Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (162 mg, 0.42 mmol), glycine (2.11 g, 28 mmol) and NaOMe solution (42 mL, 21 mmol, 0.5M in MeOH) was refluxed for 32 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was further purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 131 mg of the title compound. MS: (+) m/z 430.08 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=O)(C)(C)C.O1CCOCC1.[ClH:27]>CO>[ClH:27].[N:16]1([C:14]([CH:9]2[CH2:10][S:11][CH2:12][CH2:13][NH:8]2)=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)N1CCCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(C1CSCCN1)N1CCCC1
Yield: 96 %

Procedure:
4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine (3.2 g) was dissolved in 50 ml of methanol. A 4N 1,4-dioxane solution of hydrogen chloride (13.1 ml) was added, and the solution was condensed to yield white crystals. These crystals was recrystallized from ethanol and diethyl ether to give 2.47 g (96%) of 3-(pyrrolidine-1-carbonyl)thiomorpholine monohydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:13].CC1(C)O[C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1>O>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([CH:6]=[C:19]([C:17]([OH:18])=[O:16])[C:20](=[O:21])[O:13]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)c(O)c1OC
Solvent: O
Product: COc1ccc2cc(C(=O)O)c(=O)oc2c1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
3,4-dimethoxy-salicylaldehyde (252.8 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 271.0 mg of 7,8-dimethoxy-3-carboxy-coumarin in an 78% yield.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>ClCCl>[C:1]1([NH:7][NH:8][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: NNc1ccccc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)NNc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.5 g (23 mmol) of phenylhydrazine were dissolved in 30 ml of dichloromethane and 2.3 g (23 mmol) of succinic anhydride were added portionwise. The reaction mixture was stirred at room temperature for 16 h. The precipitated product was isolated by filtration and washed with dichloromethane. Yield: 4.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O>[CH3:10][C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(O)c1
Solvent: O
Product: CC(=O)Nc1cccc(O)c1
Temperature: 0 °C
Yield: 89.3 %

Procedure:
To a stirred solution of 66.0 g (0.60 mole) of 3-aminophenol in 180 mL of water was added dropwise 77.9 g (0.76 mole) of acetic anhydride. After complete addition, the reaction mixture was heated on a steam bath for 10 minutes, then cooled to 0° C. A precipitate formed and was collected by filtration. The filter cake was washed with cold water and dried in a desiccator for two hours to yield 81.0 g of 3-hydroxyacetanilide (mp 144°-146° C.).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]([F:22])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:23])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:20]([F:22])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 40.8 %

Procedure:
Using an analogous procedure to that described in the preparation of the starting material in Example 8, 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 2.62 mmol) was reacted with 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (845 mg, 3.93 mmol), (prepared as described for the starting material in Example 1), to give 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (620 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N1CC=C(c2ccc(Br)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
A mixture of 4-(4-bromo-phenyl)-1-methanesulfonyl-piperidin-4-ol (60.00 g, 179.51 mmol) and p-toluenesulfonic acid (9.37 g, 53.85 mmol) in toluene (1.08 L) is stirred at 100° C. for 16 h. The reaction is cooled to 23° C. and successively washed with 2 M aq. sodium hydroxide to pH 10, and water. The phases are separated and the organic layer is dried over anhydrous sodium sulfate, filtered and the solvent is removed. Methyl tert-butyl ether (200 mL) is added and the solid is filtered and washed with methyl tert-butyl ether to obtain 35.0 g of the title compound as a pale brown solid. MS m/e (79Br/81Br) 315, 317 (M+1).
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[F:29])=[C:6](\[C:9]1[C:18]([O:19][CH2:20][CH3:21])=[C:17]([Br:22])[C:16]2[C:15]([CH3:24])([CH3:23])[CH2:14][CH:13]=[C:12]([CH:25]([CH2:27][CH3:28])[CH3:26])[C:11]=2[CH:10]=1)/[CH2:7][CH3:8])C.[H-].C([Al+]CC(C)C)C(C)C>>[Br:22][C:17]1[C:16]2[C:15]([CH3:24])([CH3:23])[CH2:14][CH:13]=[C:12]([CH:25]([CH2:27][CH3:28])[CH3:26])[C:11]=2[CH:10]=[C:9](/[C:6](/[CH2:7][CH3:8])=[C:5](/[F:29])\[CH2:4][OH:3])[C:18]=1[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)CC

Procedure:
As described in General Procedure G-1, (2E)-3-(4-bromo-8-sec-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-enoic acid ethyl ester (Compound A-132, 567 mg, 1.18 mmol) and diisobutylaluminum hydride (1M in methylene chloride, 2.84 mL, 2.84 mmol) were reacted to give the title compound as a colorless oil aft er purification by flash chromatography (silica gel, 10% to 15% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:27])=[O:28]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: C1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCCCC5)c4)cc23)CCS1(=O)=O
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 25.1 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.093 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and acetic acid (0.056 mg, 0.929 μmol) was added, hexahydro-1H-azepine (0.453 mL, 4.02 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (399 mg, 0.929 mmol). The vial was sealed and the mixture heated in a microwave 10 minutes at 100° C. The sodium triacetoxyborohydride polymer bound was removed by filtration, and the mixture was run through prep HPLC from 10% acetonitrile containing 0.1% TFA to 50% acetonitrile containing 0.1% TFA in 25 minutes. The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-{1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (763 mg; compound B18) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml, 4.0 M). The solution is stirred for 1 h at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried to give the crude title compound. To remove impurities the free base is submitted to flash column chromatography (silica gel, eluent: MeOH). The purified free base of the title compound is taken up in diethyl ether and the solution is treated with chlorotrimethylsilane. The resulting precipitate is filtered off and dried to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=[O:31])[C:25]=2[CH:24]=[CH:23][N:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:26]3([OH:31])[CH2:27][CH2:28][CH2:29][C:30]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]3=4)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cnccc21
Reactant: Fc1ccc(-c2nccs2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cnc(-c3ccc(F)cc3)s2)CCCc2cnccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of DIPA (0.424 g, 4.2 mmol) in dry THF at −78° C. was added n-BuLi (0.268 g, 4.2 mmol) dropwise at −78° C., and the mixture was stirred for 30 min to produce LDA. A solution of 2-(4-fluorophenyl)thiazole (0.510 g, 2.8 mmol) in dry THF at −78° C. was then added to the above LDA solution. 7,8-Dihydroisoquinolin-5(6H)-one (0.419 g, 2.8 mmol) [prepared as described in Vanotti, International Patent Publication No. WO-2008/065054] was added dropwise to the reaction mixture, which was then stirred for 20 min at −78° C. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (3×30 mL), washed with water followed by brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude solid was purified by washing with the mixture of MeOH and ether, followed by filtering resulted in 5-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol (0.42 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.67 (m, 1H), 1.97 (m, 1H), 2.16 (t, 2H), 2.80 (t, 2H), 6.50 (s, 1H), 7.26 (s, 1H), 7.29 (m, 3H), 7.92 (m, 2H), 8.36 (m, 1H), 8.41 (s, 1H); LC-MS m/z calculated for [M+H]+327.09. found 327.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:9])=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: C1CCNC1
Solvent: CC#N
Product: O=C(NCc1ccc(Br)cc1)N1CCCC1
Yield: 99.7 %

Procedure:
A solution of 4-bromobenzylisocyanate (408 mg, 1.92 mmol) in acetonitrile (15 ml) was treated with triethylamine (390 mg, 3.86 mmol) followed by pyrrolidine (137 mg, 1.93 mmol) at room temperature with stirring under argon. The reaction was stirred at 20° C. for 30 minutes and then partitioned between ethyl acetate (10 ml) and water (20 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless solid (542 mg, 99%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH2:15][OH:16])[CH:14]=[C:8]2[CH2:7]1>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:8]2[CH2:7]1
Reactant: OCc1cc2n(n1)CCN(C1=NCCS1)C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCN(C1=NCCS1)C2

Procedure:
The activated manganese (IV) oxide (16.75 g) was added to the mixture of chloroform (180 ml) solution of [5-(4,5-dihydrothiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-methanol (3.35 g) at room temperature. The reaction mixture was refluxed for 1 hour. After refluxing, the mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was dried in vacuo and the crude 5-(4,5-dihydrothiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde was obtained as a colorless solid. The crude aldehyde thus obtained (2.56 g) was added to a dry acetonitrile (200 ml) solution of MgBr2 (7.36 g) under a nitrogen atmosphere at room temperature then the mixture was stirred for 10 minutes. A dry THF (200 ml) solution of WLJ 20,014 (4.16 g) was added and the mixture was cooled to −20° C. Then triethylamine (11.3 ml) was added in one portion. The reaction vessel was covered with foil to exclude light. The reaction mixture was stirred for 1.5 hours at −20° C. and treated with 4-dimethylaminopyridine (132 mg) and acetic anhydride (4.2 ml) in one portion. The reaction mixture was warmed to 0° C. and stirred for 20 hours at 0° C. The mixture was diluted with ethyl acetate and washed with 5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with n-hexane-AcOEt (1:2) and chloroform-methanol (9:1). The (5R,6RS)-6-{(RS)-acetoxy-[5-(4,5-dihydrothiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]-methyl}-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester was obtained (5.41 g, 75.4%).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[C:1]1([NH:7][C:8]2[O:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
A solution of 1-phenylurea (2.0 g, 14.69 mmol) and ethyl 3-bromo-2-oxopropanoate (2.16 ml, 14.69 mmol) in DMF (58 ml) was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to rt and quenched with water (300 ml)/Na2CO3-solution (50 ml). The product was extracted with EA (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude product. Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.)) afforded the title compound. HPLC (Method U): RtU=1.91 min, MS (Method D) [M+H]+=233.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9]C2C=C(C(F)(F)F)C3C(=CC=C(O[C@H]4CC[C@H](C(C)(C)C)CC4)C=3)N=2)[CH2:6]1)=[O:4].[C:35]([C@H:39]1[CH2:44][CH2:43][C@H:42]([O:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[C:51](C=O)[CH:52]=3)[N:47]=2)[CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][CH:50]=2)[N:47]=[C:46]([O:45][C@H:42]2[CH2:41][CH2:40][C@H:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:44][CH2:43]2)[CH:55]=[CH:54]3)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Product: COC(=O)C1CN(Cc2ccc3nc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 2-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline-6-carbaldehyde as starting material. ESI-MS (M+H+): 411.30.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1
Reactant: CON=Cc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C(F)(F)F)cc1
Yield: 73 %

Procedure:
Reduction 4-trifluoromethyl-benzaldehyde O-methyloxime of with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (73% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s, OCH3), 4.09 (2H, s, NCH2), 5.80 (1H, broad s, NH), 7.48 (2H, m, aromatics), 7.60 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 132-133° C. Anal. calcd for C9H10F3NO—HCl: C, 44.74; H, 4.59; N, 5.80. Found: C, 44.71; H, 4.53; N, 5.68.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.[ClH:51]>C1(C)C=CC=CC=1.CCOCC>[ClH:51].[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1)(=[O:40])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(C(C)=O)ccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To N-[(1S,2R)-3-{[(4-bromo-1,1′-biphenyl-2-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (120 mg, 0.24 mmol) in toluene (1 mL) was added tributyl(1-ethoxyvinyl)tin (100 μL, 0.28 mmol) and bis-triphenylphoshine palladium(II) dichloride (10 mg, 0.012 mmol), and the reaction was heated at 100° C. 3 h under N2. The solution was cooled to room temperature, 1N hydrochloric acid (1 mL) was added, and the mixture was stirred 20 min. The mixture was partitioned, and the organics were washed with saturated potassium fluoride (aq). The reaction mixture was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 8% methanol/methylene chloride) provided an oil. The residue was dissolved in ether, precipitated with excess 1N HCl in ether, and concentrated to provide the title compound (11 mg). ESI MS m/z 467.28 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14]Br)([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:17]=[N+:18]=[N-:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of crude 2-bromomethylphenylacetic acid t-butyl ester (0.349 mol) in 600 mL DMF was added 34.1 g (0.524 mol) sodium azide and the mixture stirred at 65° C. for 3 h. After cooling to ambient temperature, the mixture was diluted with 1.2 L ethyl acetate. The organic layer was washed with water (3×800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound as a yellow oil. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][O:38][CH3:39])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 537.98 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)=[O:4].[C:26]([OH:28])([C:25]([F:30])([F:29])[F:24])=[O:27]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(N2CCNCC2)nc1
Reaction time: 2 h

Procedure:
2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid methyl ester (140 mg, 0.434 mmol) is dissolved in dichloromethane (3.0 mL) under N2. Trifluoroacetic acid (0.83 ml, 10.85 mmol) is added and the reaction mixture is stirred for 2 h. The reaction mixture is concentrated under reduced pressure and co-evaporated several times with dichloromethane. It is dried under high vacuum to afford the title compound as a TFA salt (130 mg, 90% yield).