Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:15])C=CC=CC=1.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:6](=[O:15])([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:3]
Reactant: OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 271 %

Procedure:
To a mixture of 27 (5.32 g, 11.2 mmol, 1 equiv), triethylamine (6.24 mL, 44.8 mmol, 4.0 equiv), and crushed, activated 4 Å molecular sieves (~20 g) in toluene (53 mL) was added diphenylphosphoryl azide (3.10 mL, 14.4 mmol, 1.2 equiv), and the resulting suspension was heated to 70° C. for 2 h. The reaction mixture was cooled to 23° C., and benzyl alcohol (1.73 mL, 16.8 mmol, 1.5 equiv) was then added. The suspension was stirred at 23° C. for 1 h, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (gradient elution: 20→50% ethyl acetate in hexanes) to afford 3 (5.90 g, 93%) as a pale yellow solid (mp 102°-103° C.). Rf 0.25 (33% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3) d 7.40 (m, 1H, Ph-H & ArCH), 6.92 (s, 1H, ArH), 6.70 (s (br), 1H, NH), 5.99 (s, 2H, ArOCH2OAr), 5.10 (s, 2H, Cbz CH2), 4.70 (m (br), 2H, Bn CH2), 4.58 (t (br), 1H, J=unres, CH(OCH3)2), 4.23 (d (br), 2H, J=unres, CO2 CH2CH), 3.39 (s, 6H, OCH3), 2.18 (s, 3H, ArCH3), Z configuration verified by 5.8% NOE of Ar-H upon irradiation of N--H; 13C NMR (100 MHz, CDCl3) d 165.0, 151.7, 148.1, 143.4, 136.3, 135.9, 128.6, 128.5, 128.4, 128.3, 128.1, 126.3, 123.6, 120.1, 113.9, 105.0, 101.5, 101.1, 67.3, 64.0, 53.9, 9.4; IR (neat film) 3350 (w, br), 2940 (w), 1718 (s), 1498 (m), 1473 (m), 1423 (m), 1247 (s), 1193 (s), 1130 (m), 1094 (s), 1069 (m) cm-1 ; HRMS (FAB+) m/z: calcd for C30H31NO9Na (MNa+) 572.1896, found 572.1909.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>C(O)C>[N:20]([CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)=[N+:21]=[N-:22]
Reactant: c1cc(CN2CCCCC2)cc(OCCC2CO2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCC(O)CCOc1cccc(CN2CCCCC2)c1
Yield: 53 %

Procedure:
A solution of 1-[[3-[2-oxiranylethoxy]phenyl]methyl]piperidine (17 g), sodium azide (5.1 g) and ammonium chloride (2.73 g) in 25% aqueous ethanol (200 ml) was refluxed for 6 h and concentrated to ca. 130 ml. The concentrate was diluted with water (50 ml), saturated with potassium carbonate and extracted with isopropanol. The extract was dried and evaporated to given an oil (20 g) which was chromatographed on silica using dichloromethane:ethanol:ammonia (200:8:1) to give the title compound (10.5 g) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:18])([O-:3])=[O:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23].N1CC[CH2:29][CH2:28]1>CN(C)C=O>[N:22]1(/[CH:24]=[CH:18]/[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:23][CH2:29][CH2:28][CH2:21]1
Reactant: Cc1ccc(Oc2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Oc2ccc(F)cc2)ccc1/C=C/N1CCCC1
Temperature: 110 °C
Yield: 103.4 %

Procedure:
2-Nitro-4-(4-fluorophenoxy)toluene (11.8 g, 47.7 mmol), was dissolved in dimethylformamide (90.0 mL) under N2 atmosphere. Dimethylformamide dimethyl acetal (20.2 mL, 143 mmol), and pyrrolidine (4.0 mL, 47.4 mmol) were added via syringe and the reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between H2O and ether. The organic phase was washed with H2O. The combined aqueous extracts were washed with ether. The ether extracts were combined and dried over Na2SO4, filtered, and concentrated in vacuo to give a viscous oil (16.1 g) which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2(O)[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][CH:17]23)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=4)[O:9][N:8]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=4)[O:9][N:8]=1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccn2)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.8 %

Procedure:
To a stirred suspension of 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (Preparation 63E, 0.081 g, 0.190 mmol) in anhydrous toluene (2.0 mL) at room temperature was added thionyl chloride (0.028 mL, 0.379 mmol) followed by pyridine (3.07 μl, 0.038 mmol). The reaction mixture was stirred at room temperature for 30 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid. The crude products were combined and triturated with methanol with sonication. The solid was collected to provide 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.098 g, 0.239 mmol, 64% yield) as a tan solid. The product had an HPLC with a ret. time=3.36 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=409.9.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[Cl:15][C:16]1[C:17]2[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[ClH:15].[Cl:26][C:24]1[N:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:12][C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)=[CH:14][CH:13]=3)[C:17]=2[CH:25]=1
Reactant: Nc1ccc(OCC2OCCO2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Cl
Product: Clc1cc2c(Nc3ccc(OCC4OCCO4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 4-(1,3-dioxolan-2-yl)methoxyaniline (prepared according to the published method: WO 96/09294) and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.06 (1H,s), 8.85 (1H,s), 8.79 (1H,s), 7.73 (2H,d), 7.05 (2H,d), 5.21 (1H,t), 3.70-4.06 (6H,m); m/z (M+1)+359.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26].[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34].FC1C=C([N+]([O-])=O)C=CC=1N=CN(C)C>>[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH:34][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26]
Reactant: Nc1ccc(F)cc1F
Reactant: CS(=O)c1ccc(N2C(=O)N(Cc3ccccc3Br)C(C)(C)C2=O)cc1C(F)(F)F
Agent: CN(C)C=Nc1ccc([N+](=O)[O-])cc1F
Product: CS(=O)c1ccc(N2C(=O)N(Cc3ccccc3Nc3ccc(F)cc3F)C(C)(C)C2=O)cc1C(F)(F)F

Procedure:
The reaction of 114.2 with 2,4-difluoroaniline under conditions as described for the preparation of compound 1 afforded 114. Molecular weight 551.13 (C26H22F5N3O3S); retention time Rt=2.06 min. [B]; MS (ESI): 552.17 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: CCC/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCC/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 60.7 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (200 mg, 0.45 mmol) and trans-1-penten-1-ylboronic acid (205 mg, 1.80 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 96 mg, 0.045 mmol) and 2M aqueous solution of K2SO4 (0.90 mL, 1.80 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (145) as white solid (107 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[CH2:13]=[C:14](B(O)O)[CH3:15].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:14]([CH3:15])=[CH2:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
Reactant: C=C(C)B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3-dibromo-5-(trifluoromethyl)benzene (3.03 g, 10 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol), prop-1-en-2-ylboronic acid (1.0 g, 12 mmol), K2CO3 (2.8 g, 20 mmol) and water (1 mL) under N2. The mixture was stirred at 90° C. overnight, concentrated and purified by CC (hexane) to afford compound P28a (1.9 g, 71%) as an oil.
Reaction SMILES: [F:1][C:2]1([C:16]([F:19])([F:18])[F:17])[O:7][C:6]([F:9])([F:8])[C:5](F)([C:10]([F:13])([F:12])[F:11])[O:4][C:3]1=[O:15].[O-2].[Ca+2].[O:22]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[O:15]=[C:3]1[C:2]([F:1])([C:16]([F:17])([F:18])[F:19])[O:7][C:6]([F:9])([F:8])[C:5]([OH:22])([C:10]([F:12])([F:11])[F:13])[O:4]1
Reactant: O=C1OC(F)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C1OC(O)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F

Procedure:
Perfluoro(2-oxo-3,6-dimethyl-1,4-dioxane), 314 g (1.01 mol), was added dropwise to a slurry of 56.1 g (1.0 mol) of calcium oxide in 500 ml of water while the slurry was stirred in an ice bath. The resultant mixture was stirred for one hour, heated nearly to reflux for 30 min, and stirred for about 65 h. Upon evaporation of the water, the crystalline residue which remained was treated portionwise with 450 g (3.2 mol) of P2O5. The resultant mixture was heated slowly (exothermic reaction) to 150° and then distilled to give 246 g of crude 2-oxo-6-hydroxyperfluoro(3,6-dimethyl-1,4-dioxane), bp 70°-75° (50 mm); upon redistillation from a small amount of P2O5 208 g (67%) of purified lactol was recovered, bp 71°-73° (50 mm). IR: 2.90 (free OH), 5.51 (fluorolactone C=O), 7.5-10μ (C--F, C--O). NMR: 19F -82.7 (several m, 7, CF3 +part of AB for O--CF2) -113.0 and -115.6 ppm (m, 1 CF).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of (R)-4-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (294.3 mg, 0.7714 mmol) and lithium hydroxide (203 mg, 8.48 mmol) in Ethanol (4.9 mL, 0.084 mol) and water (1.6 mL, 9.1 mmol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous was extensively extracted with CH2Cl2. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into CH2Cl2 and subjected to chromatography purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product. LCMS 339.53 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.92 (t, J=7.0 Hz, 3H), 1.21-1.50 (m, 9H), 1.54 (s, 3H), 1.56-1.71 (m, 4H), 2.05 (brd, J=13.3 Hz, 2 H), 3.71 (AB, J=10.8 Hz, 2H), 4.69 (brs, 1H), 7.14 (dd, J=8.8, 3.3 Hz, 1H), 7.19 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.83 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: BrCC1CCOCC1
Reactant: Oc1cccc(Br)c1F
Product: Fc1c(Br)cccc1OCC1CCOCC1

Procedure:
Prepared as described for 1-bromo-2-fluoro-3-isopropoxy-benzene SM23 starting from 3-bromo-2-fluorophenol and 4-bromomethyltetrahydropyran. MS m/z: 290 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=2)[C:16]1=[O:15])=[O:22]
Reactant: O=C(O)C1CCN(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(OC(F)(F)F)cc2)C1=O
Yield: 37.2 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-(4-(trifluoromethoxy)phenyl)pyrrolidine-3-carboxylic acid (0.125; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.075 g (37%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide as a solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][CH:12]([SiH3:16])[O:13][CH2:14][CH3:15])[CH3:10].C([Si]([CH:26]=[CH2:27])(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:9]([O:11][CH:12]([SiH2:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][SiH2:16][CH:12]([O:13][CH2:26][CH3:27])[O:11][CH2:9][CH3:10])[O:13][CH2:14][CH3:15])[CH3:10]
Reactant: C=CCCCCC=C
Reactant: CCOC([SiH3])OCC
Reactant: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(OCC)[SiH2]CCCCCCCC[SiH2]C(OCC)OCC
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A solution of 11.0 g of 1,7-octadiene (Wako Pure Chemical Industries) and 26.9 g of diethoxymethylsilane (Shin-etsu Silicones) dissolved in toluene was incorporated with 0.05 mmols of a solution of Karstedt catalyst (U.S. Pat. No. 3,775,452) prepared from a chloroplatinate (Wako Pure Chemical Industries) and divinyl tetramethyldisiloxane (Gelest, Inc.), and the resulting mixture was stirred at 30° C. in a nitrogen atmosphere for 24 hours. The reaction effluent was purified by distillation, to obtain 1,8-bis(diethoxymethylsilyl)octane. Its structure was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:13](=[O:51])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18](=[O:32])[CH:17]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36](C(OC(C)(C)C)=O)[N:35]=4)[C:16]3=[O:50])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:52]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([CH2:33][CH:17]2[C:16](=[O:50])[N:15]([CH2:14][C:13]([N:12]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][C:7]=4[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:51])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]2=[O:32])=[N:35]1
Reactant: COc1ccc2c(c1)CCCCN2C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)CCCCN2C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.75 h
Yield: 29.8 %

Procedure:
A solution of tert-butyl 3-({1-[2-(7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) -2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl) -1H-indazole-1-carboxylate (47 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 45 minutes then concentrated to dryness. The residue was chromatographed on silica gel (Hexane:Ethyl Acetate) to yield a foamy oil. The foam was triturated with Ethyl Ether and filtered to yield the title compound as a white solid (12 mg).
Reaction SMILES: Cl[C:2]1C=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C[N:29](C)C=O>>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([O:21][C:2]2[N:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:29]=2)[CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOc1cc(O)ccc1C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(Oc2ncc([N+](=O)[O-])cn2)ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-chloro-5-nitropyridine (114 mg, 0.716 mmol, 1 equiv) was dissolved in 3 mL of dimethylformamide. 3-(ethyloxy)-4-methylphenol (Intermediate 90, 109 mg) and potassium carbonate (198 mg, 1.432 mmol) were added. The reaction mixture was stirred at room temperature 3 hours. The reaction mixture was filtered. The filtrated solid was washed with dichloromethane. The volatiles were evaporated under vacuum. Ethyl acetate and brine were added to the residue. The compound was extracted 2 times with ethyl acetate and 2 times with dichloromethane. The gathered organic phases were dried over sodium sulphate, filtered and evaporated to afford the title compound which was used directly in the next step (113 mg).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:6]1[CH2:9][O:10][CH:18]([C:17]2[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Yield: 80.9 %

Procedure:
A mixture of 2-n-pentylpropane-1, 3-diol (8 g, 0.054 m), 4-carboxybenzaldehyde (8 g, 0.053 m), benzene (200 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The cold reaction mixture was washed with saturated NaHCO3 solution and water and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield 4-(5-n-pentyl-1, 3-dioxan-2-yl) benzoic acid (12 g, 80%)
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:29])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 40 h
Yield: 54.1 %

Procedure:
The compound of Example 1 (7.2 g, 24.8 mmol) and anhydrous potassium carbonate (7 g, 50 mmol) were suspended in DMF (50 mL), and ethyl bromoacetate (4.5 Ml, 37 mmol) was added dropwise. After stirring for 40 hours, 50 ml of distilled water and 100 mL of ethyl acetated were introduced and stirred to separate layers. The supernatant was washed with a 1N HCl aqueous solution (50 mL), a saturated NaHCO3 aqueous solution (50 mL), and distilled water (100 mL), and it was dried and concentrated under reduced pressure. The mixture was separated using hexane and ethylacetate (2:1) in a silica gel column to obtain a yellow thick oily title compound (5.04 g, yield 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise hexanoyl chloride (550 μl) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (699 mg) was obtained as a white solid (85%) in 96.9% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:9]1([C:17](O)=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:40])=O.CN(C)C=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][N:8]([C:9]1([C:17]([Cl:40])=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 15.1 mmoles of the product from Step E in 73 mL of dichloromethane is treated with 1.4 mL (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents) of dimethylformamide at ambient temperature, causing some bubbling, and is stirred overnight. The resulting solution of the title compound is used in step G without isolation.