Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]([O:32][CH:33]=[CH:34][C:35](Cl)=[O:36])[CH2:29][CH2:30][CH3:31].O>C(OC(C)C)(C)C>[CH2:28]([O:32][CH:33]=[CH:34][C:35]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:36])[CH2:29][CH2:30][CH3:31]
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CCCCOC=CC(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 98 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (1.8 g), diisopropyl ether (20 ml) and triethylamine (0.87 g) is added dropwise a solution of β-n-butoxyacrylic acid chloride (1.4 g) in diisopropyl ether (5 ml) with stirring and heating at 70° C. After completion of dropwise addition, the mixture is further stirred with heating at the same temperature for 0.5 hour. After cooling, water is added to the reaction mixture and the mixture is subjected to extraction with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give N-(β-n-butoxyacryloyl)-N-(1-benzyl-4-piperidinyl)-aniline (2.6 g).
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][NH:16][NH2:17])=[CH:13][CH:12]=1>C(O)C>[NH2:8][C:7]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][C:11]([Br:10])=[CH:12][CH:13]=2)[C:5](=[O:4])[CH:6]=1
Reactant: NNCc1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)cc2)[nH]1
Temperature: 60 °C

Procedure:
9.2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of p-bromobenzylhydrazine in 50 ml of ethanol is then added at room temperature. The mixture is warmed to 60° C for 2 hours, the substance which was precipitated is filtered off and the filtrate is evaporated. The residue is taken up with water, the mixture is shaken with ether and the aqueous phase is acidified with dilute acetic acid. The crude product is purified by twice recrystallising it from alcohol.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[O:14][C:15]([F:18])([F:17])[O:16][C:12]=3[CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C=O)C>[Br:1][C:2]1[C:3](=[O:21])[N:4]([CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[O:14][C:15]([F:17])([F:18])[O:16][C:12]=3[CH:11]=2)[C:5](=[O:8])[N:6]([C:30]2[CH:31]=[C:26]([NH:25][C:22](=[O:24])[CH3:23])[CH:27]=[CH:28][CH:29]=2)[N:7]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc2c(c1)OC(F)(F)O2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc4c(c3)OC(F)(F)O4)c2=O)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 60.8 %

Procedure:
According to Scheme 2 Step 3: A mixture of 6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione (300 mg, 0.83 mmol), DMF (5 mL), 3-acetamidophenylboronic acid (222 mg, 1.24 mmol), copper acetate (150 mg, 0.83 mmol) and pyridine (135 μl, 1.66 mmol) was stirred at 65° C. for 15 hours under room atmosphere. A saturated solution of NaHCO3 (200 mL) was added and the aqueous layer was extracted thrice with 200 mL of DCM. The organic layers were combined to be dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (AIT Flashmart 25 g prepacked column C18) using water/acetonitrile 6/4 as eluant to afford N-(3-(6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (250 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[O:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=3[C:2](=[O:3])[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1c(O)cccc1F
Product: O=c1cc(-c2ccccc2)oc2cccc(F)c12

Procedure:
4 is prepared from 2-fluoro-6-hydroxyacetophenone (see Example 6) and benzoyl chloride by the procedure of Example 1. The material is purified by flash chromatography (eluting with 25% ethyl acetate in hexane), yielding 4 with a melting point of 144°-145° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.N1C=CN=C1.C(N(CC)CC)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCC1(CO[Si](C)(C)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 10 ml of N,N-dimethyl formamide, and 0.14 g of imidazole was added thereto. The mixture was cooled in ice-water bath, and 0.87 ml of triethyl amine (6.2 mmol) was added thereto. After stirring for 5 minutes, 0.88 g of tert-butyldimethylsilyl chloride (5.8 mmol) in 10 ml of N,N-dimethyl formamide was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with 10 ml of water, and extracted twice using 20 ml of dichloromethane for each time. The combined dichloromethane extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.28 g of concentrate (yield 87.6%).
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:29]C)[N:19]2[CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:15]([NH2:31])[N:14]=1)[CH2:9][CH2:10][CH3:11].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CS(C)=O>[NH2:31][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:29])[N:19]2[CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:27][CH2:28]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C4CCCCC4)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 4.7 %

Procedure:
Iodocyclohexane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine (0.402 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added to each tube. DIPEA (40 μl, 0.229 mmol) and potassium carbonate (46 mg) was added to each tube, the tube was heated at 50° C. for 18 hours. An additional portion of iodocyclohexane (15 μl) and DIPEA (40 μl) was added and heating continued for a further 18 hours. DMSO (250 uL) was added and the solution and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (1.9 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-fluoro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 318.1 ([M−H]−).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cncc(OCCOC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Sodium hydride (1.02 g of a 50% suspension in mineral oil, 42 mmol) was added to a solution of 3-hydroxypyridine (2.01 g, 21 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (2.28 g, 48%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2.C([O-])(=O)C.[Na+]>ClCCCl>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C=O
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
After phosphorus oxychloride (2.0 ml) was added to N-methylformanilide (2.9 g), and the mixture was stirred for 15 minutes, 1,2-dichloroethane (50 ml) and ethyl 5-chloroindole-2-carboxylate (4.0 g) were added, and the resultant mixture was heated under reflux for 1 hour. The reaction mixture was poured into an aqueous solution (28 ml) of sodium acetate (14 g) under ice cooling. After stirring for 18 hours, insoluble matter was collected by filtration. This product was successively washed with water and diethyl ether to obtain the title compound (3.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.B(OC)(OC)OC.Br[C:21]1[CH:39]=[CH:38][C:24]([C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:23][CH:22]=1>C(OCC)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:39][CH:38]=1)[CH3:37]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 3-bromopyridine (728 mg, 4.6 mmol) in dry diethyl ether (9 mL) at −78° C. was added n-BuLi (2.5M solution in hexane, 1.8 mL, 4.5 mmol). The reaction mixture was stirred for 20 minutes at 0° C. After a dropwise addition of trimethyl borate (0.5 mL, 4.5 mmol) the mixture was stirred for 1 hour at 0° C. and then a solution of bromoester 49d (1.02 g, 3 mmol) in THF (9 mL) and water (2.3 mL) containing Pd(PPh3)4 (278 mg, 8 mol %, 0.27 mmol) was added. The reaction mixture was refluxed at 70° C. for 24 hours, cooled to room temperature, filtered through a pad of Celite and rinsed with ethyl acetate. The solution was extracted with ethyl acetate (2×30 mL), washed with brine (10 mL), dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (1% methanol in dichloromethane) afforded the corresponding ester 125 (259 mg, 25% yield) as a white solid. MS (ESI)=340 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([N:8]([CH3:23])[C:6]2[C:5]([CH3:24])=[C:4]([CH:3]=[C:2]([Br:1])[CH:7]=2)[C:25]([NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])=[O:37])[CH2:14][CH2:13]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@H](N)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of trans-tert-butyl (4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)cyclohexyl)carbamate (0.7 g, 1.21 mmol) in DCM (8 mL) was cooled to 0° C. and TFA (2.5 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford crude material which was then purified by solvent washings giving desired compound (0.5 g, 86%). LCMS: 475.20 (M+1)+; HPLC % 92.35 (@ 254 nm) (Rt; 4.416; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 8.21 (t, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H), 2.63-2.66 (m, 2H), 2.55 (s, 3H), 2.17 (s, 3H), 2.10 (s, 6H), 1.79-1.82 (m, 2H), 1.60 (m, 2H), 1.46-1.49 (m, 2H), 1.06-1.09 (m, 2H).
Reaction SMILES: CS(O[C:6]1[C:17]2=[C:18]3[N:13]([CH2:14][CH2:15][CH2:16]2)[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10](=[O:22])[C:9]3=[CH:8][CH:7]=1)(=O)=O.[F:23][C:24]([F:32])([F:31])[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[ClH:33]>CS(C)=O>[ClH:33].[F:23][C:24]([F:32])([F:31])[N:25]1[CH2:30][CH2:29][N:28]([C:6]2[C:17]3=[C:18]4[N:13]([CH2:14][CH2:15][CH2:16]3)[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10](=[O:22])[C:9]4=[CH:8][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CS(=O)(=O)Oc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3
Reactant: FC(F)(F)N1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Reaction time: 20 h

Procedure:
A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 170° to 180° C. for 20 hours under nitrogen gas flow at a pressure of 8 atms. The reaction mixture was treated in the same manner as in Example 73 and further treated with concentrated hydrochloric acid to obtain 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[CH2:16]1[O:18][CH2:17]1>O1CCCC1.CCCCCC>[OH:18][CH2:17][CH2:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:9][CH3:10]
Reactant: C1CO1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCO)c1OC
Reaction time: 17 h
Yield: 18.9 %

Procedure:
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 mL of anhydrous tetrahydrofuran stirred at room temperature under argon was added 90 mL (0.145 mol) of 1.6 M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled in an ice bath. Ethylene oxide (14 mL. 0.29 mol) was allowed to distill into the ice cooled reaction mixture over 45 minutes. The reaction mixture was stirred with ice bath cooling for 1.5 hours and then at room temperature for 17 hours. Most of the solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated under reduced pressure to an oil. The remaining 1,2-dimethoxybenzene (7.5 g) was removed by distillation (bP 45°-60°/0.2 mm) and the residue was purified by HPLC using 20% ethylacetate-toluene to give 5 g (19 % yield) of 1-(2-hydroxyethyl)-2,3-dimethoxybenzene. This intermediate (5 g, 0.028 mol) was dissolved in 100 mL of anhydrous methylene chloride and the solution was cooled in an ice bath. Triethylamine (7.7 mL, 0.056 mol) was added and followed by 2.6 mL (0.033 mol) of methane sulfonyl chloride added dropwise. The reaction mixture was stirred with ice bath cooling for two hours and then was washed with water, with sodium bicarbonate solution, dried and concentrated under reduced pressure to give (7.2 g) of 1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as an oil which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](=O)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1.B.[Na].Cl>C(O)C>[O:14]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=Cc1ccco1
Reactant: Nc1ccccc1O
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1ccccc1NCc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
In 20 ml of ethanol was dissolved 5.0 g (45.8 millimoles) of 2-aminophenol, and 4.8 g (50.0 millimoles) of furfural was added to the solution and the mixture was stirred for 1 hour at room temperature. Then, 2.3 g (60.8 millimoles) of sodium boron hydride was added to the mixture and the mixture was stirred at room temperature for 2 hours, and 2N hydrochloric acid was added to the mixture and ethanol was removed by distillation under reduced pressure. Then, the residue was neutralized with a 5% aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure, and the residue was purified by the silica gel column chromatography (developing solvent: ethyl acetate/hexane=3/7) to obtain 5.0 g (the yield was 58%) of 2-(2-furyl)methylaminophenol in the form of a brown oil. The oil was dissolved in 200 ml of an aqueous solution of 2.5 g of sodium hydroxide, and 2.5 ml (30 millimoles) of 1,2-chlorobromoethane was added to the solution and the mixture was heated and refluxed for 5 hours. The reaction mixture was extracted, and the extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oil. The oil was purified by the silica gel column chromatography (developing solvent: chloroform/hexane=1/3→1/1) to obtain 0.5 g (the yield was 7.5%) of intended compound No. 11 in the form of a light-brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[K+].[Br:21]Br>C(O)(=O)C>[Br:21][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]=1[OH:15]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
1.74 kg (8.2 mol) of ethyl 5-nitrosalicylate and 700 g of potassium acetate were dissolved in 5000 ml of acetic acid. 1.312 kg of bromine was dropwise added to the obtained solution at room temperature in one hour. Thereafter, the resulting mixture was further stirred for one hour and then concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate. The obtained solution was washed with water, dehydrated and concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 2.38 kg of the title compound as a colorless crystal.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][N:12]=1)[NH2:10]>N1C=CC=CC=1>[CH2:1]([O:5][C:6]([NH:10][NH:9][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][N:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NNc1n[nH]c2cc(Cl)ccc12
Reactant: CCCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)NNc1n[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.04 mol of chlorocarbonic acid n-butyl ester is added dropwise at 0° - 5° C, while stirring, to 0.04 mol of 3-hydrazino-6-chloro-indazole in 20 ml of pyridine. The reaction mixture is stirred for 3 hours at room temperature and then poured into ice water, and the colorless crystals which have precipitated are isolated by filtration. 3-n-Butoxycarbonylhydrazino-6-chloroindazole is obtained. After recrystallisation from a mixture of ligroin and ethanol (9 : 1), the melting point is 150° - 152° C. (Yield, 78% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH3:28])=[C:9]2[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1)=[O:30])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([C:9]2[N:8]3[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7]3)=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[O:30])[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)ccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
The compound of step 5 (0.159 g, 0.27 mmol) was dissolved in 2 ml of dioxane, and a solution of lithium hydroxide hydrate (0.034 g, 0.82 mmol) in 0.8 ml water was added. The solution was stirred at 50° C. overnight. The solvents were then evaporated under reduced pressure, the residue was dissolved in 6 ml of water and acidified to pH 1 with 1 N hydrochloric acid. The product was filtered off, dissolved in EA and the solution washed with brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give 0.139 g of the title compound as a light-brown powder.