Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[O:19][CH:10]([C:11]3[C:16]2=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)[CH2:9]1)=O)(C)(C)C.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>COCCO.C([O-])(O)=O.[Na+]>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:20][C:14]2[CH:13]=[CH:12][C:11]3[CH:10]4[O:19][CH:17]([CH2:18][NH:8][CH2:9]4)[C:16]=3[CH:15]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2OC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CNCC3O2)ncc1Cl
Temperature: 120 °C
Yield: 9.7 %

Procedure:
4-Amino-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene-10-carboxylic acid tert-butyl ester (220 mg, 0.80 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (236 mg, 0.80 mmol) were combined in 2-methoxyethanol (3 mL) and heated at 120° C. for 6 h. The reaction was then was diluted with saturated aqueous NaHCO3 (3 mL), extracted with CH2Cl2 (3×5 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-30% MeOH in EtOAc) to obtain 2-[5-Chloro-2-(12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a tan solid (34 mg, 10%). 1HNMR (400 MHz, CDCl3) δ 11.0 (bs, 1H), 8.6 (d, 1H, J=8.3 Hz), 8.0 (s, 1H), 7.6 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.4 (m, 2H), 7.3 (d, 1H, J=7.8 Hz), 7.1 (d, 1H, J=8.1 Hz), 7.0 (appt t, 1H, J=7.6 Hz), 6.5 (bs, 1H), 5.0 (s, 1H), 4.9 (s, 1H), 3.3 (t, 2H, J=13.5 Hz), 3.0 (d, 3H, J=4.8 Hz), 2.9 (bs, 1H), 2.6 (t, 2H, J=13.5 Hz); MS (m/e) 437 (M+1); mp 164-168° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][C:9]1[CH:10]=[C:11]([C:15](=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 70 °C

Procedure:
Add Ti(OEt)4 (7 mL, 17 mmol) to a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0 g, 8.3 mmol) and 1-(3-bromophenyl)ethanone (1.8 g, 9.1 mmol) in anhydrous THF (30 mL) at RT. Heat the mixture at 70° C. for 24 h. Allow the reaction mixture to cool to RT and pour into 30 mL of brine under vigorous stirring. Filter the suspension through a pad of Celite and wash the solid with EtOAc (2×20 mL). Wash the filtrate with brine (30 mL), dry (Na2SO4), and concentrate in vacuo. Chromatograph the residue on a silica gel column and elute with Et2O/hexanes to give (R)—N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH2:9])=[CH:4][C:3]=2[O:2]1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>CCCCCC>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH:9][C:31]([NH:30][C:22]3[C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=[CH:24][C:23]=3[CH:27]([CH3:29])[CH3:28])=[O:32])=[CH:4][C:3]=2[O:2]1
Reactant: CCCCC(CN)Cc1ccc2c(c1)OCO2
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Product: CCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 60 %

Procedure:
To 1.01 g (4.33 mmol) of 2-(3,4-methylenedioxybenzyl)hexylamine, was added 9.2 ml of a hexane solution (0.47 mmol/l) of 2,6-diisopropylphenyl isocyanate and stirred for 3 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (developed with hexane/ethyl acetate=2/1) to obtain 1.13 g of 1-(2-(3,4-methylenedioxybenzyl)hexyl)-3-(2,6-diisopropylphenyl)urea as amorphous solid (yield: 60%).
Reaction SMILES: NC([N:4]1C[C:11]2[C:6](=[CH:7][CH:8]=[C:9](CN)[CH:10]=2)[CH2:5]1)=O.Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH2:27]Br)[C:20]([O:22][CH3:23])=[O:21].CC1C=C(C=CC=1C)C(OC)=O.C(N)C1C=CC=CC=1>>[C:6]1([CH2:5][N:4]2[CH2:16][C:17]3[C:26](=[CH:25][CH:24]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=3)[CH2:27]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccc2c(c1)CN(C(N)=O)C2
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: COC(=O)c1ccc(C)c(C)c1
Solvent: NCc1ccccc1
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
The [2-(aminocarbonyl)-2,3-dihydro-1H-isoindol-5-yl]methanamine of general formula III may be prepared as follows, for example: The methyl 3,4-bis-(bromomethyl)benzoate obtainable in situ from methyl 3,4-dimethylbenzoate by photobromination, on being reacted with benzylamine, yields methyl 2,3-dihydro-2-(phenyl-methyl)-1H-isoindol-5-carboxylate, the ester function of which is converted in the usual way into a carboxamide function and then, by reduction with lithium aluminium hydride, into an aminomethyl function; the primary amino group is protected with a tert.butoxycarbonyl group, the benzyl group in the 2-position is removed by hydrogenolysis and replaced by an aminocarbonyl group, e.g. by treating the hydrochloride of the resulting 5-[[(tert.butoxycarbonyl)amino]methyl]-2,3-dihydro-1H-isoindole with sodium cyanate; removal of the tert.butoxycarbonyl protecting group, e.g. with methanolic hydrogen chloride solution, then yields the desired 2-(amino-carbonyl)-2,3-dihydro-1H-isoindol-5-yl]methanamine in the form of the hydrochloride.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH:10]([C:11]([OH:13])=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([S:7][CH:8]2[CH:10]([C:11]([O:13][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:24]=3)=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(Sc2ccccc2)C1C(=O)O
Product: CC1(C)C(Sc2ccccc2)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Using the method of Example 3, the above product is hydrolyzed to 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid, which is then reacted with m-phenoxybenzyl bromide to yield m-phenoxybenzyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:34]([CH3:36])[CH3:35])[C:14]([O:16][CH:17](C#N)C1C=CC=C(OC2C=CC(F)=CC=2)N=1)=[O:15].ClC1C=C(C(F)(F)F)C=CC=1NC(C(C)C)C(OC(C#N)C1C=CC=C(OC2C=CC(C)=CC=2)N=1)=O.ClC1C=C(C(F)(F)F)C=CC=1NC(C(C)C)C(OC(C#N)C1C=CC=C(OC2C=CC(OC)=CC=2)N=1)=O.ClC1C=C(C(F)(F)F)C=CC=1NC(C(C)C)C(OC(C#N)C1C=CC=C(OC2C=CC(Cl)=CC=2)N=1)=O.ClC1C=C(C(F)(F)F)C=CC=1NC(C(C)C)C(OC(C#N)C1C=CC=C(OC2SC=CC=2C)N=1)=O.ClC1C=C(C(F)(F)F)C=CC=1NC(C(C)C)C(O)=O.C(C(C1C=CC=C(OC2C=CC(F)=CC=2)N=1)O)#N.C(C(C1C=CC=C(OC2C=CC(C)=CC=2)N=1)O)#N.C(C(C1C=CC=C(OC2C=CC(OC)=CC=2)N=1)O)#N.C(C(C1C=CC=C(OC2C=CC(Cl)=CC=2)N=1)O)#N.C(C(C1C=CC=C(SC2C=CC(C)=CC=2)N=1)O)#N.C(C(C1C=CC=C(OC2C=CC(C(F)(F)F)=CC=2)N=1)O)#N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:34]([CH3:36])[CH3:35])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OC(C#N)c1cccc(Oc2ccc(F)cc2)n1
Agent: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Agent: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OC(C#N)c1cccc(Oc2ccc(Cl)cc2)n1
Agent: COc1ccc(Oc2cccc(C(C#N)OC(=O)C(Nc3ccc(C(F)(F)F)cc3Cl)C(C)C)n2)cc1
Product: COC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
By the above procedure, each of cyano[6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, cyano[6-(4-methylphenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, cyano[6-(4-methoxyphenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, cyano[6-(4-chlorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, cyano[6-(methylthiophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, and cyano[6-(4-trifluoromethylphenoxy)-2-pyridyl)]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate is prepared by the reaction of the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid with each of cyano[6-(4-fluorophenoxy)-2-pyridyl]methanol, cyano[6-(4-methylphenoxy)-2-pyridyl]methanol, cyano[6-(4-methoxyphenoxy)-2-pyridyl]methanol, cyano[6-(4-chlorophenoxy)-2-pyridyl]methanol, cyano[6-(4-methylthiophenoxy)-2-pyridyl]methanol and cyano[6-(4-trifluoromethylphenoxy)-2-pyridyl]methanol, respectively.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25].CCN(C(C)C)C(C)C>CS(C)=O.O>[CH2:23]([N:26]([CH2:27][CH2:28][CH3:29])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH2:24][CH3:25]
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCN(CCC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (3 mL) was added dipropylamine (100 mg, 0.99 mmol) and DIEA (100 mg, 0.77 mmol). The resulting solution was stirred overnight at 85° C. and then diluted with water (50 mL), extracted with ethyl acetate (3×20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2.5%-4% ethyl acetate in petroleum ether) to afford methyl 3-(dipropylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (50 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:68])=[C:53]([C:55]2[C:56](=[O:67])[N:57]([CH3:66])[C:58]3[C:63]([CH:64]=2)=[CH:62][N:61]=[C:60]([CH3:65])[CH:59]=3)[CH:54]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:68])=[C:53]([C:55]2[C:56](=[O:67])[N:57]([CH3:66])[C:58]3[C:63]([CH:64]=2)=[CH:62][N:61]=[C:60]([CH3:65])[CH:59]=3)[CH:54]=1)=[O:7]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)c3cc(Br)cc(C(F)(F)F)c3)ccc1C)c(=O)n2C
Reaction time: 0.03 h

Procedure:
To a solution of 3-bromo-5-trifluoromethyl-benzoic acid 21 (193 mg, 0.716 mmol) in DMF (5 mL) is added HATU (272 mg, 0.716 mmol) and di-isopropylethylamine (278 mg, 2.15 mmol) at rt. The resulting mixture is stirred for 2 min. A solution of 3-(5-amino-2-methyl-phenyl)-1,7-dimethyl-1H-[1,6]naphthyridin-2-one 15 (200 mg, 0.716 mmol) in DMF (5 mL) is added. The reaction mixture is stirred at rt overnight, diluted with EtOAc, and washed with brine three times. The organic layer is dried (MgSO4) and concentrated. The residue is purified by automated chromatography to give the desired product 22 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.62 (dd, J=8.3, 2.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.63 (s, 3H), 2.65 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH3:20])[C:10](O)=[O:11]>C1COCC1>[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH3:20])[CH2:10][OH:11]
Reactant: Cc1c(F)cccc1C(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(F)cccc1C(N)CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 27.9 %

Procedure:
To a stirred solution of lithium borohydride in THF (48.9 ml, 2 M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (25.0 ml). The resulting suspension was cooled to 0° C. and (RS)-amino-(3-fluoro-2-methyl-phenyl)-acetic acid (7.1 g) was added portionwise, whereby the temperature of the reaction mixture rose transiently to 45° C. The ice bath was removed and stirring was then continued at r.t. for 90 min. The mixture was quenched by dropwise addition of methanol (20 ml) and then concentrated in vacuo. The residue was suspended in ethyl acetate and washed with 2 N aq NaOH. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo to afford (RS)-2-amino-2-(3-fluoro-2-methyl-phenyl)-ethanol (1.83 g, 28%) as a light yellow solid. MS (ISP): 170.3 ([M+H]+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>C(O)(=O)C>[Br:13][C:14]1[CH:15]=[C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]2=[N:12][CH:17]=1
Reactant: Nc1ccnn1-c1ccccc1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: Brc1cnc2c(cnn2-c2ccccc2)c1
Yield: 28.7 %

Procedure:
Dissolve 1-phenyl-5-aminopyrazole (Tokyo Kasei Kogyo Co. LTD; 1.5 g, 9.4 mmol) and 2-bromomalonaldehyde (Aldrich; 1.42 g, 9.4 mmol) in glacial acetic acid (170 mL) and reflux under nitrogen for 5 h. Concentrate under reduced pressure and purify via chromatography (silica gel, dichloromethane) to obtain 740 mg (28%) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C12H9N3Br (p+H): m/z=273.9980, Found. 273.9965.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[N:5]1[C:4]2[CH:8]=[CH:9][NH:10][C:3]=2[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.78 g), ethyl 3-aminobenzoate (4.49 g) and 1-methyl-2-pyrrolidone (20 mL) was stirred at 120° C. for 1.5 hrs. To the reaction mixture were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the mixed ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate) and crystallized from methanol-acetone-diisopropyl ether to give the title compound (2.85 g) as a pale-brown powder.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: CCCCOC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O

Procedure:
127 mg of 4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.36 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 118 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.33 (t, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.79 (s, 1H), 7.49 to 7.65 (m, 6H), 4.01 (d, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].[H-].[Na+].C1C=CC=CC=1.Cl[N:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[NH:25]1>O>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:14][N:24]2[N:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[NH:29]2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: COC(=O)c1c(O)cccc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1c(ON2N=C(OC)C=C(OC)N2)cccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
1.0 g of methyl 6-acetylsalicylate was added to a suspension solution of 0.23 g of sodium hydride and 30 ml of benzene, and the resultant mixture was stirred for 10 minutes at room temperature. 0.95 g of 2-chloro-4,6-dimethoxytriazine was added to the resultant mixture, and the mixture was stirred for one day and one night at room temperature. After completing the reaction, the reaction liquor was poured into water, and was extracted with ethyl acetate. The extracted product was washed with water, dried and concentrated to obtain a crystal. The product thus obtained was purified by column chromatography to obtain 1.15 g of the aimed compound (melting point=151° to 156° C.) at a yield of 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=O)[N:7]([CH2:31][C:32](=O)[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:6]=2[CH:40]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][N:7]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:6]=2[CH:40]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CC(=O)N2CCCCC2)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CCN2CCCCC2)CC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of ethyl 3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (886 mg, 1.57 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution (8.2 ml) of 1M BH3 THF complex in tetrahydrofuran under ice-cooling, and the mixture was stirred under ice-cooling for 30 min., at room temperature for 3 hr, at 30° C. for 2 hr, and further at 60-70° C. for 1 hr. The reaction mixture was allowed to cool, a solution (4.1 ml) of 1M BH3 THF complex in tetrahydrofuran was added, and the mixture was allowed to stand overnight at room temperature. The reaction mixture was stirred at 70° C. for 2 hr, 5M hydrochloric acid (8 ml) was added under ice-cooling, and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution under ice-cooling, saturated sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give ethyl 3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (512 mg, yield 61%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([F:21])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:21][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][CH:5]([CH2:4][NH2:1])[O:6][C:7]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1-c1c(F)ccc2c1OC(CN=[N+]=[N-])C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(F)ccc2c1OC(CN)C2
Yield: 106.9 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (10.06 g, 58.84 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.16 mmol), and sodium carbonate (6.2 g, 58.84 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (37%) of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether. A solution of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether (2.35 g, 10.86 mmol) in hydrogen bromide (40 mL, 30 wt. % in acetic acid) was heated to 55° C. for 12 h. The reaction mixture was concentrated under in vacuo and the crude residue diluted with ethyl acetate (200 mL). The organic layer was carefully extracted with saturated bicarbonate solution (3×200 mL) was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Treatment of 6-fluoro-2′-methybiphenyl-2-ol (2.17 g, 10.84 mmol) with sodium hydride (0.65 g, 16.26 mmol, 60 wt. %) and allyl bromide (0.96 g, 16.26 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.77 g, 7.3 mmol) with 3-chloroperoxybenzoic acid (3.2 g, 10.96 mmol, 77%) followed by potassium carbonate (1.2 g, 8.76 mmol) generally according to the procedure described for Intermediate 9 afforded 1.5 g (80%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 2.17 g (90%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.23 g, 0.56 mmol) with sodium azide (0.23 g, 3.54 mmol) generally according to the procedure described for Intermediate 98 afforded 0.135 g, (86%) of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran (0.135 g, 0.4 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.30 g, 0.9 mmol) generally according to the procedure described for Example 154 provided 0.11 g (67%) of (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.