Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=O.CO.[CH3:26][NH2:27].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO.O1CCCC1>[CH3:26][NH:27][CH2:7][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:2]=1[CH3:1]
Reactant: CN
Reactant: Cc1c(C=O)cc(-c2cccnc2)n1S(=O)(=O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(-c2cccnc2)n(S(=O)(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methyl-1-(phenylsulfonyl)-5-(3-pyridyl)-1H-pyrrole-3-carbaldehyde (276 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) were added 40% methylamine methanol solution (1.0 mL) and anhydrous magnesium sulfate (270 mg), and the reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture was added sodium borohydride (43 mg) at room temperature and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free base of the title compound as a yellow oil. To a solution (4 mL) of the obtained free base in ethanol was added a solution (2 mL) of oxalic acid (18 mg) in ethanol. The mixture was stirred at room temperature for 10 min, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 103 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH:41]([NH2:43])[CH3:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:43][CH:41]([CH3:42])[CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCC(C)N
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: COCC(C)Nc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxy-1-methylethylamine according to conditions described in general procedure C. Mp: 94-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.97 (s, 3 H), 1.56-1.61 (m, 6 H), 3.00-3.32 (m, 9 H), 4.10 (s, 1 H), 6.31 (s, 1 H), 6.95-7.03 (m, 2 H), 7.15 (d, J=9.1 Hz, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.50-7.62 (m, 3 H), 7.79-7.82 (m, 1 H), 7.95-7.97 (m, 1 H), 8.20 (s 1 H), 10.40 (s, 1H).
Reaction SMILES: [CH:1]1([C@@H:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:22][C:23]([CH3:25])=[CH2:24]>ClCCl>[CH:1]1([C@@H:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([O:9][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccc([C@@H](C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 g (732.9 mmol) of (2S)-cyclopentyl-(4-methylphenyl)acetic acid were initially charged in 480 ml of dichloromethane, and 2.1 ml of sulfuric acid and 172 ml (1722.4 mmol) of condensed 2-methylprop-1-ene were added at 10° C. The mixture was stirred at RT overnight. If required, the addition of sulfuric acid and 2-methylprop-1-ene was repeated until all the starting material had been consumed. After the reaction had ended, 21 g of potassium carbonate were added and the mixture was stirred for another 2-3 h (evolution of gas). The mixture was then diluted with 700 ml of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 172 g (85% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][CH:16]=[O:17])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Ca+2].[C:26](Cl)(Cl)=[S:27]>O1CCOCC1.O>[CH:16]([NH:15][NH:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([N:1]=[C:26]=[S:27])[CH:20]=[CH:19][CH:18]=2)=[O:6])=[CH:13][CH:12]=1)=[O:17]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(C(=O)Nc2ccc(NNC=O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: O=CNNc1ccc(NC(=O)c2cccc(N=C=S)c2)cc1
Yield: 71.3 %

Procedure:
51 g of 2-[4-(3-aminobenzamido)phenyl]-1-formylhydrazine and 29 g of calcium carbonate were dispersed in a mixture of 120 ml of dioxane and 120 ml of water. To the dispersion, 25 g of thiophosgene was added under cooling with ice. After reacting under cooling with ice for 3 hours, the crystals deposited were collected by filtration to obtain 42 g of the object compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]([CH3:23])([CH3:22])[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:33].[Na+].OO.Cl>C1COCC1.C(Cl)Cl.O.C(O)C>[CH:16]1([NH:15][C:13](=[O:14])[C:12]([S:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH2:3][OH:33])=[CH:10][CH:9]=2)([CH3:23])[CH3:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CCOc1ccc(SC(C)(C)C(=O)NC2CCCCC2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(Sc1ccc(OCCCO)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-{[4-(Allyloxy)phenyl]thio}-N-cyclohexyl-2-methylpropanamide was dissolved in THF and treated with 9-BBN at rt under N2. After stirring at rt for 18 h, ethanol, 1N NaOH and a 30% H2O2 solution were added successively to the reaction mixture. After stirring for a few hours, the reaction mixture was acidified with 1N HCl to pH 2. Water and CH2Cl2 were added and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, hexanes:EtOAc, 2:1 to 1:1) to provide the desired alcohol as a white solid. LCMS: (M+H)+=352.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:24])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:27](=[O:29])[CH3:28])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-methylphenyl}methanamine (0.2 g) and acetic anhydride (0.1 g) in dichloromethane (50 mL), triethylamine (0.1 g) in dichloromethane (5 mL) was added dropwise under ice cooling, and the mixture was then stirred for one hour at room temperature. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-methylbenzyl}acetamide (0.2 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([O:23][C:24]1[CH:46]=[CH:45][C:27]2[C:28]3[N:32]([CH2:33][CH2:34][O:35][C:26]=2[CH:25]=1)[CH:31]=[C:30]([C:36]1[N:37]([CH:42]([CH3:44])[CH3:43])[N:38]=[C:39]([CH3:41])[N:40]=1)[N:29]=3)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH:42]([N:37]1[C:36]([C:30]2[N:29]=[C:28]3[N:32]([CH2:33][CH2:34][O:35][C:26]4[CH:25]=[C:24]([O:23][C:11]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)([CH2:12][OH:13])[CH2:10][OH:9])[CH:46]=[CH:45][C:27]=43)[CH:31]=2)=[N:40][C:39]([CH3:41])=[N:38]1)([CH3:44])[CH3:43]
Reactant: CCOC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)(C(=O)OCC)c1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)c4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a suspension of LiAlH4 (15 mg, 0.389 mmol) in THF (2 mL) was added a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-phenylmalonic acid diethyl ester (72.5 mg, 0.13 mmol) in THF (1 mL). The mixture was stirred at RT for 2 h, then EtOAc (5 mL) was added and stirring was continued for 10 min. An aqueous solution of Rochelle's salt was then added and stirring continued for a further 30 min. The mixture was filtered through a Celite® pad and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 4-12% MeOH in DCM) affording the title compound (28.1 mg, 46%). LCMS (Method B): RT 2.75 min [M+H]+ 476
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=O)=[CH:12][CH:11]=1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[N:16]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Reaction time: 3 h
Yield: 99 %

Procedure:
Thionyl chloride (1.55 g, 13.09 mmol, 1.1 equiv.) is added dropwise to 4-(3-chloropropoxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax53 (3.18 g, 11.9 mmol, 1 eq) in dry dichloromethane (100 ml), under a nitrogen atmosphere over 30 min. The solution is then stirred for 3 h. Water and potassium carbonate are finally added and the mixture is stirred until no more bubbles are formed (pH=10). The layers are separated and the dichloromethane layer is washed with brine, dried over sodium sulfate and evaporated under vacuum to give 3.18 g of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]#[N:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:16][OH:17]>CCO.[OH-].[Na+].CCOC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:17][N:16]=[C:13]([NH2:14])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#CC#Cc1ccc2cnccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccc3cnccc3c2)on1
Reaction time: 3 h
Yield: 97.5 %

Procedure:
3-(Isoquinolin-6-yl)propiolonitrile (0.060 g, 0.34 mmol) was suspended in 3.0 mL of EtOH. Hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added to the mixture in 1.5 mL of 10% aq. NaOH. The solution turned a clear, light yellow color immediately. After 3 hours, the reaction mixture was diluted with 20 mL of EtOAc and transferred to a separatory funnel. The mixture was washed with 3 mL of water and 5 mL of brine. The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure, affording 5-(isoquinolin-6-yl)isoxazol-3-amine (0.070 g, 98% yield) as a yellow solid. MS m/z: 212 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.93 (d, J=5.9 Hz, 1H), 6.57 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CO.I[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24](=[O:30])[CH:23]=[CH:22]2>ClCCl>[CH3:29][N:25]1[C:26]2[C:21](=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][CH:6]=[CH:5]4)=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]1=[O:30]
Reactant: Cn1c(=O)ccc2cc(OCCCI)ccc21
Reactant: Nc1ccc2ncccc2c1
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)ccc2cc(OCCCNc3ccc4ncccc4c3)ccc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
6-Aminoquinoline (360 mg) was added to the methanol solution (10 ml) of 6-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg) and stirred at 60° C. for 17 hours. The reaction mixture was added to ice water, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (86.4 mg) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane (3 mL) at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2.eq.) and 2,4-dimethoxy-benzoyl chloride (220 mg, 1.1 mmol, 1 eq.) dissolved in 3 mL of dichloromethane. The solution was allowed to warm to 0° C. and stirred for 1 hour. The solution was washed with 1N HCl, and 5% sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 324 mg (69%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:25]([CH3:39])[CH2:26][CH2:27][N:28]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:25]([CH3:39])[CH2:26][CH2:27][NH2:28])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: COc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (335 mg, 1.02 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (837 mg, 2.56 mmol) and then using general procedure D afforded 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (240 mg, 62% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:15]1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.5 g of 4-(2-tert-butoxycarbonylaminoethyl)-piperidine and 0.61 ml of triethylamine are dissolved in 5 ml of dichloromethane and, at 0° C., 0.22 ml of acetyl chloride is added. The reaction mixture is stirred at room temperature for 7 hours and then washed with water. The organic phase is concentrated by evaporation and purified by FC (10 g of silica gel, ethyl acetate/methanol=9:1). The title compound is obtained: Rf (ethyl acetate/methanol=9:1)=0.39.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[NH:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.C(N(C(C)C)CC)(C)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24].C(Cl)CCl>ClCCl.[NH4+].[Cl-].O.CO.C(OCC)(=O)C.C(OCC)(=O)C>[OH:8][C@H:5]1[CH2:6][N:7]([C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[C:22]2[CH:30]=[CH:31][CH:32]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=2)[C@H:3]([CH3:2])[CH2:4]1
Reactant: C[C@@H]1C[C@@H](O)CN1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@@H](O)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,5R)-5-Methylpyrrolidin-3-ol hydrochloride (1.80 g, 13 mmol) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (2.1 mL, 12.0 mmol) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (2.93 g, 11.85 mmol) was added followed by EDC (3.41 g, 17.8 mmol) and the mixture was stirred at room temperature for four hours. The mixture was diluted with NH4Cl/H2O and extracted twice with ethyl acetate. The combined extracts were washed with NaHCO3/H2O and brine, dried over MgSO4, filtered and concentrated to give a dark orange oil. Chromatography on silica gel eluting with ethyl acetate to 5% methanol/ethyl acetate gave the coupled product as a pale orange solid, 3.19 g (81%, 2 steps). LC/MS (M+H)+ m/z=331.1. 1H NMR (CDCl3, major rotamer) δ 8.12 (s, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 7.57 (t, 1H), 7.50 (m, 1H), 4.56 (m, 1H), 4.34 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 3.61 (dd, 1H), 3.51 (d, 1H), 2.71 (d, 1H), 2.17 (m, 1H), 1.81 (m, 1H), 1.32 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=O)[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(O)C.[BH4-].[Na+]>C1COCC1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3Nc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (850 mg, 2.6 mmol) and 4-fluoroaniline (877 mg, 7.89 mmol) in THF (10 mL) was added Ti(OPr-i)4 (823 mg, 2.9 mmol) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to 0° C., and 10.0 mL of dry ethanol was added, followed by NaBH4 (149 mg, 3.4 mmol). The mixture was stirred for 1 hr, precipitate was removed by filtration and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-7% of MeOH in DCM to afford the 660 mg of the title product.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][CH:7]=1)[CH2:4][CH3:5]>CO>[CH2:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=1)[CH2:4][CH3:5]
Reactant: CCCc1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(CCC)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Methanol (150 ml) and an aqueous solution of 1N-potassium hydroxide (100 ml) were added to 14.2 g (65.7 mmol) of 1-(4-n-propylphenyl)-2-trimethylsilylacetylene synthesized in the step (i), and the mixture was subjected to hydrolysis with vigorously stirring overnight. After completion of the reaction, methanol was removed and the resultant residue was extracted with hexane. After removing hexane from the hexane phase, the resultant residue was washed with water to give 9.4 g (65.3 mmol) of 4-n-propylphenylacetylene.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8](OC(C)(C)C)=O.[CH3:15][O:16][C:17]1[CH:26]=[C:25](CBr)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]([CH2:8][N:2]2[CH2:3][C@@H:4]3[CH2:7][C@H:1]2[CH2:6][NH:5]3)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COC(=O)c1ccc(CBr)cc1OC
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1OC

Procedure:
In like manner, 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and methyl 2-methoxy-4-(bromomethyl)benzoate are reacted together to give methyl 2-methoxy-4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH:13]1([CH:16]([NH2:19])[CH2:17][CH3:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CC#N>[CH:13]1([CH:16]([NH:19][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH3:18])[CH2:15][CH2:14]1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CCC(N)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(Nc1cc[nH]c(=O)c1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Part A. A mixture of 4-chloro-3-nitro-2-pyridone (2.0 g, 11.4 mmol), 1-cyclopropylpropyl amine hydrochloride (1.5 g, 11.4 mmol) and N,N-diisopropylethylamine (4.8 ml, 27.4 mmol) in CH3CN (50 ml) were stirred at 25° C. for 16 h and at reflux for 4 h. After cooling it was stripped in vacuo, and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The insolubles were separated, washed with H2O and EtOAc and vacuum dried 1.51 g. The filtrate layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The Combined extracts were washed with brine, dried over MgSO4, filtered and concd. in vacuo. The residue was washed with EtOAc (2×) and vacuum dried, to give 0.69 g; yellow solid. Combined wt. of 4-(1-cyclopropylpropyl)amino-3-nitro-2-pyridone 2.20 g, 81% yield. 1H NMR (300 MHz, dmso d6): 11.19 (1H, br), 8.94 (1H, d J=8.8 Hz), 7.33 (1H, t J=6.9 Hz), 6.03 (1H, d J=7.7 Hz), 3.18-3.24 (1H, m)r, 1.60-1.74 (2H, m), 1.03-1.11(1H, m), 0.91 (3H, t), 0.40-0.60 (1H, m), 0.20-0.39 (1H, m).