Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][Br:14]
Reactant: BrP(Br)Br
Reactant: COc1cc(Cl)cc(CO)c1Cl
Solvent: Cc1ccccc1
Product: COc1cc(Cl)cc(CBr)c1Cl
Yield: 86.6 %

Procedure:
By the method of Example 1, Step B, 13.95 grams (0.0674 mole) of 2,5-dichloro-3-methoxyphenylmethanol and 7.295 grams (0.270 mole) of phosphorus tribromide were reacted in toluene, yielding 15.76 grams of 2,5-dichloro-3-methoxyphenylmethyl bromide as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[CH3:17][S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2)(=[O:16])=[O:15]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH (0.098 g). The reaction mixture was left to stir for 2 hours. Acetic acid was added and the product extracted with dichloromethane. The organic extracts were combined, dried with magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a solid (0.110 g).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (80 mg, 0.42 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (136 mg, 0.28 mmol), triethylamine (0.096 ml, 0.69 mmol), L-lactic acid (30 mg, 0.33 mmol), and 1-hydroxybenzotriazole (47 mg, 0.30 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:10) to give the title compound (31 mg) as a pale yellow solid.
Reaction SMILES: NCC[NH:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1OC)=[O:6].C(Br)CC1C=CC=CC=1>C(N(CC)CC)C>[S:11]1[C:7]([C:5]([NH2:4])=[O:6])=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: COc1c(C(=O)NCCN)sc2ccccc12
Agent: BrCCc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-(2-Aminoethyl)-3-methoxybenzo[b]thiophene-2-carboxamide (1.56 g) was dissolved in dimethyl fomamide (50 ml) and triethylamine (0.63 g) added. To this stirred solution was added phenethylbromide (1.27 g) and left overnight at ambient temperature. Ice-water was added, and the product extracted with ethyl acetate (3×50 ml). Organic fractions were collected, washed with water (4×50 ml),dried, filtered to yield, after removing the solvent, a clear oil. Flash chromatography eluting with 5% methanol-dichloromethane gave 3-methoxy-N-<2-[N- (2-phenylethyl)amino]ethyl>-benzo[b]thiophene-2-carboxamide which was converted to its hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=1)[O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])([O-:19])=[O:18]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[CH:29]=[CH:30][CH:31]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCCCCOc1cccc([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 12 h

Procedure:
A solution of 2.28 g (10 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.4 ml of triethylamine (10 mmol) in 32 ml of acetonitrile is mixed at 4° C. while being stirred with a solution of 2.1 g (10 mmol) of 4-(3-nitro-phenoxy)-butylamine in 5 ml of acetonitrile. After 12 hours, it is diluted with ethyl acetate and filtered. The filtrate is concentrated by evaporation in a rotary evaporator, and the remaining residue is purified by chromatography (hexane/ethyl acetate 1:1, Flashmaster II). 2.7 g (7 mmol, corresponding to 70% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccccc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 50.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 2-Chlorobenzaldehyde (34.3 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 50.82 mg (50%) of the title compound. (300 MHz, DMSO-d6) 13.16 (s, 1H), 8.07 (s, 1H), 7.84 (m, 1H), 7.72 (s, 1H), 7.64 (m, 1H), 7.52 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=9 Hz, 1H), 6.29 (s, 2H), 5.21 (t, J=17 Hz, 8.5 Hz, 1H), 2.86 (s, 1H), 2.77 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=460 (M+H), HPLC: 2.46 min. (G Method)
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:4]([C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:3]
Reactant: C[Si](C)(C)C#CC1(O)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-(2-trimethylsilyl-1-ethynyl)cyclohexanol (1.79 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1

Procedure:
A solution of 8-benzo[1,3]dioxol-5-yl-1,4-dioxa-spiro[4.5]decan-8-ol (as prepared in the previous step, 4.50 g, 16.2 mmol) in acetone (40 mL) was treated with 1N HCl (˜15 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[CH2:38]Br.O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:38][C:30]3[C:29](=[CH:34][CH:33]=[CH:32][C:31]=3[N+:35]([O-:37])=[O:36])[C:28]2=[O:27])=[N:2]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cccc([N+](=O)[O-])c2CN1c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 7 h
Yield: 59.2 %

Procedure:
To a solution of Compound 2 (70 mg, 0.26 mmol) in DMF (1.4 mL), triethylamine (91 μL, 0.68 mmol) and 2-bromomethyl-3-nitrobenzoic acid methyl ester (79 mg, 0.29 mmol) were added, followed by stirring at 80° C. for 7.0 hours under nitrogen atomosphere. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-4-nitro-2,3-dihydroisoindol-1-one (61 mg, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[N:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:21].O>CN(C)C=O.CC(=O)OCC.CCCCCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:33]=[CH:32][CH:31]=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[O:21])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
A solution of 1-benzyl-4-hydroxypiperidine (209 mg, 1.1 mmol, 1.1 eq) and 95 w % sodium hydride (1.2 mmol) in 5 ml of dimethylformamide was stirred at a room temperature for 30 min, mixed with 2-chloro-N-(3-chlorophenyl)nicotinamide (1.0 mmol), and stirred for 20 hrs under reflux. The reaction mixture was cooled to a room temperature, and added with 20 ml of pure water to terminate the reaction. After two rounds of extraction with 20 ml of ethylacetate per round, water was removed with a desiccant and the resulting product was concentrated under reduced pressure. Then, the residue obtained by the concentration was subjected to silica gel column chromatography (mobile phase: 30 (v/v) % hexane in EA) to obtain the desired fraction. The desired fraction was dried in a reduced pressure to afford 0.25 g of the title compound (Yield: 33.7%). 1H NMR (CDCl3) δ 8.60 (d, 1H), 8.29 (d, 1H), 7.88 (s, 1H), 7.48 (d, 1H), 7.36-7.27 (m, 6H), 7.17-7.05 (m, 2H), 5.51-5.38 (m, 1H), 3.59 (s, 2H), 2.89-2.80 (m, 2H), 2.42 (t, 2H), 2.29-2.23 (m, 2H), 2.06-1.87 (m, 2H) ppm.
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[CH2:6]([NH:13][C:14](=[O:28])[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:27])([CH3:26])[CH:20]=[CH:19]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[CH2:6]([NH:13][C:14](=[O:28])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[O:22][C:21]([CH3:26])([CH3:27])[CH:20]3[O:2][CH:19]3[C:18]=2[CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)C=Cc2cc(CC(=O)NCc3ccccc3)ccc2O1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
980 ml of a saturated aqueous sodium hydrogen carbonate solution was added to a solution of 28 g of the N-benzyl-2-(2,2-dimethyl-2H-chromen-6-yl)acetamide obtained above in 480 ml dichloromethane. A total of 44.1 g MCPBA in three 14.7 g portions was added to this receiving solution at 5 min. intervals, and the mixture was stirred for 18 hours at room temperature. The organic phase was separated, extracted once with 200 ml of a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was then substantially completely evaporated at reduced pressure. 35 g N-benzyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide was obtained as crude oil, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([N:16]1[CH2:22][CH2:21][CH:20](Br)[C:19](=O)[CH2:18][CH2:17]1)C1C=CC=CC=1>CO>[CH3:6][C:5]1[NH:8][C:19]2[CH2:18][CH2:17][NH:16][CH2:22][CH2:21][C:20]=2[N:7]=1
Reactant: CC(=N)N
Reactant: O=C1CCN(Cc2ccccc2)CCC1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c([nH]1)CCNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 equivalents (4.463 g) of sodium methoxide are placed in MeOH at ambient temperature, 7.8 g of acetamidine-hydrochloride are added and the mixture is stirred for 30 min. Then 10 g of N-benzyl-5-bromohexahydro-4-azepinone are added. After another 30 minutes an additioal 2 eq. (2.976 g) of sodium methoxide are added to the mixture which is refluxed for 11 hours. After cooling to ambient temperature the mixture is fully concentrated by evaporation in vacuo, the material remaining is triturated with about 140 ml of isopropanol, filtered and the filtrate is evaporated down again. The crude product is taken up in 50 ml of 1N K2CO3 solution and extracted 3× with 40 ml of CH2Cl2. The organic phases are dried with MgSO4, filtered off and evaporated to dryness. The residue is chromatographed over silica gel (CH2Cl2/MeOH=87:13 to 70:30). Yield: 1.7 g MS (M+H)+=242
Reaction SMILES: [C:1]([N:20]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>C(O)C.N1C=CC=CC=1.O>[C:1]([N:20]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[N:31][OH:32])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 2-trityl-2,5,6,7-tetrahydro-indazol-4-one (1.32 mmol) in ethanol (5 mL) and pyridine (0.16 mL), hydroxylamine hydrochloride (1.2 eq) was added and the mixture was stirred at 55° C. for 1.5 h. After cooling to rt, the mixture was diluted with water and filtered. The solid was washed with water and dried. Obtained the title compound in 90% yield. ESI (+) MS: m/z 394 (MH+). 1H NMR: 1.69-1.88 (m, 2H), 2.07-2.25 (m, 2H), 2.59-2.67 (m, 1H), 2.77-2.86 (m, 1H), 6.99 (s, 1H), 7.19-7.31 (m, 15H), 9.94 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23](N)=[O:24])[CH2:4][CH2:3]1.[OH-:32].[Na+].Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23]([OH:24])=[O:32])[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(N)=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(=O)O)CC1
Temperature: 125 °C

Procedure:
To 4-(1-methyl piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid amide (example 254) (250 mg, 0.6 mmole) is added 30% aqueous NaOH solution (2 mL). The reaction mixture is heated to 125° C. overnight. Water (2 mL) is added as well as 1N HCl to pH 6-7. The solvent is removed under reduced pressure. The residue is dissolved in absolute EtOH and filtered to remove inorganic salts. EtOH is removed under reduced pressure. The residue is triturated in Et2O, filtered to afford 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid melting at 185° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1CF
Temperature: 25 °C

Procedure:
2-(S)-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (5.62 g, 21.2 mmol) was treated with tetrabutylammonium fluoride (1 M solution in THF, 191 mL) under N2, heated to reflux for 1 hour, cooled to ambient temperature, concentrated to 50 mL, treated with water (100 mL) and extracted with ethyl acetate (2×250 mL). The combined ethyl acetate layers were washed with 0.25 M HCl (100 mL), washed with NaHCO3 solution, washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (10:1 and then 5:1 hexane:ethyl acetate) to provide 2.9 g (72%). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9 H) 2.26 (m, 2 H) 3.84 (t, J=7.46 Hz, 2 H) 4.35 (m, 1 H) 4.42 (ddd, J=46.36, 9.92, 2.71 Hz, 1 H) 4.72 (ddd, J=48.31, 10.00, 3.05 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:3][C:4]=1[N:13]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=1)[S:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(Br)c3ccccc3c2C)cc1
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(N3CCCC3)c3ccccc3c2C)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 24.3 %

Procedure:
A mixture of ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (93.5 mg, 0.15 mmol) prepared in Example 9-(1), pyrrolidine (0.015 mL, 0.18 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.3 mg, 0.015 mmol), trisdibenzylideneacetone dipalladium (6.9 mg, 0.0075 mmol) and sodium-t-butoxide (20.2 mg, 0.21 mmol) in toluene (2 mL) was stirred at 100° C. for 4 hours under argon atmosphere. The mixture was cooled to room temperature, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10%→25%) to give ethyl 4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (22.4 mg, 24%) as a yellow viscous material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1.C(O)(=O)[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=1.C(OCCCC)(=O)C1C(=CC=CC=1)[C:36]([O:38]CCCC)=[O:37].[N-]=C=O.NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[CH2:19]1[O:20][CH2:18]1.[C:25]([OH:27])(=[O:26])[C:24]1[CH:23]=[CH:22][C:30]([C:36]([OH:38])=[O:37])=[CH:29][CH:28]=1
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCOC(N)=O
Agent: [N-]=C=O
Solvent: C1CO1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 110 °C

Procedure:
In a reaction vessel having a cooler, a stirrer and a nitrogen introducing tube, 343 parts of adduct of bis-phenol A and 2 moles of ethylene oxide, 166 parts of iso-phthalic acid and 2 parts of dibutyl phthalate are put, and reacted for 8 hours at 230° C. under an ordinal pressure, and further reacted for 5 hours under a reduced pressure of from 10 to 15 mmHg (from 1.33 to 1.99 Pa) and then cooled by 110° C. Then 17 parts of isoborondiisocyanate was added in toluene and reacted for 5 hours at 110° C., and the solvent was removed. Thus Urethane-modified Polyester 1 was obtained, which has a weight average molecular weight of 72.000 and a free isocyanate content of 0.7%. Besides, 570 parts of adduct of bis-phenol A and 2 moles of ethylene oxide and 217 parts of terephthalic acid were condensed-polymerized for 6 hours at 230° C. in a manner similar to the above-mentioned. Thus unmodified Polyester 1 with a number average molecular weight of 2.400, a hydroxide group value of 51 and an acid value of 5. In 2,000 parts of ethyl acetate, 200 parts of Urethane-modified Polyester 1 and 800 parts of Polyester 1 were dissolved and mixed to obtain Resin Solution 1. The Tg of the resin component in the Resin Solution 1 was 64° C.