Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:28]([C:35]([NH:37][OH:38])=O)C1C=CC=CC=1>C1COCC1>[OH:38][NH:37][C:35]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCNCC2)c(C)c1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)NO)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine (118 mg, 0.327 mmol) in anhydrous THF (3.5 mL) was added N-(phenoxycarbonyl)hydroxylamine (57.5 mg, 0.344 mmol). The mixture was warmed to reflux and stirred for 17 h, then cooled to ambient temperature and concentrated to a yellow solid. Purification by column chromatography on silica gel (eluted with CH2Cl2/MeOH/NH4OH) follow by purification by radial chromatography (eluted with CH2Cl2/MeOH/NH4OH 94:5:1) afforded 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-piperidine-1-carboxylic acid hydroxyamide (86 mg, 61%) as a yellow solid. 1H NMR (CDCl3) δ 1.69-1.79 (m, 2H), 1.96 (d, 1H, J=11.1 Hz), 2.04 (s, 3H), 2.27 (s, 3H), 2.63-2.77 (m, 3H), 3.85 (s, 2H), 4.05 (d, 2H, J=12.7 Hz), 4.25 (s, 2H), 6.88 (s, 1H), 7.22 (s, 1H), 7.35 (t, 1H, J=7.7 Hz), 7.54 (d, 1H, J=5.9 Hz), 7.59 (t, 1H, J=7.5 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.5 Hz), 8.18 (s, 1H), 8.39 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 17.9, 18.1, 26.9, 43.8, 53.4, 54.6, 57.7, 120.6, 126.3, 126.9, 127.7, 129.8, 132.0, 132.9, 136.3, 138.9, 141.3, 146.4, 153.8, 158.9, 160.7; ES-MS m/z 420 (M+H). Anal Calcd. For C24H29N5O2.0.1(CH2Cl2): C, 67.63; H, 6.88; N, 16.36. Found: C, 67.59; H, 6.99; N, 16.02.
Reaction SMILES: C1(CCO[P:10]2[O:15][CH2:14][C:13]3([CH2:20][O:19][P:18](OCCC4C=CC=CC=4)[O:17][CH2:16]3)[CH2:12][O:11]2)C=CC=CC=1.C1(CCBr)C=CC=CC=1>>[CH2:20]1[C:13]2([CH2:12][O:11][PH:10][O:15][CH2:14]2)[CH2:16][O:17][PH:18][O:19]1
Reactant: c1ccc(CCOP2OCC3(CO2)COP(OCCc2ccccc2)OC3)cc1
Agent: BrCCc1ccccc1
Product: C1OPOCC12COPOC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 184.8 %

Procedure:
436.4 g (1.0 mol) of 3,9-di(2-phenylethoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane and 370.1 g (2.0 mol) of 2-phenylethyl bromide were charged into a reactor equipped with a stirrer, thermometer and capacitor, and dry nitrogen was caused to flow into the reactor under agitation at room temperature. Thereafter, heating was started with an oil bath which was kept at 180° C. for 10 hours. The oil bath was removed to cool the reactor to room temperature. 2,000 ml of methanol was added to the obtained reaction product which was a white solid and stirred to clean the reaction product, and the white powder was separated by filtration with a glass filter. Then, the separated white powder was cleaned with 2,000 ml of a 50 wt % aqueous solution of methanol and dried at 100 Pa and 120° C. for 8 hours to produce 362.3 g of 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-di (2-phenylethyl)-3,9-dioxide. It was confirmed from mass spectral analysis, 1H, 31P nuclear magnetic resonance spectral analysis and elemental analysis that the product was bis-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-di(2-phenylethyl)-3,9-dioxide. This compound had a yield of 83%, an HPLC purity of 99.3% and an acid value of 0.41 mgKOH/g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCOS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (178 mg, 0.57 mmol) in DCM (8 mL), Et3N (0.24 mL, 1.71 mmol) was added. After stirring for 5 min at 0° C., methanesulfonyl chloride (0.11 mL, 1.43 mmol) was added dropwise, and the resulting suspension was stirred at 0° C. for 1 h 15, then quenched with water and extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4) and concentrated in vacuo to obtain the title compound as an oil. LC-MS conditions A: tR=0.90 min, [M+H]+=391.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:25])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cccc(COc2cncc(Cl)n2)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Cl)nc(OCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 3-chloro-5-(3-chloro-benzyloxy)-pyrazine I-3l (500 mg, 1.97 mmol) in CHCl3 (10 ml) at 0° C. under a nitrogen atmosphere, was treated with 680 mg (3.94 mmol) m-chloroperbenzoic acid (mCPBA). The resulting mixture was allowed to warm to room temperature, stirred at 23° C. for 16 h, heated at reflux for 2 h and cooled to room temperature. The reaction mixture was treated with Ca(OH)2 (680 mg, 3.94 mmol), stirred at room temperature for 3 h and filtered. The solid was washed with CH2Cl2. The filtrate and washings were combined, dried over MgSO4 (anhydrous), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc-hexanes 4:6) to provide 465 mg of the title compound (I-3m) as a white solid (87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2([C@@H:19]3[CH2:23][CH2:22][N:21](CC4C=CC=CC=4)[CH2:20]3)[CH2:18][CH2:17]2)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:16]2([C@@H:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1([C@@H]2CCNC2)CC1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
(R)-4-{[1-(1-benzyl-pyrrolidin-3-yl)-cyclopropyl]-methyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in 150 mL glacial acetic acid at room temperature in a hydrogenation flask, air was evacuated, and filled with nitrogen. To this was added 30% Pd/C (5 g), flask was mounted to Parr shaker, nitrogen was evacuated and filled with hydrogen, and the mixture was shaken under hydrogen atmosphere at 60 psi in a Parr for 18 h. Reaction mixture was diluted with toluene (300 mL), filtered through a pad of celite. The filtrate was concentrated in vacuo, residue was digested in cold 30% NaOH at 0° C. and the product was extracted with ethyl acetate. The combined ethyl acetate solution was charged with 50 g of charcoal (Darco G-60), allowed to stir for 2 h, filtered, concentrated to give pale yellow oil, which can be vacuum distilled to give a clear oil (9.6 g). 1H NMR (400 MHz, CD3OD) δ 4.04 (br s, 1H), 3.01 (dd, J=10.4 Hz and 7.6 Hz, 1H), 2.84 (dd, J=8.0 Hz and 5.2 Hz, 2H), 2.64-2.55 (m, 3H), 2.48-2.43 (m, 2H), 2.30 (s, 3H), 2.28-2.23 (m, 1H), 2.23-1.74 (m, 3H), 1.40 (s, 9H), 1.35-1.28 (m, 2H), 1.18-1.12 (m, 2H), 0.53-0.45 (m, 4H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>O.C(O)C>[C:1]1([S:7][CH2:11][CH2:12][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ClCCCSc1ccccc1

Procedure:
A mixture of thiophenol (1 mole), sodium hydroxide (1 mole) and 3-bromo-1-chloro-propane (2 moles) in water (1000 ml) and ethanol (250 ml) is refluxed duting 20 hours, with stirring. After cooling, sodium hydroxide (30 g) is added to the reaction medium which is then extracted with methylene chloride. The organic phase is washed with water to neutral pH, after which it is dried over sodium sulfate, concentrated and distilled. B.p. = 165° C./15 mm Hg. N.M.R.: consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:9])=[CH:4][CH:3]=1>C(OCC)C.CCCCCC.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[C:25]([F:28])([F:26])[F:27])=[O:9])=[CH:29][CH:30]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(C(F)(F)F)cc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(C(F)(F)F)cc(CCCO)cc2c1O
Yield: 10.7 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3-quinolinecarboxamide (397 mg) from Example No. 121 is dissolved in methanol/dichloromethane (1/1, 87 mL) and palladium on carbon (5%, 80 mg) are added. The mixture is placed under a hydrogen atmosphere (28 psi) for 1 h, filtered through celite, and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 100/1 to 100/3) to afford 43 mg (10%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([NH2:15])=O>>[Br:11][C:10]1[CH:9]=[C:8]([Cl:12])[CH:7]=[C:3]2[C:2]=1[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Product: O=c1[nH]cnc2c(Br)cc(Cl)cc12

Procedure:
8-Bromo-6-chloro-4(3H)quinazolinone was prepared from 2-amino-3-bromo-5-chlorobenzoic acid (10 g, 40 mmol). The acid was heated in excess formamide (50 mL) at reflux overnight. The mixture was cooled and quenched with water. The solid that formed was washed with acetonitrile, 6.7 g crude (65%); MS: 260.8 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:18]1([O:17][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([OH:25])=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A rapidly stirred solution of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (10.5 g; that is prepared as described in Reference Example 37) in glacial acetic acid (100 mL) is treated with sulfamic acid (4.85 g) and stirred at room temperature for 10 minutes. The solution is then cooled in an ice bath and treated with a solution of sodium chlorite (4.2 g) in water (100 mL) during 15 minutes at 13°-15° C. During the addition a white precipitate forms and, because stirring becomes difficult, a further quantity of glacial acetic acid (60 mL) is added. After warming to room temperature, the solution is stirred for a further 6 hours and further quantities of sodium chlorite (1.6 g) and sulfamic acid (1.7 g) are added. The mixture is poured onto water and the resulting solid is filtered off and dried, to give 3-cyclopentyloxy-4-benzyloxybenzoic acid (10g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11].[ClH:12].C[OH:14]>CCOCC>[ClH:12].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[OH:14])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(C#N)cc1C
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=N)O)cc1C
Reaction time: 3 h
Yield: 82 %

Procedure:
Under a nitrogen atmosphere was prepared a slurry of 21 (25.6 g, 0.174 mol) in a mixture of MeOH (10 ml) and Et2O (12 ml). With cooling, a stream of hydrogen chloride was passed through, giving a solution momentarily followed by a precipitate. The total uptake of HC1 was 15 grams. The reaction mixture was refrigerated for 3 hours, and the solid collected and washed with Et2O to yield 31 grams (82%) of 4-methoxy-3-methylbenzimidate hydrochloride; m.p. 137-140°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:12]=2)[N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of Intermediate 6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acid methyl ester (109 g, 212 mmol) in THF (1000 mL) at room temperature was added tetrabutylammonium fluoride (1.0 M in THF, 400 mL, 400 mmol). The reaction was stirred at reflux for 3 h before cooling to room temperature and diluting with ethyl acetate (2000 mL). This was washed with sat. aq. NaHCO3 (2×750 mL), sat. aq. NH4Cl (2×750 mL), water (750 mL), and brine (750 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with methanol (˜500 mL) and filtered. The solids were washed with methanol (300 mL) and suction dried overnight to afford desired product (71.8 g, 94%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ=11.99 (s, 1 H) 8.13 (s, 1 H) 7.82 (s, 1 H) 7.57 (s, 1 H) 7.32 (d, J=8.20 Hz, 1 H) 6.22 (d, J=8.20 Hz, 1 H) 3.78 (s, 3 H) 3.76 (s, 3 H) 3.07 (s, 6 H); MS (ES+) 360.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 0.93 (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.42 g of trans-3-[(4-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]2[CH:17]([CH2:18][N:19]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:20]2)[C:16]1=[O:38])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:31]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:38])[CH2:20]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OC1CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)C(O)CC(C)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
37 cm3 of 1.38 molar 2-methoxyphenylmagnesium bromide solution in tetrahydrofuran are added to a solution containing 2.4 g of (3aRS,5RS,7SR,7aRS)-5-acetoxy-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone in 50 cm3 of tetrahydrofuran at 4° C. The reaction mixture is stirred at room temperature for 18 hours, treated with 150 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of water and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 27 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 35 cm3 fractions. Fractions 8 to 15 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.65 g of (3aRS,4RS,5RS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained in the form of a yellow foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][Cl:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 91.6 %

Procedure:
To a solution of 4-butoxy-6-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (from Example 1(3), 1.68 g, 5 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionylchloride (0.73 ml, 10 mmol), and the resulting mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.62 g, 92.0%) as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([CH3:21])=[C:14](F)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:14]1[C:15]([CH3:21])=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([Cl:11])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1cccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
3.81 g (27.9 mmol) of 3-isopropylphenol, 5.30 g (27.9 mmol) of 4-chloro-2-fluoro-5-nitrotoluene and 5.79 g (41.9 mmol) of potassium carbonate are stirred in 30 ml of N,N-dimethylformamide at 100° C. for 7 h and the mixture is poured onto ice, stirred at 0° C. for 15 min and then filtered. The solid is washed with water and hexane and dried under reduced pressure (4.03 g, 98.5% purity, 46.5% yield, log P (pH 2.3)=5.54).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]1[CH2:14][CH2:13]1)(=[O:10])=[O:9].C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C(Cl)Cl>[CH:12]1([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1S(=O)(=O)NC1CC1
Solvent: ClCCl
Product: O=C1Nc2ccccc2S(=O)(=O)N1C1CC1
Reaction time: 12 h
Yield: 83.9 %

Procedure:
A solution of of 2-amino-N-cyclopropyl-benzenesulfonamide (6.9 g, 32.5 mmol) in CH2Cl2 (50 ml) was treated with CDI (6.5 g, 40 mmol) and stirred for 12 h at reflux. The solution was a washed with HCl (1N), dried over MgSO4 and concentrated to give 6.5 g (84%) of 2-cyclopropyl-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:24][NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Yield: 108.5 %

Procedure:
50 g (156.4 mmol) of ethyl 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were stirred at boiling temperature for 6 hours with 90 ml (1.85 mol) of hydrazine hydrate in 500 ml of ethanol. By cooling to -10°, filtering the suspension under suction and drying the crystallizate there were obtained 51.9 g (100%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of m.p. 287°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:48][N:49]2[CH:53]=[N:52][CH:51]=[N:50]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:39])[N:37]([CH:40]([CH3:47])[CH:41]([NH:43]C(=O)[O-])[CH3:42])[N:36]=[CH:35]5)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:43][CH:41]([CH3:42])[CH:40]([N:37]1[C:38](=[O:39])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:48][N:49]6[CH:53]=[N:52][CH:51]=[N:50]6)[O:13]5)=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:35]=[N:36]1)[CH3:47]
Reactant: CC(NC(=O)[O-])C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound (28)(0.0038 mol) in CF3COOH (10 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 4 hours and neutralized with a NaHCO3 solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, filtered off and dried, yielding 2.4 g (92%) of [2S-[2α,4α(S*,R*)]]-2-(2-amino-1-methylpropyl)-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (compound 37; mp. 168.5° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][N:5]=1)([O-:3])=[O:2].C=O.[C:18](O)(=O)C>CO>[CH3:18][N:13]1[CH2:12][CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cn1
Agent: C=O
Solvent: CO
Product: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 232a (1.2 g, 5.8 mmol) in CH3OH (25 mL) was added HCHO (1 mL, 35 mmol) and acetic acid (1 mL), followed by the addition of NaBHCN3 (1.0 g, 12 mmol). The mixture was stirred at room temperature for 2 h. It was then evaporated under reduced pressure and the residue was purified by reverse-phase Combiflush eluting with 0.3% NH4HCO3 in water/acetonitrile to afford 232b as a yellow solid (1.0 g, 78%). MS-ESI: [M+H]+ 220.