boiled under reflux for 10 minutes. The crude product which remains as the residue after evaporation of the solution is crystallized from methanol/water. Ethyl [(7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)methyl]carbamate of melting point 124°-216° is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>CN(C)C=O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][O:17][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCc4nc5ccccc5s4)ccc3c2s1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol and anhydrous N,N-dimethylformamide (DMF, 2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq.) and a solution of 2-(bromomethyl)benzothiazole dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture dropwise to water (60 mL) with stirring. A precipitate formed. The solid was collected by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from acetonitrile to provide 7-[(1,3-benzothiazol-2-yl)methoxy]-2-ethylthiazolo[4,5-c]quinolin-4-amine as a white crystalline solid, mp. 211-212° C. MS (APCI) m/z 393 (M+H)+. Anal. calcd C20H16N4OS2.0.6H2O: C, 59.56; H, 4.30; N, 13.89. Found: C, 59.66; H, 4.08; N, 13.80.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([OH:12])[CH2:10][C:9]2[C:8]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.[OH-].[K+]>CO>[OH:1][C@H:2]1[C@@H:11]([OH:12])[CH2:10][C:9]2[C:8]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1C[C@H](O)[C@H](O)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1cccc2c1C[C@H](O)[C@H](O)C2)C(=O)O

Procedure:
To a solution of 0.05 mole of the product of Example 1 in 50 ml. of methyl alcohol, 30 ml. of 40% methanolic potassium hydroxide is added and the mixture is refluxed for 0.5 hours. The solvent is removed in vacuo, the residue dissolved in water, acidified and extracted with chloroform. The chloroform extract is washed with water, dried and concentrated to give the title compound as a thick oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1.CN(C1C=CC=CN=1)C>[C:37]([O:36][C:34]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:10]=1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(CO)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 56.5 %

Procedure:
Methyl 2,6-di(bis(tert-butoxycarbonyl)amino)pyrimidine-4-carboxylate Crude methyl 2,6-diaminopyrimidine-4-carboxylate (2.52 g, 15 mmol) was suspended in dry tetrahydrofuran (200 ml) then treated sequentially with di-tert-butyl dicarbonate (19.6 g, 90 mmol), triethylamine (16.7 ml, 120 mmol), and 4 dimethylaminopyridine (0.092 g, 0.75 mmol). This mixture was refluxed gently for 16 h, evaporated, dissolved in diethyl ether, washed with water and brine, dried and evaporated to give a dark red gum. This residue was purified by flash chromatography, eluting with 0-18% ethyl acetate in petroleum ether, to give the title compound as an off-white foam (4.58 g, 54%); m/z (APCI+) 569 [MH]+100%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([CH2:19][NH2:20])C1C=CC=CC=1>>[CH3:19][NH:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)CCCCCBr
Product: CCOC(=O)CCCCCNC
Yield: 99.8 %

Procedure:
Ethyl 6-bromohexanoate (6.00 g, 26.9 mmol) and benzylmethylamine (6.52 g, 53.8 mmol) were used to give the title compound (4.65 g; yield, 99%) as a colorless oily substance according to the method described in Example 68a.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1)[CH2:12][CH:13]([CH3:15])[CH3:14].[CH2:31]([O:38][C:39](=[O:42])[CH2:40]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH2:40][C:39]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:42])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:21][CH:22]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)CCOc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc(C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.06 M in THF; 7.11 mL, 7.54 mmol) was added dropwise over 10 min to a stirred solution of tert-butyl [4-(isopentyloxy)phenyl]acetate (2.00 g, 7.18 mmol) in THF (25 mL) at −78° C. under nitrogen. On completion of addition stirring was continued at −78° C. for 30 min then benzyl-2-bromoacteate (1.97 g, 1.36 mL, 8.61 mmol) was added dropwise over 5 min. The reaction was allowed to warm slowly to room temperature over 4 h. Once at room temperature saturated ammonium chloride solution (25 mL) was added and the resulting suspension extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5-10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (2.00 g, 66%). LC/MS: 4.20 min; z/e 427, calcd (M+1) 427. 1H NMR (400 MHz: CDCl3): 7.35 (5H), 7.2 (2H), 6.80 (2H), 5.10 (2H), 3.95 (3H), 3.15 (1H), 2.65 (1H), 1.85 (1H), 1.65 (2H), 1.45 (9H), 0.95 (6H).
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:25]=[CH:26][C:27]=1[NH2:28].O>CN(C=O)C>[NH2:6][C:7]1[C:12]([C:13]2[NH:21][C:22]3[CH:23]=[C:24]([C:29]4[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:25]=[CH:26][C:27]=3[N:28]=2)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1
Reactant: Cn1cc(-c2cnc(N)c(C=O)c2)cn1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cc(-c4cnn(C)c4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
1.2 300 μl (1.485 mmol) of 38-40% sodium hydrogensulfite solution are added to a solution of 100 mg (0.495 mmol) of 2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbaldehyde and 108 mg (0.495 mmol) of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one in 4 ml of DMF, and the resultant suspension is stirred at 50° C. for 72 hours. The reaction mixture is cooled to RT, water is added, and the precipitated product is filtered off with suction, washed with water and dried, giving 6-{2-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]-3H-benzimidazol-5-yl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one as yellow solid; APCI-401;
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]([NH2:8])[CH2:6][CH3:7].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[CH3:2][O:3][CH2:4][CH:5]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([CH2:17][CH2:16][O:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH:19]=1)[CH2:6][CH3:7]
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Reactant: CC[C@H](N)COC
Agent: Cl
Product: CCC(COC)NCc1cccc(CCOC2CCCCO2)c1

Procedure:
The sub-titled compound was prepared from (S)-1-methoxymethyl-propylamine hydrochloride (0.36 g) and 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (Example 50, step a, 0.5 g) using the method of Example 75, step b. Yield 0.6 g.
Reaction SMILES: BrCC1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:15][CH:16]=C>C(O)CC>[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:15][CH3:16]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCO
Product: CCCOCc1ccc(C(=O)O)cc1

Procedure:
The reaction of propanol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-propoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (d, J=8.2, 2 arom.H); 7.40 (d, J=8.2, 2 arom.H); 4.50 (s, OCH2C6H4—); 3.38 (t, CH3CH2CH2O); 1.54 (m, CH3CH2CH2O); 0.87 (t, CH3CH2CH2O).). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 143.94; 129.67; 129.30 (2 arom. C); 127.03 (2 arom. C); 71.53; 71.13; 22.43; 10.55.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>CN(C)C=O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:25]([NH:24][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[S:26])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: S=C=Nc1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Yield: 68.1 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (356 mg, 1.42 mmol) and 2,3-dichlorophenylisothiocyanate (318 mg, 1.57 mmol) in 1.0 mL of N,N-dimethylformamide was stirred at room temperature for 3 hours. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v) to give the desired product (440 mg, 68%). EI-MS (m/z) 455.5 (M+).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccc(F)c2)C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.22 mmol), 3-fluorophenylboronic acid (171 mg, 1.22 mmol), ethanol (1 ml), 2N aqueous sodium carbonate solution (5 ml), and tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.147 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (390 mg, 93.1%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]([C:12]([OH:14])=O)[CH:4]=1.Cl.[F:16][C:17]1[CH:18]=[C:19]([C@@H:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[NH2:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C@@H:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[NH:29][C:12](=[O:14])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: COc1cc(C(=O)O)ncc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-methoxy-5-nitropicolinic acid (1 g, 0.005 mol) in DMF (10 mL) were added (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g, 0.0075 mol, Molicula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich). The reaction mixture was stirred for 12 h at rt. The reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, water (100 mL) was added and aqueous solution was extracted with EtOAc (50 mL×3) and concentrated to give the product. The product thus obtained was purified by column chromatography, silica gel (60-120 mesh), using 80-100% EtOAc in petroleum ether as the eluent to give the title compound. 1H NMR (400 Mhz, DMSO-d6) δ ppm 9.89 (d, J=7.2 Hz, 1H), 9.13 (s, 1H), 8.57 (d, J=4.5 Hz, 1H), 7.92 (s, 1H), 7.82 (t, J=8.7 Hz, 1H), 7.56 (t, J=4.8 Hz, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.54 (d, J=6.3 Hz, 1H), 4.11 (s, 3H). MS (ESI, positive ion) m/z: 485.0 (M+H).
Reaction SMILES: [CH2:1]([C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:8]=2[C:7](=[O:14])[O:6]1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>C1COCC1>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:14])[O:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH2:10]1)=[O:41]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)c1ccc3ccccc3c1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol) and N,N′-diisopropylethylamine (71 mg, 0.552 mmol) in THF (5 mL) at 0° C. was added 2-naphthoylchloride (35 mg, 0.184 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then room temperature overnight. The crude mixture was concentrated to dryness and purified by column chromatography (4 g, SiO2, 0 to 30% ethyl acetate in hexanes) to provide 5-(2-naphthoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (68 mg, 87%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.77-1.08 (m, 6H), 1.63-1.78 (m, 1H), 1.79-1.95 (m, 1H), 2.28-2.59 (m, 3H), 3.28-3.60 (m, 1H), 3.73 (br. s., 1H), 4.09-4.27 (m, 1H), 4.85 (br. s., 1H), 7.29-7.51 (m, 6H), 7.52-7.62 (m, 2H), 7.77-7.98 (m, 4H); MS m/z 426 (M+H)+, 449 (M+23)+, 424 (M−H)−.