Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38](Cl)=[O:39])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:39])[N:33]=[N:32]1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Reactant: O=C(Cl)CCc1c[nH]nn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCc3c[nH]nn3)CC2)c1
Reaction time: 1 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate HCl salt (Example 64, step 3) (234 mg, 0.709 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.248 mL, 1.418 mmol). 3-(1H-1,2,3-Triazol-4-yl)propanoyl chloride (113 mg, 0.709 mmol) in DCM (2 mL) was then added and the mixture stirred for 1 hour. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and then the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: C([Li])CCC.CCCCCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1Br.C1(CO[CH2:25][C:26]2([OH:40])[CH2:32][O:31][CH2:30][CH2:29][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27]2)CC1.B(F)(F)F.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:25][C:26]1([OH:40])[CH2:32][O:31][CH2:30][CH2:29][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Reactant: Fc1ccccc1Br
Agent: FB(F)F
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2F)C1
Temperature: -80 °C
Yield: 54.5 %

Procedure:
1.6M Butyllithium/hexane (150 mL, 0.24 mol, 1.09 eq) was added to a solution of 2-fluorobromobenzene (26 mL, 0.24 mol, 1.09 eq) in THF (200 mL) in a stream of argon at −90° C. The reaction mixture was cooled to −80° C., and a solution of compound tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 44, 50 mL, 0.22 mol, 1 eq) in THF was added dropwise. Then the mixture was cooled to −100° C., and a solution of borontrifluoride diethyletherate (30.4 g, 0.24 mol, 1.09 eq) in THF (300 mL) was added at this temperature for 30 min. The reaction mixture was heated to 0° C. for 5 h, and a 5M sodium hydrogen sulfate solution (50 mL) was added. The organic layer was separated and evaporated, and the residue was distributed between water and ether. The organic layer was separated, washed with water and brine, dried, and evaporated. The residue was dissolved in MeOH (200 mL). Ethylenediamine (30 mL) was added to the mixture, which was brought to boiling, cooled, evaporated, and coevaporated with dioxane. The residue was subjected to chromatography (silica gel, carbon tetrachloride→chloroform→chloroform/MeOH 19:1), evaporated, and dried to title compound (38 g, 0.12 mol, 55%).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[F:17][C:16]([F:18])([F:19])[O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:20])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
TFA (80 mL) was added to (4-trifluoromethoxyphenoxy)-acetic acid tert-butyl ester (25.8 g, 88 mmol). The mixture was stirred for three hours. The TFA was removed in vacuo affording the title compound as a white solid: MS (ESI-LCMS) for C9H6F3O4: 235 (M-H—).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (6.0 g, 17 mmol), as prepared in step 2 of Example 1, in methylene chloride (12 mL) was added trifluoroacetic acid (12 mL) and the reaction stirred at ambient temperature. After 30 minutes the reaction was concentrated in vacuo, dissolved in methylene chloride, and diluted with hexane. The precipitated product was collected by filtration and dried in vacuo giving a quantitative yield of white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.36 (s, 1H), 7.74 (d, 1H, J=7.5 Hz), 7.35 (m, 5H), 6.18 (d, 1H, J=7.7 Hz), 5.15 (s, 2H), 4.77 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[C:22]1[CH3:31]>>[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([CH3:27])[C:28]#[C:29][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[N:23]=[C:22]1[CH3:31]
Reactant: C#CC(C)(O)c1cn(C)c(C)n1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)cn1C
Yield: 4 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,2-dimethyl-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (5 mg, 4%).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>C(#N)C>[F:14][C:13]([F:16])([F:15])[O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([CH2:2][NH:20][CH2:17][C:18]#[CH:19])[S:4][C:5]=2[CH:11]=1
Reactant: C#CCN
Reactant: FC(F)(F)Oc1ccc2nc(CBr)sc2c1
Solvent: CC#N
Product: C#CCNCc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 85.9 %

Procedure:
2-(bromomethyl)-6-(trifluoromethoxy)benzo[d]thiazole (3.8 g, 0.0122 mol) and propargylamine (1.7 g, 2.5 eq) were dissolved in acetonitrile (50 ml) and the reaction mixture was heated to reflux for 1 h. Then it was cooled, evaporated to dryness and the residue was partitioned between EtOAc and water, 0.5 ml of NH4OH was add (pH=9-10) and the organic phase was separated, dried over Na2SO4, evaporated and the residue purified by chromatography (hexane-EtOAc) to give 3 g (86%) of N-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)methyl)prop-2-yn-1-amine. The free base was dissolved in 100 ml Et2O and HCl/IPA was added. The white suspension that was obtained was filtered and dried to give 2.7 g (mp=188-189° C., dec) of white solid, which was identified as the HCl salt of Compound B. 1H-NMR (of the HCl salt of the title compound, DMSOd6) δ 10.23 (br s, 2H, NH2), 8.35 (s, 1H, Ar), 8.16 (d, 1H, Ar), 7.57 (d, 1H, Ar), 4.76 (s, 2H, C—CH2) 4.04 (d, 2H, N—CH2—C), 3.74 (s, 1H, CH); 13C-NMR (DMSOd6) δ 164.40, 150.66, 145.74, 136.53, 124.01, 120.39, 120.10, 115.54, 79.84, 74.88, 46.05, 35.80; LCMS (ES-API for free base) 287.0 (M+H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:29]=1[Cl:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1cc(F)ccc1Cl
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CNc1cc(F)ccc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
10.0 g of sodium triacetoxyborohydride (47.2 mmol) was added to a solution of 6.0 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (32.0 mmol), 4.6 g of 2-chloro-5-fluoroaniline (32.0 mmol) and 1.8 ml of acetic acid (32.0 mmol) in methylene chloride (320 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 5.36 g of the title compound (yield: 53%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH2:24])=[O:23])[C:18]([OH:20])=[O:19]>>[C:22]([CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])(=[O:23])[NH2:24]
Reactant: NC(=O)CC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: NC(=O)CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-succinamic acid to provide the title compound in moderate yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:26][N:25]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH2:24]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:24][N:25]([C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:28])[CH2:26]1
Reactant: O=C(c1ccccc1)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccccc1)N1CC(c2ccc(O)cc2O)C1
Reaction time: 18 h
Yield: 66.8 %

Procedure:
In a 10 ml round-bottomed flask, 0.2 g of [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is dissolved in 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (1/1 heptane/ethyl acetate). 0.08 g of [3-(2,4-dihydroxyphenyl)azetidin-1-yl]phenylmethanone is obtained. Yield=67%.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[N+:30]([O-])=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2]>[Pd].CO>[NH2:30][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:24]=1[NH:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3[N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3N)ccc21
Yield: 83.4 %

Procedure:
10% Palladium on carbon (0.7 g) was added to a methanol solution (30 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(3-nitropyridin-4-ylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.8 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure to give the title compound (1.4 g) as an orange amorphous solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]4[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=4[S:17][C:18]=3[NH2:19])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1)=[O:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]4[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=4[S:17][C:18]=3[NH:19][C:34]([CH:31]3[CH2:30][CH2:29][CH:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:33][CH2:32]3)=[O:35])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1CCC(C(=O)Cl)CC1
Reactant: Nc1sc2c(c1C(=O)NCc1ccc3c(c1)OCO3)CCCC2
Product: COC(=O)C1CCC(C(=O)Nc2sc3c(c2C(=O)NCc2ccc4c(c2)OCO4)CCCC3)CC1

Procedure:
Analogously to Example 1, the reaction of N-(benzo[1,3]dioxol-5-ylmethyl)-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide with 4-methoxycarbonylcyclohexanecarbonyl chloride ("B") gives the compound methyl 4-{3-[(benzo[1,3]dioxol-5-ylmethyl)carbamoyl]-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylcarbamoyl}cyclohexanecarboxylate, m.p. 173°.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32](Cl)=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=4)=[O:27])[CH:22]=[CH:21][C:20]=3[CH3:40])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.N(C1C=CC=C(C(F)(F)F)C=1)=C=O>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=4)=[O:27])[CH:22]=[CH:21][C:20]=3[CH3:40])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Agent: O=C=Nc1cccc(C(F)(F)F)c1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Yield: 9 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 12 and Step (4) of Example 1 were repeated step by step, except for using 1-isocyanato-3-(trifluoromethyl)benzene instead of benzene in Step (1) of Example 12 to obtain the title compound (4.0 mg, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]([OH:39])=[O:38])=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:30])([F:29])[F:31])[CH:4]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCC[C@@H]5C(=O)O)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCCCCCCO)OCc1ccccc1

Procedure:
This compound was prepared from 16-hydroxyhexadecanoic acid (2.45 g; 9.0 mmol), benzyl alcohol (4.9 g; 45 mmol), and p-toluenesulphonic acid (100 mg) in toluene (100 mL) using Procedure B. 2.82 g crude product that was a 1:1 mixture of the expected product and the ester between two molecules of 16-hydroxyhexadecanoic acid was obtained. A solution of NaH (ca. 100 mg) (previously washed three times with dry hexane) in benzyl alcohol (10 g) was added to the crude product and the mixture was stirred at 100° C. (bath temperature) under argon for 3 h. After cooling to ambient temperature, the mixture was diluted with dichloromethane (75 mL) and washed with 10% aqueous citric acid solution (1×10 mL) and dried (Na2SO4). After filtration and evaporation, the residue was vacuum dried at 50° C. (bath temperature) and 0.014 mm Hg using a Kugelrohr apparatus. 2.56 g (76%) product was obtained (white solid). Proton NMR indicated that ca. 10% of the dimer ester remained.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:20][C:11]2=[C:12]([O:16]C(=O)C)[N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].Cl>[OH-].[Na+].O>[S:5]([C:8]1[S:20][C:11]2[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1)(=[O:6])(=[O:7])[NH2:4]
Reactant: CC(=O)Oc1nccc2cc(S(=O)(=O)N=CN(C)C)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc2cc[nH]c(=O)c2s1
Temperature: 60 °C
Yield: 54.1 %

Procedure:
An initial suspension of N,N-dimethyl-N'-(7-acetoxythieno[2,3-c]pyridine-2-sulfonyl)formamidine (2.0 g, 6.1 mmol) in 10 N sodium hydroxide (4 ml) diluted with water (15 ml) was warmed at 60° C. for 1 hour. This clear solution was cooled and acidified with concentrated hydrochloric acid to give a precipitate of product. This precipitate (1.2 g) was collected by filtration and dried in a vacuum oven. Recrystallization by dissolution in a minimum amount of hot dimethyl sulfoxide, followed by dilution with ethanol gave 0.76 g (54% yield) of pure product; m.p. 295°-297° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#N)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[OH:26]S(O)(=O)=O>C(Cl)Cl>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH:13]=[O:26])=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(-c2coc(C3CC3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2coc(C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a 0C solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzonitrile (0.984 g, 4.68 mmol) in anhydrous CH2Cl2 (3 ml) was added dropwise a 1M solution of DIBAL in CH2Cl2 (5.60 ml, 1.22 mmol). Upon completion of addition, the solution was warmed to 45C for 3 h. The solution was cooled and 10% aqueous H2SO4 was slowly added until pH<4. The mixture was stirred overnight at rt. The aqueous phase was extracted with CH2Cl2 (3×40 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes, 1:4) to yield the title compound as a yellow solid (0.92 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:14][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(F)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)C(Br)c1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
Methyl 2-chloro-4-fluorophenylacetate (3.15 g, 15.6 mmol), N-bromosuccinimide (2.77 g, 15.6 mmol) and AIBN (255 mg, 1.56 mmol) were suspended in benzene (50.0 mL) and degassed via N2 stream. The resulting mixture was heated to 80° C. for 12 h. After cooling to rt, the mixture was partially concentrated in vacuo and partitioned between ether and water. The layers were separated, and the organic layer was washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude oil was purified by by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.82 (dd, 1H, J=6.0, 8.8 Hz), 7.17 (dd, 1H, J=2.6, 8.3 Hz), 7.08 (m, 1H), 5.88 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].B1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:28]=2)OC(C)(C)C(C)(C)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:35])(=[O:34])[NH2:36])[CH:28]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with benzenesulfon-amide-3-boronic acid pinacol ester gives “A78”; method 1: HPLC/MS: 1.13 min, [M+H]=370;
Reaction SMILES: [NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C[O-].[Na+]>CO>[NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:22][OH:23])=[O:18])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCS(=O)(=O)Nc1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCCS(=O)(=O)Nc1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a mixture of ethyl 6-(anilinosulfonyl)hexanoate (64b) and hydroxylamine hydrochloride (0.43 g, 6.2 mmol) in methanol (5 ml) the 3.43 N solution of sodium methylate (2.62 ml, 9.0 mmol) in methanol was added and the reaction was stirred at ambient temperature for 40 min. The reaction mixture was poured into saturated NaH2PO4 (15 ml) and extracted with ethyl acetate. The extract was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated, the residue was washed with diethyl ether and crystallised from ethyl acetate. The title compound (0.3 g, 69%) was obtained as white crystals, m.p. 97-98° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.02-1.78 (m, 6H, CH2); 1.90 (br t, 2H, J=6.4 Hz, CH2); 3.06 (t, 2H, J=7.0 Hz, CH2); 6.94-7.60 (m, 5H, arom.); 8.66 (br s, 1H, NH); 9.76 (br s, 1H, NH); 10.36 (br s, 1H, OH). HPLC analysis on Symmetry C8 column: impurities 3.5% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 30:70; detector UV 220 nm; flow rate 1.1 ml/min; sample concentration 0.4 mg/ml). Anal. Calcd for C12H18N2O4S, %: C, 50.33; H, 6.34; N, 9.78; S, 11.20. Found, %: C, 50.10; H, 6.22; N, 9.83; S, 11.10.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@:13]34[C:14]5[C:15]6[O:22][CH:12]3[C:11](=[O:25])[CH2:10][CH2:9][C@@:8]4([F:26])[C@H:7]2[CH2:20][C:19]=5[CH:18]=[CH:17][C:16]=6[OH:21])[CH2:4][CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@:13]34[C:14]5[C:15]6[O:22][CH:12]3[CH:11]([OH:25])[CH2:10][CH2:9][C@@:8]4([F:26])[C@H:7]2[CH2:20][C:19]=5[CH:18]=[CH:17][C:16]=6[OH:21])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CC[C@@]2(F)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)C1O5
Solvent: C1CCOC1
Product: Oc1ccc2c3c1OC1C(O)CC[C@@]4(F)[C@@H](C2)N(CC2CCC2)CC[C@]314
Reaction time: 3 h
Yield: 72.3 %

Procedure:
17-(Cyclobutylmethyl)-4,5-epoxy-14-fluoro-3-hydroxymorphinan-6-one (1.1 g) was dissolved in tetrahydrofuran (50 ml) and dried over molecular sieves. This dried solution was then added to a solution of lithium tri(tertiarybutoxy)aluminum hydride (7.5 g in 50 ml THF) and stirred for three hours. Excess reducing agent was decomposed by cautious addition of water followed by sodium carbonate to pH 8.2. The aqueous tetrahydrofuran was filtered off, and the filter cake washed with tetrahydrofuran to leach out the adhering product. The organic solvent was removed by evaporation, the residue dissolved in chloroform, and the chloroform solution washed with water and filtered through a fluted filter. Evaporation of the chloroform yielded 800 mg of a solid which was recrystallized from ethanol to give the title product, m.p. 236°-239°.