Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(C(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(C(Cl)=NOS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of 8.5 g of 4-methylbenzohydroximoyl chloride and 8.8 g of 3-chloropropanesulfonyl chloride in 175 ml of benzene, 7.6 g of triethylamine was added dropwise during 8 minutes. The temperature of the reaction mixture rose to 35°. The reaction mixture was stirred for 1 hour and filtered, the filtrate was evaporated under reduced pressure, and the product was recrystallized twice from ethanol to give 8.4 g of N-(3-chloropropanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 56°-58°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:8][CH:7]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CCCCO)cc1
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(4-hydroxy-but-1-ynyl)-benzyl]-isoindole-1,3-dione (2.0 g, 6.55 mmol) in ethanol/ethyl acetate (3:1, 163 mL) was added palladium on carbon (10 wt. %, 1.04 g). The reaction stirred at room temperature overnight under 50 psi of hydrogen. The reaction was monitored by 1H NMR to see conversion to product. Upon completion, the reaction mixture was filtered through diatomaceous earth (Celite®), washed with ethyl acetate, and concentrated to obtain the product as a yellow oil (1.88 g, 93% yield). 1H NMR (600 MHz, CDCl3): δ 7.81 (2H, m), 7.67 (m, 2H), 7.33 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 4.79 (s, 2H), 3.69 (q, 3H, J=7.0 Hz), 3.60 (t, 2H, J=6.5 Hz), 2.58 (t, 2H, J=7.4 Hz), 1.64 (m, 2H), 1.55 (m, 2H); 13C NMR (150 MHz, CDCl3): 168.3, 142.2, 134.1, 134.0, 132.3, 128.8, 128.8, 123.5, 62.9, 41.5, 35.4, 32.4, 27.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH:11]=[CH2:12])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][C:26]#[CH:27])=[O:24])=[CH:19][C:18]=1[N+:28]([O-:30])=[O:29].[CH3:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34]>CC(C)=O>[CH3:31][O:32][C:33]([NH:35][C:36](=[S:37])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH:11]=[CH2:12])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])=[O:34].[CH3:31][O:32][C:33]([NH:35][C:36](=[S:37])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][C:26]#[CH:27])=[O:24])=[CH:19][C:18]=1[N+:28]([O-:30])=[O:29])=[O:34]
Reactant: C=CCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)N=C=S
Reactant: C#CCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: C#CCS(=O)c1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Product: C=CCS(=O)c1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1

Procedure:
1.5 G. of 1-amino-2-nitro-4-(prop-2-en-1-ylsulfinyl)-benzene or 1-amino-2-nitro-4-(prop-2-yn-1-ylsulfinyl)benzene, prepared according to Example XXII, in 200 ml. acetone is treated with 4 g. methoxy carbonyl isothiocyanate at room temperature for several days (i.e., until no starting material is present). The mixture is concentrated and the residue triturated with methanol to yield 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-en-1-ylsulfinyl)benzene or 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-yn-sulfinyl)benzene, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]CC.[Na+]>C(O)C>[OH:28][C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]2[CH:10]=[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]3=[N:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(C(=O)c2cc3c(nc2N)CCCC3)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2nc3c(cc2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 25.7 %

Procedure:
To a solution of (2-amino-5,6,7,8-tetrahydroquinolin-3-yl)(p-tolyl)methanone (0.533 g; 2 mmol) and diethyl malonate (1.22 mL; 8 mmol) in ethanol (10 mL) under nitrogen atmosphere was added a solution of sodium ethoxide 21% (w/w) in ethanol (2.24 mL; 6 mmol). The mixture was stirred in a sealed tube and heated to 100° C. for 48 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel column using a gradient of ethyl acetate (1 to 60%) in dichloromethane as eluent to furnish 0.186 g (25%) of ethyl 2-hydroxy-4-(p-tolyl)-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate as a white solid. ESI/APCI(+): 363 (M+H). NMR 1H (DMSO-d6) (ppm): δ 12.37 (s, 1H, NH); 7.35-7.19 (m, 5H, 5×Harom.); 4.00 (q, 2H, OCH2CH3); 2.88 (m, 2H, CH2); 2.66 (m, 2H, CH2); 2.35 (s, 3H, CH3); 1.86-1.79 (m, 2H, CH2); 1.74-1.69 (m, 2H, CH2); 0.90 (t, 3H, OCH2CH3).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].[CH:15]1[C:23]2[N:18]([CH:19]=[CH:20][C:21](=O)[CH:22]=2)[CH2:17][CH:16]=1>>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:21]2[CH2:22][CH:23]3[N:18]([CH2:17][CH2:16][CH2:15]3)[CH2:19][CH:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1ccc2cc(N)ccc21
Reactant: O=c1ccn2c(c1)C=CC2
Product: CS(=O)(=O)n1cc(C2=CCN3CCCC3C2)c2cc(N)ccc21

Procedure:
The N-(methanesulfonyl)-5-amino-1H-indole (1.06 g, 5.00 mmol) and the 7-indolizinone (900 mg, 6.50 mmol) were converted to product by the procedure of Example 2 to give 807 mg. (48.7%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)[nH]c1N
Reaction time: 48 h

Procedure:
In a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [preparation see: Liebigs Ann. Chem., 1895 (1977)] are cooled to 0-5° C. and 2.65 g (390 mmol) of sodium ethanolate are added. 5 g (195 mmol) of 2-bromo-1-(4-nitro-phenyl)-ethan-1-one are then added and the mixture is allowed to rise to room temperature and is stirred for a further 48 hours. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with sat. NaCl solution, dried and filtered, and the filtrate is concentrated by evaporation. The reddish-brown residue is made into a slurry in hexane, the title compound precipitating in the form of a crude product (purity 93%) which is used for the next step without further purification; MS: (M)+ =275.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][CH2:25][CH2:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[N:26]([C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=1)[CH2:25][CH2:24]2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Fc1cc2c(cc1F)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3cc(F)c(F)cc32)nc(N2CCOCC2)cc1=O
Yield: 42.8 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 232 mg of 5,6-difluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 167 mg of 2-[2-(5,6-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].C1(C)C=CC=CC=1.O.[H][H]>[Rh].CO>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: [H][H]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
A suitable inert reactor is charged with 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) (13.6 kg, 55.5 mol) as a toluene wet cake and 5% rhodium on carbon catalyst (2.7 kg, 50% wet with water) as a water wet cake at about 25° C. About 190 kg of methanol is added and the reactor is pressured to about 100 psig with hydrogen for about 4-12 hours at about 50° C. The catalyst is removed by filtration and the reactor and catalyst are rinsed with about 7 kg of methanol. Deionized water is used as a final wash of the catalyst wet cake. The reactor rinse filtrate and the reaction mixture filtrate are combined. The concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is about 7 wt %, affording about 13 kg (90% average yield) of the title compound (11).
Reaction SMILES: [CH:1]([N:4]([CH3:28])[C:5]1[C:6]([C:19]2[C:20]([C:24]([F:27])([F:26])[F:25])=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:28])[C:5]1[C:6]([C:19]2[C:20]([C:24]([F:25])([F:26])[F:27])=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3c[nH]nc3C(F)(F)F)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To solution of methyl 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylate (80.0 mg, 0.20 mmol) in methanol (30 mL) was added sodium hydroxide (24 mg, 0.60 mmol) and water (1 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and then adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration, dried in an oven under reduced pressure to afford 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid as a light yellow solid (64.0 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1Cl

Procedure:
4-Bromo-2-chloro-benzoic acid (0.64 g, 2.7 mmol) and DMF (50 μl) were added to dichloromethane (9 ml). Oxalyl chloride (0.47 ml, 5.4 mmol) was then added to the mixture and the resultant solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 4-bromo-2-chloro-benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.[H][H].[ClH:26]>C(O)C.[Pd].CCOCC>[ClH:26].[ClH:26].[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1
Reactant: CN1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Reaction time: 48 h

Procedure:
A solution of 3.7 g of the free base of cis-1-methyl-4-(4-nitrophenoxy)-3-phenylpiperidine, of Example 7, in 100 ml of absolute ethanol is hydrogenated over 0.37 g of 10% Pd on carbon catalyst at 45 psi of hydrogen and room temperature. Uptake stops after 48 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo to a gum. This material is chromatographed on silica gel using acetone and then 25% methanol/acetone as solvent. A purified free base is obtained and a portion of this material is dissolved in ether and is then added dropwise to a solution of dry HCl in ether. The resulting precipitate is filtered, washed with ether, and is then immediately suspended in boiling ether. Absolute ethanol is added until the mixture grows clear. Scratching of the cold solution causes crystallization to occur. The recrystallized solid is filtered, washed with cold acetone, then ether, and dried to afford a solid (m.p. 226°-227° C. dec.) of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine dihydrochloride.
Reaction SMILES: CCCCCCC=CCCC.[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CN(C=O)C.CCCCC>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[S:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: SCc1ccccc1
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
]undec-7-ene (DBU) is added dropwise at 20° C., under argon, to a solution of benzenemethanethiol (11.72 ml; 100.0 mmol) in anhydrous DMF (20.0 ml). After 0.5 hour at 20° C., the reaction mixture is cooled to 0° C. and tributyltin chloride is added dropwise. The mixture is allowed to warm to room temperature and stirring is continued for 5 hours. The reaction mixture is taken up in pentane (400 ml), washed with water (3×300 ml) and brine (100 ml), washed with sodium sulphate, filtered and then concentrated under reduced pressure. 39.0 g of tributyl[(phenylmethyl)thio]stannane are obtained in the form of a colourless oil, which is used without further purification in the following step.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:40][N:20]([CH:21]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH:18]([C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2N(C)C(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 48.6 %

Procedure:
A solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.24 g), iodomethane (77 mg) and K2CO3 (82 mg) in DMF (5 ml) was stirred for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[N-methyl-N-[1-(4,5-diphenyloxazol-2-yl)ethyl]amino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.12 g).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:28][N:14]3[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:10][C@@H:11]1[CH2:28][N:14]2[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:19][C@@H:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To tert-butyl (8S,9aS)-8-[(4-nitrobenzoyl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (495 mg, 0.291 mmol, Part A) in methanol (8 ml) was added potassium carbonate (98 mg, 0.708 mmol). The mixture was stirred at room temperature for one hour, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 280 mg (88% yield) of the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.61 (m, 1H), 2.24 (m, 1H), 2.38 (m, 1H), 2.58 (m, 1H), 2.80-3.15 (m, 2H), 3.23 (dd, J=13, 4 Hz, 1H), 3.42 (dd, J=13, 4 Hz, 1H), 3.81 (m, 1H), 3.98 (m, 2H), 4.18 (m, 1H), 5.02 (t, J=4 Hz, 1H); MS (ESI) m/z 271.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:10])[CH3:11])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1N(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CO[C@@H]1CNCC[C@@H]1N(C)C
Yield: 100 %

Procedure:
A mixture of cis-3-methoxy-N,N-dimethyl-1-(phenylmethyl)-4-piperidinamine was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 17 parts (100%) of cis-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([O:25]CC)=[O:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([OH:25])=[O:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.00 g (5.07 mmol) of the compound of Example 32A are provided in 37 ml of 1,4-dioxane, a solution of 1.07 g (20.0 mmol) of lithium hydroxide in 37 ml of water is added, and the mixture is stirred at room temperature overnight. The mixture is concentrated, a 1N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. 0.74 g (40% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:50][CH2:49][C:48]2[C:51]3[CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[S:53][C:47]=2[C:46]1=[O:58])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[CH2:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:35]4[C:30]([CH2:29][O:28][C:25](=[O:27])[CH3:26])=[C:31]([N:45]5[C:46](=[O:58])[C:47]6[S:53][C:52]7[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=7[C:48]=6[CH2:49][CH2:50]5)[CH:32]=[CH:33][CH:34]=4)[CH:3]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)[CH3:24]
Reactant: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCc6c(sc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 5-bromo-3-(5-(4-ethyl-piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 138c (250 mg, 0.637 mmol), boronic ester 111a (308 mg, 0.701 mmol), Pd(PPh3)4 (36.8 mg, 0.0319 mmol), Na2CO3 aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), 1,2-dimethoxyethane (3.0 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 181a.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][N:14]=1.[OH-].[Na+]>C(O)(=O)C.ClCCl.O>[CH3:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][N+:14]=1[O-:9]
Reactant: Cc1nsc2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1c2cccnc2s[n+]1[O-]
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of m-chloroperbenzoic acid (160 mmol) in acetic acid (200 mL) was added dropwise to a solution of 3-methylisothiazolo[5,4-b]pyridine (107 mmol) in dichloromethane (200 mL). The reaction mixture was maintained for 6 h at 25° C. The reaction mixture was diluted with water (100 mL), the pH was adjusted to 8 with 10% sodium hydroxide, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide 3-methylisothiazolo[5,4-b]pyridine-N-oxide in 62% yield as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([CH:13]=[O:14])[CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:13]([CH:10]2[CH2:12][CH2:11]2)[OH:14])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ccnc1Br
Reactant: O=CC1CC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 2-bromo-4-chloro-3-methylpyridine (7 g, 28.1 mmol) in dry THF (150 mL) was cooled down to 0° C. An isopropyl magnesium chloride-Lithium chloride complex (26 mL, 33.8 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled down to 0° C. and cyclopropane carboxaldehyde (2.5 mL, 33.5 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled to 0° C. and water (150 mL) was added carefully so temperature would not rise above 10° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography over silica gel (0-30% ethyl acetate in heptane) yielding a yellow oil (3.47 g, 16.8%).