Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([OH:17])[CH3:16].[CH3:19]I>CCOC(C)=O.[Ag]=O>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH:15]([O:17][CH3:19])[CH3:16]
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)O
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)OC
Temperature: 60 °C

Procedure:
10 mg of 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol in 1 ml of EtOAc was added a small amount of activated silver oxide and 0.5 ml of methyl iodide. The mixture was heated for 5.5 hours at N 60° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash chromatography to yield 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane. ##STR22##
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>CO.[Pd]>[OH:31][C:28]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:26]([C:10]2[CH:11]=[C:12]([CH:23]([CH3:24])[CH3:25])[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:30][N:29]=1
Reactant: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(O)cc2O)ccc1OC
Reaction time: 16 h
Yield: 90.9 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-ol (240 mg, 0.4 mmol) was dissolved in methanol (10 mL) then 10% palladium on charcoal (200 mg) was added and the reaction was stirred under an atmosphere of hydrogen for 16 hrs. Filtration was carried out through a silica gel plug and removal of the solvent under reduced pressure produced the desired compound as a white solid (150 mg, 94%).
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21](O)[CH2:22][CH3:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:21][CH2:22][CH:23]=[O:3]
Reactant: CCC(O)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(CCC=O)cc1OC
Temperature: -45 °C
Yield: 70.7 %

Procedure:
To a solution of oxalyl chloride(0.67 ml) in dichloromethane (80 ml) was added dropwise a solution of DMSO (1.18 ml) in dichloromethane(5 ml) at −78° C. To the mixture was added a solution of 1-(3,4-dimethoxyphenyl)propanol (1.50 g) in dichloromethane(25 ml) after 15 minutes. The mixture was stirred for an hour at −78° C. and for another hour at −45° C., then triethylamine(3.52 ml) was added. After stirring 20 minutes at 0° C., the mixture was quenched by a saturated aqueous NH4Cl solution, and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:7 to 1:1) to give 3,4-dimethoxy-hydrocinnamaldehyde (1.05 g, 70.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:16][C:3]1[C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]([CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a mixture of ethyl 7-amino-6-chloro-1H-indole-2-carboxylate (1.59 g) and pyridine (10 ml) was added thiophene-2-sulfonyl chloride (1.46 g), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.17 g, yield 85%) as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 191-192° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C@@H:10]1[CH2:14][NH:13][CH2:12][C@H:11]1[C:15]([O:17][CH3:18])=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[N:21]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[Cl:19][C:20]1[N:21]=[C:22]([N:13]2[CH2:14][C@@H:10]([C:4]3[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=3[F:2])[C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: Clc1cccc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)[C@@H]1CN(c2cccc(Cl)n2)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
Methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate hydrochloride (prepared according to Young, J. R. et. al. Bioorganic and Medicinal Chemistry Letters 2007, 17, 5310-5315; 100 mg, 0.360 mmol), 2,6-dichloropyridine (107 mg, 0.720 mmol) and N,N-diisopropyl-N-ethylamine (0.189 ml, 1.080 mmol) in NMP (2.0 ml) was heated by microwave (150° C., 30 min). The mixture was cooled to rt, poured into water and extracted with MTBE. Purification on SiO2 (0 to 30% EtOAc, hexanes) afforded the title compound. HPLC/MS: 353.1/354.9 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][O:21]C(=O)C)[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1.O1CCOCC1.[Li+].[OH-].N>CO.ClCCl>[Cl:1][C:2]1[C:3]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OCCN1CCN(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc2C1
Agent: N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(CCO)Cc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
To a 25 ml round bottom flask, acetic acid 2-{8-[5-chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-1-methyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-ethyl ester (50 mg, 0.09 mmole), dioxane (5 ml), and 1M LiOH (1 mL, 1 mmole) were added and stirred at room temperature for 18 hours. The reaction was then acidified to pH 2 with 1NHCl. The solvents were removed under vacuum to give a white solid. The desired product (10 mg, 21% yield) was isolated via column chromatography with dichloromethane and ammonia in methanol as eluant. NMR 1H-(CDCl3)-δ-7.93 (s, 1H), 7.15 (d, 1H, J=7.83 Hz), 7.04 (d, 1H, J=7.83 Hz), 6.93 (s, 1H), 6.89 (s, 1H), 5.38 (d, 1H, J=5.73 Hz), 5.29 (s, 1H), 3.82-3.95 (m, 1H), 3.80 (s, 2H), 3.61 (t, 2H, J=5.31 Hz), 3.15-3.30 (m, 1H), 2.99 (bs, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.61 (t, 2H, J=5.30Hz), 2.10-2.30 (m, 2H), 1.75-1.90 (m, 2H), 1.30-1.50 (m, 4H)
Reaction SMILES: [OH-].[Na+].[CH:3]([N:6]1[C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:13]=[C:14]([C:15]([O:17]CC)=[O:16])[C:9]=2[CH:8]=[N:7]1)([CH3:5])[CH3:4]>CCO>[CH:3]([N:6]1[C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:9]=2[CH:8]=[N:7]1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1cc(N2CCN(C)CC2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(N3CCN(C)CC3)nc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Aqueous NaOH (0.193 g, 4.833 mmol) was added to a solution of ethyl 1-isopropyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.32 g, 0.966 mmol) in EtOH (6 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using DCM; the combined organic layers were washed with water, brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the desired compound (0.2 g, 64.9%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:33][CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[C:37]([C:35]1[N:36]=[C:32]([C:11]2[CH:10]=[C:9]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:8]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[N:6][C:7]=3[CH:12]=2)[S:33][CH:34]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1csc(Br)n1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2nc(C(C)(C)C)cs2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 35.9 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 2-bromo-4-(tert-butyl)thiazole (128.5 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.73 mL, 0.73 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (14.0 mg, 0.012 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 44.5 mg (yield 35.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.61-7.58 (m, 1H), 7.59 (s, 1H), 7.35 (d, J=1.2 Hz, 1H), 4.81 (p, J=6.0 Hz, 1H), 3.77-3.65 (m, 1H), 3.45-3.35 (m, 1H), 3.25-3.14 (m, 1H), 2.89-2.74 (m, 1H), 2.41-2.20 (m, 2H), 1.35-1.29 (d, J=6 Hz, 3H), 1.16-1.08 (m, 2H), 1.08-0.98 (m, 2H) ppm; MS (ESI+) m/z 425.16 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC(N)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-methoxy-2-tetralone (12.4 g; 70.7 mmol) dissolved in MeOH (350 mL) was added ammonium acetate (82 g; 1.06 mol) and the reaction was stirred for 30 min at room temperature. To the reaction was then added sodium cyanoborohydride (21.5 g; 353 mmol) and the reaction was refluxed for 1 h. Upon completion of the reaction, the reaction was cooled and the solvent removed under reduced pressure. The residue was diluted with EtOAc and 1N NaOH was added to quench the reaction. The aqueous phase was separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to yield 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine as a dark oil.
Reaction SMILES: [ClH:1].Cl.[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][C:16]3[C:21]([C:22]=2[C:23](O)=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:63]1([C@@H:69]([NH2:71])[CH3:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>C(Cl)Cl.CC#N.C(Cl)Cl>[ClH:1].[ClH:1].[CH:63]1([C@@H:69]([NH:71][C:23]([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:13]=2[CH2:12][N:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[O:24])[CH3:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)N[C@@H](C)C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
2.3 g (5.0 mmol) of crude 3-(4-isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 6) were dissolved in 200 ml of a 1:1 mixture of CH2Cl2/CH3CN; 2.0 ml (15 mmol) of triethylamine (TEA) and 2.5 g (6.5 mmol) of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) were added and the reaction mixture was cooled at 0° C. 0.74 ml (5 mmol) of (S)-1-cyclohexyl-ethylamine, dissolved in 10 ml of dry CH2Cl2, were added dropwise and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated in vacuo to dryness and the residue was taken up with EtOAc and washed with H2O, 1 N NaOH and brine, dried over Na2SO4 and evaporated to dryness to yield a crude material which was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of CH2Cl2/MeOH 95:5 containing 0.5% NH4OH (28%). The residue was dissolved in acetone and acidified with HCl/Et2O; the precipitate so formed was recovered by suction filtration to yield 0.9 g of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:38]=1>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:39]=1[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH3:45]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CCOc1ccc(CBr)cc1OCCCOC
Product: CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
Analogously to Method D, 0.496 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.502 g of 4-bromomethyl-1-ethoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.26 (1:2 EtOAc-heptane); Rt=6.20.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.I[CH:23]([CH3:25])[CH3:24]>>[CH3:24][CH:23]([O:21][C:19]1[O:20][C:16]([C:13]2[O:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][O:4][CH3:3])[C:15]=3[CH:14]=2)=[N:17][N:18]=1)[CH3:25]
Reactant: CC(C)I
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Agent: [H-]
Agent: [Na+]
Product: COCOc1cccc2oc(-c3nnc(OC(C)C)o3)cc12
Yield: 86.2 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 117 using sodium hydride (0.28 g), 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (1.5 g) and 2-iodopropane (1.1 g), the title compound (1.5 g) was obtained as brown crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[CH3:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1coc(-c2ccc(Br)cc2)n1
Reactant: CC1CCCCN1
Product: CC1CCCCN1Cc1coc(-c2ccc(Br)cc2)n1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 16 using 2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) and 2-methylpiperidine. MS (m/e): 336.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([F:11])[F:10]>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:12]=[O:13]
Reactant: OCc1cnc(OC(F)F)c(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cnc(OC(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (5-chloro-6-(difluoromethoxy)pyridin-3-yl)methanol (1.000 g; 4.77 mmol) in anh. DCM (40 ml) was treated with MnO2 (6.222 g; 71.57 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 3 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 5-chloro-6-(difluoromethoxy)nicotinaldehyde as a yellow oil. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[S:27][C:26]=2[CH:34]=1.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:28]4[S:27][C:26]5[CH:34]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=5[CH:29]=4)(=[O:32])=[O:31])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2ccc(Cl)nc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN from 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 9, Parts A, B and C in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from EtOAc/hexanes to afford the title compound as a beige solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[CH:12]([C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
DMSO (3.3 ml, 46.6 mmol, 2.2 eq) in dichloromethane (20 ml) is added dropwise to a solution of oxalyl chloride (2.03 ml, 23.2 mmol, 1.1 eq) in dichloromethane (80 ml) cooled to −78° C. This mixture is stirred for 10 mins and then tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (4.56 g, 21.1 mmol, 1 eq) in dichloromethane (20 ml) is added dropwise. This is stirred for 20 mins and then triethylamine (15.0 ml, 105 mmol, 5 eq) is added in one portion and then warmed to room temperature over 30 mins. The solution is poured onto diethyl ether (300 ml) and brine (300 ml), separated and the aqueous layer is extracted with diethyl ether (2×100 ml). The organic layers are combined, washed with brine (100 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to give tert-butyl (3R)-3-formylpiperidine-1-carboxylate (4.33 g, 96%) 1H NMR (300 MHz, CDCl3) δH 9.63 (1H, s), 3.75-3.98 (1H, m), 3.48-3.66 (1H, m), 3.16-3.34 (1H, m), 2.90-3.11 (1H, m), 2.26-2.44 (1H, m), 1.79-1.97 (1H, m), 1.53-1.70 (2H, m) and 1.20-1.49 (10H, m).
Reaction SMILES: C([N:8]([CH3:19])[C:9]1([C:16]([NH2:18])=[O:17])[CH2:12][N:11]([C:13]([O-:15])=[O:14])[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C.Cl.ClCCl>[NH2:18][C:16]([C:9]1([NH:8][CH3:19])[CH2:10][N:11]([C:13]([O:15][C:9]([CH3:16])([CH3:12])[CH3:10])=[O:14])[CH2:12]1)=[O:17]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)[O-])C1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 186.1 %

Procedure:
10% wt Palladium on charcoal (160 mg) in ethyl acetate (2 ml) was added to a solution of 3-[benzyl(methyl)amino]-3-(aminocarbonyl)azetidine-1-carboxylate (500 mg, 1.57 mmol) in ethanol (45 ml). After addition of a few drops of saturated hydrogen chloride in dichloromethane, the reaction mixture was stirred at room temperature under 2 bars of hydrogen for 3 hours. Filtration of the catalyst and concentration under reduced pressure afforded tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (335 mg, 93%) as a white solid; 1H NMR Spectrum: (CDCl3) 1.44 (s, 9H), 2.35 (s, 3H), 3.71 (d, 2H), 4.29 (brd, 2H), 5.51 (brs, 1H), 6.95 (brs, 1H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH:6]1[CH:7]=[CH:8]2)(=[O:4])[CH2:2][CH3:3].CC(O)CC.[BH4-].[Na+].Cl>O>[C:1]([NH:5][CH:6]1[CH2:12][CH:9]([CH2:10][OH:11])[CH:8]=[CH:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1C(=O)C2C=CC1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CCC(=O)NC1C=CC(CO)C1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
16.6 g of (±)-2-propionyl-2-azabicyclo[2.2.1]-hept-5-en-3-one were dissolved in water (140 ml) and 2-butanol (66 ml) under nitrogen and cooled to −5° C. 3 g of sodium borohydride were added in portions over the course of 2 h. The mixture was stirred at 10° C. for 2.5 h and then adjusted to pH 2.2 with a mixture of conc. hydrochloric acid and water (1/1). The solution was evaporated to 40 g and adjusted to pH 6.2 with 2N NaOH. The mixture was extracted with 5×50 ml of dichloromethane. The combined organic phases were completely evaporated, and the residue was recrystallized in toluene (150 ml). 11.1 g of title compound were obtained. The yield was 65%.