Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11]>CC(C)=O.Cl.O>[CH:2]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11])=[O:1]
Reactant: CC(C)(CCC#N)CC1OCCO1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(CC=O)CCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
50 g of 5-(dioxolan-2-yl)-4,4-dimethylvaleronitrile, prepared in D], are dissolved in 1.3 1 of acetone in the presence of 140 ml of concentrated hydrochloric acid and 700 ml of water. The mixture is stirred at room temperature for 5 hours, the acetone is concentrated under vacuum and the residue is taken up with ether, washed with water and then evaporated to dryness to give 35 g of 5-formyl-4,4-dimethylvaleronitrile.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([N:14]1[CH2:19][CH2:18][C@@H:17]([SH:20])/[C:16](=[CH:21]/[C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=2)/[CH2:15]1)[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])O.[Na+]>CC(O)C.CCCCCC>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([N:14]1[CH2:19][CH2:18][C@@H:17]([SH:20])/[C:16](=[CH:21]/[C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=2)/[CH2:15]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CCn1ccc(/C=C2\CN(C(C(=O)OC)c3ccccc3F)CC[C@H]2S)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)CCn1ccc(/C=C2\CN([C@H](C(=O)OC)c3ccccc3F)CC[C@H]2S)n1

Procedure:
(4R)-(E)-1-[(1RS)-1-(2-Fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine hydrochloride was treated with an aqueous sodium hydrogen carbonate solution. The liberated base was extracted with dichloromethane. The free base thus obtained (ca. 200 mg) was divided into five portions and subjected to preparative HPLC (Chiralcel OD-H, 20φ×250 mm, Daicel Chemical Industries Co., Ltd., eluent: 2-propanol/hexane=1/2, 4 ml/minute) to afford the more mobile isomer, (4R)-(E)-1-[(1S)-1-(2-fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine (103.9 mg), and the less mobile isomer, (4R)-(E)-1-[(1R)-1-(2-fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine (100.3 mg), both as colourless oils.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](OC)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(F)c(F)c1)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1cc(F)c(F)c(F)c1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a solution of (R)-methyl 1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (1.0 g, 1.918 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under a nitrogen atmosphere was added diisobutyl aluminium hydride (DIBAL-H) (1 M in Heptane) (7.67 ml, 7.67 mmol) dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 hour. Water (10 mL) was then added and the reaction mixture stirred at −78° C. for 5 minutes, then warmed to room temperature over 15 minutes. The solution was partitioned between ethyl acetate (150 mL) and Rochelle's salt (150 mL). The organic layer was washed with Rochelle's salt (150 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an off white solid. The crude product was purified by chromatography on silica gel (gradient: 0-90% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (680 mg) as a white solid. LCMS (Method F, ES-API): RT 2.58 min, m+H=494.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2.[C:14]([O:18]CC)(=[O:17])[CH:15]=[CH2:16]>C1COCC1.CO.[Pd]>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([CH2:16][CH2:15][C:14]([OH:18])=[O:17])[CH:11]=[CH:10][CH:9]=2
Reactant: COc1cnc2cccc(Br)c2c1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2cccc(CCC(=O)O)c2c1

Procedure:
This compound was synthesised from 5-bromo-3-methoxy-quinoline (5.0 g, 21 mmol; prepared as in DE 10316081) and ethyl acrylate (5 eq.) according to method G followed by hydrogenation over Pd/C in THF/MeOH 4:1. The hydrolysis was carried out according to method F. The product was isolated as a colourless solid (0.1 g).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4].Br>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)cs1
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)cs1
Temperature: 40 °C
Yield: 63 %

Procedure:
Following the procedure of Japan Kokai Tokkyo Koho JP 60 11,487 CA 103:22580m (1985), a solution of bromine (4.29 g, 26.87 mmoles) in 40 ml of chloroform was added dropwise to a stirred solution of methyl 4-acetyl-2-thiophenecarboxylate, prepared according to Example 15 (4.95 g, 26.87 mmoles) in 150 ml of chloroform containing four drops of 50% (v/v) 48% hydrobromic acid/glacial acetic acid. After 10 minutes at 40° C. the solution was cooled to room temperature, concentrated in vacuo and the residue triturated with methanol (25 ml). Filtration furnished an off-white solid (4.96 g, 63%), m.p. 112°-4° C. EIMS (m/z): 264/262 (M+, 11%), 233/231 (M+ -CH3O, 11%), 171/169 (M+ -CH2Br, base); 1HNMR (CDCl3) delta, 8.31 (1H, d, J=1.5Hz), 8.17 (1H, d, J=1.5Hz), 4.29 (2H, s), 3.90 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[O:9][CH:8]2S(C1C=CC=CC=1)(=O)=O.CC(C)([O-])C.[Li+].[C:28]([CH:31]1[CH2:40][CH2:39][CH:38]2[CH:33]([CH2:34][CH:35]=[CH:36][C:37]2=[O:41])[CH2:32]1)(=[O:30])[CH3:29]>C1COCC1>[C:28]([C:31]1[CH:32]=[C:33]2[C:38]([C:37](=[O:41])[C:36]3[CH:10]([OH:12])[CH:11]4[C:7](=[C:8]([OH:9])[C:35]=3[CH2:34]2)[CH2:6][CH2:5][CH2:4][CH:3]4[O:2][CH3:1])=[CH:39][CH:40]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)C1CCC2C(=O)C=CCC2C1
Reactant: COc1cccc2c1C(=O)OC2S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1CCCC2=C(O)C3=C(C(=O)c4ccc(C(C)=O)cc4C3)C(O)C21
Yield: 95 %

Procedure:
Continuing with a synthesis utilizing the object compound (5) to produce the tetrahydronaphthacene dione intermediate, the anion of 7-methoxy-3-phenylsulfonyl-1(3H)-isobenzofuranone (6) as generated at -78° C. using lithium t-butoxide in THF and reacted with the hexahydronaphthalenone (5) to furnish 9-acetyl-5,12-dihydroxy-4-methoxy-6(11H)-hexahydronaphthacenone (7) in 95% yield. Conversion of (7) to 9-acetyl-6-hydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (8) was achieved by heating (7) in dimethylforamide under oxygen at 45° C. for 18 hours.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=O)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O1CCCC1.O>[C:12]1([CH2:11][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc(Cc2ccc(C(=O)c3ccccc3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(Cc2ccc(Cc3ccc(Cc4ccccc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
In a 5-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 54.4 g of lithium aluminum hydride and 382.6 g of aluminum chloride were introduced slowly in 2.0 liters of tetrahydrofuran to make a mixed solution, to which 150 g of 1,1-bis(4-benzoylphenyl)methane was added at room temperature and then heated for 1 hour at 60° C. and then stirred for 4 hours with maintaining the temperature. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was cooled to room temperature and 600 milliliters of ethyl acetate was added dropwise for 30 minutes with stirring, then 500 milliliters of water was added dropwise for 30 minutes with stirring. Thereafter, the reaction solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform and nitrobenzene by a rotary evaporator, and then subjected to a column purification with a mixed solvent of 2:1 toluene and heptane, removed off the solvent and then recrystallized from ethyl acetate, to obtain 115 g of 1,1-bis(4-(1-phenylmethyl)phenyl)methane as crystals.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (21.04 g, 46.09 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.46 g, 98.1% yield). 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 7.77 (s, 1H), 7.06 (m, 4H), 6.95 (m, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.68 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[K].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>O>[O:31]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26](=[O:36])[N:30]1[CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (200 g) was added phthalimide potassium salt (101 g), and the mixture was stirred overnight at 75° C. To the reaction mixture was added water (6 L), and the mixture was extracted with ethyl acetate (6 L). The organic layer was washed with water (1.5 L×3) and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with hexane (500 ml). The collected crystals was washed with hexane (100 ml×3), and the mother liquor was recrystallized from hexane (300 ml) and combined with the former crystals to give di-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,3-propanediyl]biscarbamate (168 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1>C(O)C.C(N)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:11][CH:8]([CH3:9])[CH3:4])[N:21]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2nc(Cl)ncc2Cl)CC1
Solvent: CCO
Solvent: CC(C)N
Product: CC(C)Nc1ncc(Cl)c(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)n1
Yield: 61.6 %

Procedure:
The 1-(2,5-dichloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide (60 mg, 0.14 mmol) compound was dissolved in absolute ethanol (1 mL) and isopropyl amine (0.2 mL). The mixture was heated in a sealed Teflon reaction vial at 70° C. overnight. The resulting mixture was filtered and purified by preparative HPLC (Gilson: Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient). Further purification by preparative TLC (1 mm silica; eluent ethyl acetate) afforded the title compound as a colorless oil (19.5 mg) Rt=4.82 minutes; LCMS 453.1 (M+1); 1H NMR δ 7.87 (s, 1H) 7.25 (m, 4H) 5.28 (NH) 4.95 (dd, J=5.9, 3.9 Hz, 1H) 4.81 (NH) 4.01 (m, 1H) 3.89 (dd, J=11.2, 3.9 Hz, 1H) 3.83 (dd, J=11.2, 5.9 Hz, 1H) 3.65 (m, 4H) 3.52 (m 4H) 2.1 (OH) 1.20 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[N:12]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)[nH]c2c(=O)n(C)ccc12
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2c(=O)n(C)ccc12
Yield: 69.3 %

Procedure:
To a stirred solution of ethyl 2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 6.4 mmol) in N,N-dimethylformamide (50 mL) was added (1-bromoethyl)-benzene (1.5 g, 7.9 mmol) and cesium carbonate (3.14 g, 9.6 mmol). The resultant solution was stirred at 80° C. for 12 hours. Once starting material was consumed, the reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 69%) as a yellow solid. LRMS (M+H+) m/z: calcd 338.16. found 338.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9]2)[CH3:2].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=1)[CH2:10][CH2:9]2)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A mixture of (4-nitro-1-oxo-indan-5-yl)-carbamic acid ethyl ester (0.47 g, 1.8 mmol), 4-fluoroaniline (0.24 g, 2.2 mmol), and decaborane (200 mg) in 20 ml of anhydrous methanol was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by chromatography using a mixture of hexane/EtOAc (5:1) as eluant to give a pure product (0.54 g, 83%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([N:21]1[CH2:24][C:23](=O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[B][B][B][B][B][B][B][B][B][B]>CO>[C:17]([O:16][C:14]([N:21]1[CH2:24][CH:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[O:8])[CH2:6][CH2:5]2)[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(c1nccs1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 18 h

Procedure:
A solution of compound 7b (6.1 g, 0.031 mol) and (5.1 g, 0.03 mol) compound 4a in MeOH (30 mL) was stirred for 15 min. Decaborane (1 g, 0.008 mol) was added and the reaction was stirred for 18 h. The solvent was evaporated in vacuo. The residue was used without further purification for the next step. MS m/z (M+H+) 353.1.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Br:22])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[NH2:19][C:17]1[CH:16]=[C:15]([Br:22])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=2)=[C:2]([Br:1])[CH:18]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(Oc2c(Br)cc(N)cc2Br)ccc1O
Temperature: 33 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
4-(2,6-Dibromo-4-nitrophenoxy)-2-isopropylphenol (795 g, 1.84 moles) was divided into three roughly equal portions. Each portion was dissolved in THF (2.6 L) and charged into a 12 L three-necked round bottom flask equipped with a mechanical stirrer, addition funnel, and temperature probe. The solutions were heated to 33° C. Sodium dithionite (482 g, 2.4 moles) dissolved in deionized water (2.6 L) was added to each flask. The reaction temperature was held at 50° C. until each reaction was complete as assayed by HPLC. Hydrochloric acid (6N aqueous) was added dropwise to the heated reaction mixtures until their pH was about 3, and heating was continued for 45 min. The reaction mixtures were cooled to room temperature and their pH was adjusted to 6.6 by addition of saturated aqueous sodium bicarbonate solution. Ethyl acetate (2.5 L) was added to each flask with stirring for 2 min. Each reaction mixture was separated, and each organic layer was washed once with half-saturated aqueous sodium chloride solution, then once with saturated aqueous sodium chloride solution. The solvents were removed by rotary evaporation and the solids were dried overnight in a vacuum oven at 40° C. to yield crude 4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol (657 g, 96.9%). The crude 4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol was purified by recrystallization from isopropanol upon addition of 2.5 volumes of deionized water (90% recovery).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]/[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=O)(C)(C)C>CCOC(C)=O>[NH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]/[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C/C2CCCCC2)nc1
Solvent: CCOC(C)=O
Product: NCc1ccc(/C=C/C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Dissolve (E)-3-(tert-butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyridine (1.3 g, 4.11 mmol) in EtOAc (60 mL) and bubble hydrogen chloride through the solution for 20 min. Stir the mixture overnight at room temperature. Concentrate the mixture in vacuo and dissolve the resulting solid in water. Adjust the pH to 9-11 with 20% aqueous K2CO3 and extract with DCM. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound (0.78 g, 88%). MS (APCI+) m/z: 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:4][N:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:10][C:11]([CH3:14])([O:13][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH3:12])=[CH:4][N:3]=1
Reactant: CC(C)(O)CNc1cnc(Cl)nc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CNc1cnc(Cl)nc1Cl)OC1CCCCO1
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a mixture of 1-(2,4-dichloropyrimidin-5-ylamino)-2-methylpropan-2-ol (258 mg, 1.09 mmol) and 3,4-dihydro-2H-pyran (0.200 ml, 2.18 mmol) in dichloromethane (7 ml) was added pyridine 4-methylbenzenesulfonate (13.7 mg, 0.055 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was poured into water and extracted with Et2O. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 3:1) to afford 2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine (315 mg, 0.982 mmol, 90% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (s, 3 H) 1.23 (s, 3 H) 1.25-1.75 (m, 6 H) 3.27-3.32 (m, 2 H) 3.37-3.49 (m, 1 H) 3.69-3.83 (m, 1 H) 4.74-4.86 (m, 1 H) 5.75 (t, J=6.32 Hz, 1 H) 8.36 (s, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][NH:25][C:24]4=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[CH2:30][C:31](=[O:33])[CH3:32]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][N:25]([CH2:30][C:31](=[O:33])[CH3:32])[C:24]4=[O:28])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(C)=O)c4=O)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
Reaction under N2 atmosphere. NaH 60% (0.12 mol) was added to 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.1 mol) in DMF, and stirred for 30 minutes at 50° C. A solution of 1-chloro-2-propanone (0.1 mol) in DMF was added dropwise and the resulting reaction mixture was stirred overnight at 50° C. The reaction mixture was cooled, poured out into ice-water and the resulting precipitate was filtered off, washed with water, and dried. This fraction was recrystallized from CH2Cl2/CH3OH. The precipitate was filtered off and the filtrate was evaporated. The residue was crystallized from methanol, filtered off and dried. The residue was combined with the crystallized compound, recrystallized from CH2Cl2/CH3OH, filtered off and dried, yielding 0.65 g of 2,4dihydro-4-[4-[4-(4-methoxy-phenyl)-1-piperazinyl]phenyl]-2-(2-oxopropyl)-3H-1,2,4-triazol-3-one (interm. 20).