Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:11][O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cccnc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A reaction flask was loaded with 3-hydroxy-2-nitropyridine (20 g), dimethylformamide (80 ml), and potassium carbonate (23.4 g), and they were mixed, followed by dropwise addition of methyl iodide (52.4 g) to the flask in 2.2 hours. After stirring overnight, water was added to this for crystallization. The crystals were filtrated for collection and dried to give 3-methoxy-2-nitropyridine (16.5 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][C:12]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:2]>[Pd].O1CCOCC1>[CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][C:12]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc(-c2cc(C=Cc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1

Procedure:
Palladium on charcoal catalyst (10%; 50 mg) was added to a degassed solution of 5-(2,4-Bis-benzyloxy-5-styrylphenyl)-isoxazole-3-carboxylic acid ethylamide (690 mg, 1.30 mmol) in 1,4-dioxane (50 mL) under a nitrogen atmosphere. The reaction mixture was hydrogenated for a total of 4.75 hrs with further Pd on charcoal catalyst (50 mg) added at 0.75 and 2.5 hrs. The reaction mixture was filtered through a pad of celite, which was washed with 1,4-dioxane (20 mL) and dichloromethane (20 mL). The combined filtrate solvents were removed in vacuo to afford a cream-coloured solid, which was purified by flash chromatography on silica gel (20 g, IST) eluting with 10 to 50% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-isoxazole-3-carboxylic acid ethylamide as a pale yellow solid (609 mg, 88%). LCMS: [M+H]+ 533. 1H NMR (400 MHz, CDCl3) 1.26 (t, 3H), 2.86-2.96 (m, 4H), 3.49 (m, 2H), 5.03 (s, 2H), 5.18 (s, 2H), 6.56 (s, 1H), 6.81 (t, 1H), 7.07 (s, 1H), 7.15-7.20 (m, 3H), 7.23-7.28 (m, 2H), 7.31-7.42 (m, 10H), 7.73 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([NH:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)NCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 104.6 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperazine-1-carboxylic acid benzylamide (0.5 g, 1.2 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.18 g, 3.1 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.47 g, 100% yield) as a colourless oil. Tr=1.60 min, m/z (ES+) (M+H)+ 375.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC(=O)C)C>C1COCC1>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[CH2:16][CH2:17]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(C2CCC(OCC(=O)CC)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC1CCC(C2CCC(OCC(O)CC)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
While keeping inside of a reaction system at a temperature of lower than 10° C., a solution of 5.24 g (16.3 mmol) of 4-(4-pentylcyclohexyl)-(2-oxobutyloxy)cyclohexane produced in Example 3 and dissolved in 35 ml of THF was added dropwise to a mixture of 0.46 g (12.2 mmol) of LAH and 2.5 ml of THF and further stirred for 5 hours at a room temperature. To this solution, under cooling, were added 5 ml of ethylacetate and then 10 ml of 2N aqueous solution of sodium hydroxide to terminate the reaction. After undissolved products were separated, the solvent was distilled off under a reduced pressure and the residue thus obtained was recrystallized from 15 ml of hexane to obtain 5.0 g (yield 95%) of 4-(4-pentylcyclohexyl)-(2-hydroxybutyloxy)cyclohexane.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:20])[C:11]4[C:16]([O:17][C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1.[N+:21]([O-])([O-:23])=[O:22].[K+]>S(=O)(=O)(O)O>[N+:21]([C:13]1[CH:14]=[CH:15][C:16]2[O:17][C:18]3[C:9](=[CH:8][CH:7]=[C:6]([C:5]4[NH:1][N:2]=[N:3][N:4]=4)[CH:19]=3)[C:10](=[O:20])[C:11]=2[CH:12]=1)([O-:23])=[O:22]
Reactant: O=c1c2ccccc2oc2cc(-c3nnn[nH]3)ccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc([N+](=O)[O-])cc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3-(5-Tetrazolyl)xanthone (1.0 g) was dissolved in concentrated sulphuric acid (10.0 ml) and the resulting solution cooled to below 15° C. Potassium nitrate (0.50 g) was added in small portions over 10 min. with cooling to maintain the temperature between 10° and 15° C. and the reaction mixture was then stirred at 20° C. for 1 hr. The reaction mixture was poured on to ice and the precipitated product filtered off, washed with water and recrystallised from dimethylformamide. The crystallised product was washed with methanol and dried at 156° C./20 mm Hg to yield 0.78 g, mpt. ca. 280° C. with decomposition.
Reaction SMILES: O[CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.O1CCOCC1.CCN(S(F)(F)[F:30])CC>O>[F:30][CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCCOCC(O)Cn1cnc([N+](=O)[O-])n1
Solvent: C1COCCO1
Solvent: O
Product: COCCOCC(F)Cn1cnc([N+](=O)[O-])n1
Yield: 44.8 %

Procedure:
To 1.1 g (4.5 mmol) of 1-[2'-hydroxy-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole, 10 ml of 1,4-dioxane was added and then 1.0 g (6.2 mmol) of DAST was dropwise added. Then, the mixture was reacted for a day at room temperature with stirring. After the reaction, to the reaction solution, 2 ml of water was added to decompose excess DAST. The solution was concentrated and partitioned between chloroform and water. The chloroform phase was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel column chromatography to give 500 mg of 1-[2'-fluoro-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:34][CH3:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH3:41])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:34][CH3:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3s2)cc1
Temperature: 70 °C
Yield: 82.1 %

Procedure:
To a solution of 0.30 g (0.58 mMol) 4-[2-(4-chloromethyl-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 10 ml THF were added 0.16 g (1.75 mMol) N-(2-methoxyethyl)-methyl amine. The reaction mixture was heated to 70° C. for 5 h. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 19:1) to yield 0.27 g (82%) of 4-[4-methoxy-2-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoylamino)-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white foam. ES-MS m/e (%): 567 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[N:6][CH:7]=1>C(O)C.ClCCl.[Pt](=O)=O>[F:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccc(F)cn2)c1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccc(F)cn2)c1
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-5-nitrophenyl)pyridine (1.23 g) in ethanol (70 ml) and dichloromethane (30 ml) was added platinum(IV) oxide (150 mg) and the mixture shaken on a Parr hydrogenation apparatus under an atmosphere of hydrogen at 45 psi for 1 h. Filtration and evaporation of the filtrate afforded 4-fluoro-3-(5-fluoropyridin-2-yl)phenylamine: MS (ES+) m/z 207.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.9 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (29-03) (3.5 g, 55.85%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (28-02) (4.3 g, 9.817 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8-b) (2.34 g, 10.79 mmol) as a colourless gummy solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(-c2c(C(C)C)cnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(C(C)C)cnn1C
Yield: 79 %

Procedure:
A solution of methyl 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (173 mg, 0.62 mmol) in 6N sodium hydroxide (1 ml, 6.21 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (148 mg, 0.49 mmol, 79% yield) as a white foam: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [Na].Br[CH2:3][C:4]([OH:6])=[O:5].[CH3:7][CH:8]([OH:11])[CH2:9][CH3:10]>>[CH3:7][CH:8]([O:11][CH2:3][C:4]([OH:6])=[O:5])[CH2:9][CH3:10]
Reactant: CCC(C)O
Reactant: O=C(O)CBr
Agent: [Na]
Product: CCC(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 3-neck 1-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added 500 ml of 2-butanol under nitrogen. Sodium spheres (3.31 g, 0.144 moles) were then added and the mixture heated at reflux for 6 hours and then stirred at room temperature overnight. A solution of bromoacetic acid (10.00 g, 0.072 moles) in 10 ml of 2-butanol was then added dropwise and the mixture stirred at room temperature for 24 hours. The mixture was then concentrated in vacuo to remove the 2-butanol and the resulting white solid dissolved in 100 ml of water. This aqueous solution was washed with ether (2×50 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×50 ml), dried over magnesium sulfate and concentrated in vacuo to give 8.1 g of the product as a pale yellow oil.
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>FC(F)(F)C(O)=O>[CH:23]1([C:29]([O:2][CH:3]([C:11]2[CH:20]=[CH:19][C:18]([O:21][C:3]([CH:11]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:12]3)=[O:2])=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:22])[NH:16]3)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(C)C)C(OC(=O)C1CCCCC1)c1ccc(OC(=O)C2CCCCC2)c2[nH]c(=O)ccc12
Temperature: 85 °C
Yield: 136.8 %

Procedure:
3.36 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride was dissolved in 20 ml of trifluoroacetic acid, and 8.8 g of cyclohexanecarboxylic acid chloride was added to the solution. The mixture was then heated at a temperature of 85° C. while refluxing. The reaction mixture was concentrated and diethyl ether was added to the residue to crystallize the product. The crystals thus obtained were separated by filtration and washed with diethyl ether. The resulting crystals were extracted successively with a saturated aqueous solution of sodium bicarbonate and chloroform, and the organic layer was washed with water, dried and concentrated to dryness. The resulting residue was crystallized from a mixture of diethyl ether and petroleum benzene to obtain 3.59 g of 5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)-8-cyclohexylcarbonyloxycarbostyril having a melting point of 162° to 163° C. (after recrystallization from chloroform-n-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])=[O:16])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[NH:21][NH2:22]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>[CH2:25]([O:24][C:20]([NH:21][N:22]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])=[O:16])=[CH:10][CH:9]=1)[C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)NN
Reactant: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)NN=C(c1ccc(Cl)cc1)c1ccc(CS(C)=O)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
An ethanol solution (100 ml) of 4-chloro-4'-methylsulfinylmethyl benzophenone (5.8 g), ethyl carbazate (6.3 g) and pyridinium p-toluenesulfonate (0.1 g) was heated for 6 hours with refluxing. After cooling to a room temperature, the reaction mixture was poured into ice-water, and the precipitated crystals were collected by filtration, and washed successively with an aqueous sodium bicarbonate solution and water. After air-drying, 4-chloro-4'-methylsulfinylmethylbenzophenone ethoxycarbonylhydrazone (6.4 g) was obtained as an isomer mixture.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.C(#N)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 81.2 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 8.29 g (60.0 mmol) of potassium carbonate, 30 ml of acetonitrile, 8.09 g (60.0 mmol) of dimethyl malonate with a purity of 99% and 5.00 g (30.0 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added to the mixture, and 7.5 ml (90 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 20 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 6.61 g (reaction yield: 81%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [CH3:1][N:2]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:19]([N:15]1[CH2:16][CH2:17][C@H:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14]1)[CH3:20]
Reactant: CCI
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](N(C)C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
A mixture of benzyl N-methyl-(S)-pyrrolidin-3-ylcarbamate (Intermediate 129, 1.28 g), iodoethane (0.853 g), and potassium carbonate (1.51 g) in acetonitrile (12 mL) was stirred at room temperature for 4 hours. The mixture was evaporated in vacuo and the residue was basified with 5M sodium hydroxide and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30% to give benzyl N—((S)-1-ethylpyrrolidin-3-yl)-N-methylcarbamate (0.686 g) as a colourless oil.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]([N:63]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=4[Cl:71])[CH3:64])=[O:62])=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:72]=1.[C:73](=[NH:86])([C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:71][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=1[N:63]([CH3:64])[C:61]([C:59]1[S:58][C:57]2[C:51]3[CH:50]=[CH:49][C:48]([N:86]=[C:73]([C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)[C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)=[CH:72][C:52]=3[O:53][CH2:54][CH2:55][C:56]=2[CH:60]=1)=[O:62]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(N=C(c3ccccc3)c3ccccc3)cc1OCC2)c1ccccc1Cl
Temperature: 80 °C
Yield: 65.6 %

Procedure:
Solid Pd2(dba)3 (101 mg, 0.11 mmol) and BINAP (205 mg, 0.33 mmol) was added to a 10 mL flask and the whole purged with nitrogen. To the flask was added 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (500 mg, 1.11 mmol), benzophenone imine (303 mg, 1.67 mmol), NaOtBu (213 mg, 2.22 mmol) and toluene (30 mL). The mixture was heated to 80° C. with stirring until the starting material had been consumed (determined by TLC analysis). The mixture was cooled to room temperature, diluted with EtOAc, filtered and concentrated. The crude product was purified by column chromatography (5:1 hexanes:ethyl acetate) to give N-(2-chlorophenyl)-8-(diphenylmethyleneamino)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide as a yellow solid (400 mg, yield 65%). N-(2-chlorophenyl)-8-(diphenylmethyleneamino)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (4.9 g, 8.92 mmol) was dissolved in 10 mL of MeOH. To the solution was added 6 mL of CH3COCl in MeOH (1:10). The mixture was stirred at room temperature for 15 min before concentrated under vacuum. The residue was washed with EtOAc to give 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide as a white solid (3.6 g, yield 95%). 1H NMR (MeOD, 400 MHz): δ 7.59-6.60 (m, 8H), 4.21 (t, J=5.2 Hz, 2H), 3.31 (s, 3H), 2.96 (t, J=4.8 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1)=O.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)CCNCc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12
Reaction time: 16 h

Procedure:
To 6-(1-formylisoquinolin-4-yloxy)nicotinamide (Preparation 20) (130 mg, 0.44 mmol) in dichloroethane (8 mL) was added 3-methylbutylamine (154 μL, 1.33 mmol), NaBH(OAc)3 (282 mg, 1.33 mmol) and acetic acid (76 μL, 1.33 mmol). The mixture was stirred for 16 h. NaHCO3 (50 mL) was added and the mixture extracted with EtOAc (3×40 mL). The organic phase was washed with water (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.5 NH3: 5 MeOH: 95 DCM) to give the title compound: RT=2.48 min; m/z (ES+)=365.2 [M+H]+.