Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]#[CH:3].[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1>CO>[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:3][C:2]#[CH:1]
Reactant: CC1CCCCN1
Reactant: C#CCCl
Solvent: CO
Product: C#CCN1CCCCC1C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A flask was charged with propargyl chloride (17.27 g, 0.232 mol, 70 wt % in toluene) in dry methanol (21 mL) under nitrogen atmosphere. (+/−)-2-Methyl-piperidine (55 mL, 0.46 mol) in dry methanol (43 mL) was added via drop-wise addition over 30 minutes. The material was stirred overnight. The mixture was placed on a rotovap and about half the volume of methanol was stripped, providing a precipitate. The solid precipitate was removed by filtration, rinsing through with ether (150 mL). The filtrite was placed on the rotovap and concentrated. Another small amount of precipitate was removed by filtration. The remaining oily product was purified by distillation providing 7.23 g (bp=180-185° C.) of (+/−)-2-methyl-1-prop-2-ynyl-piperidine as a clear mobile oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[OH:14])([O-:3])=[O:2].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[O:14][CH3:17])([O-:3])=[O:2]
Reactant: C=CCc1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1cc(Cl)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 2-nitro-4-chloro-6-allylphenol (21.7 g), methyl iodide (28.28 g), and potassium carbonate (16.6 g) in acetone (300 ml) was refluxed for 16 hours. After cooling to room temperature and filtration, the filtrate was concentrated in vacuo to give a residue. The residue was extracted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated to give crude 2-nitro-4-chloro-6-allylanisole (21.6 g, 96%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.69 (d, J=2.6 Hz, 1 H), 7.41 (d, J=2.6 Hz, 1 H), 5.97-5.89 (m, 1 H), 5.20-5.10 (m, 2 H), 3.88 (s, 3 H), 3.48 (d, J=6.65 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[C:30]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:29]=[CH:28][N:27]=2)=[C:20]([CH3:36])[N:19]=1)([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:31]=[C:30]([CH2:32][N:33]([CH3:34])[CH3:35])[CH:29]=[CH:28][N:27]=3)=[C:20]([CH3:36])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1Cc1cc(CN(C)C)ccn1
Reactant: COc1cccnc1CCCCN
Product: COc1cccnc1CCCCNc1nc(C)c(Cc2cc(CN(C)C)ccn2)c(=O)[nH]1

Procedure:
Reaction of 4-(3-methoxypyridyl)butylamine with 2-nitroamino-5-(4-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone gives 2-[4-(3-methoxypyridyl)butyl-amino]-5-(4-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][CH:11](OCC)[CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15])C>O>[O:10]=[CH:11][CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCOC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)s1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=CCNC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Add water (21 mL) followed by trifluoroacetic acid (100 g) to a 250 mL three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, and thermocouple. To the stirring TFA solution, add 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide (25 g, 0.07 mol) in one portion. Stir the reaction mixture for 4 h, pour onto ice/water (1200 mL), and stir for 1.25 h. Filter the resulting slurry and rinse the solid with water (500 mL) and heptane (500 mL), and then dry to give 18.65 g (95%) of the title compound as a yellow-white solid. LC-MS/ES m/z (35Cl) 278 (M−H)−. 1H NMR (500 MHz, CDCl3): δ 4.40 (d, J=4.0 Hz, 2H), 6.69 (bs, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.53-7.58 (m, 3H), 9.78 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>O1CCCC1.CN(C)C=O.[OH-].[Na+]>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[N:31]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55 mmol) in tetrahydrofuran (2.0 mL) were added oxalyl chloride (59 μL, 0.69 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in N-methylpyrrolidone (2 mL). N-[6-(3-Amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) was added to the mixture, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (140 mg, 62%) as a white powder.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]>CN(C=O)C>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:1])[C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1ccc(O)cc1=O
Solvent: CN(C)C=O
Product: CCCCn1ccc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-Chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution of intermediate D5 (2.0 g, 11.96 mmol) in DMF (30 ml). The reaction was stirred at room temperature overnight and then it was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 0-5% methanol/DCM as eluent) to yield intermediate D8 (2.0 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[S:19]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][C:2]=1[Cl:1])(=[O:21])(=[O:20])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CO)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
To an ice cooled solution of 2-chloro-5-(Boc-amino)benzyl alcohol (7.4 g; 29 mmol; from step (i) above) in CH2Cl2 (100 mL) was added TEA (2.9 g; 29 mmol), followed by MsCl (3.3 g, 29 mmol; added dropwise). After stirring for 2 hours the resultant mixture was poured onto water. The organic layer was separated, washed with water, dried (Na2SO4) and concentrated to yield 10 g (100%) of the sub-title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[CH2:25][CH:24]=[CH:23]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:9]1[CH:24]2[CH2:25][C:26]3[C:22]([CH:23]12)=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cccc3c2CC2OC32)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A stirred solution of 47.5 g (0.234 mole) of m-chloroperbenzoic acid (85% purity) in 390 ml of chloroform was cooled to 0° C. To this was added dropwise a solution of 45 g (0.234 mole) of 7-phenyl-1H-indene (which may be prepared as in Step G above) in 110 ml of chloroform. After complete addition, the mixture was stirred for 21/2 hours, then was allowed to stand for 21 hours at 0° C. With the temperature in the range of 0°-5° C., 100 ml of a 10% aqueous solution of sodium hydroxide, then 50 ml of a 10% aqueous solution of sodium sulfate, were added dropwise with stirring. Afte complete addition the two-phase mixture was stirred for 30 minutes. The organic phase was separated, washed first with a dilute aqueous solution of sodium bicarbonate, then with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 47.7 g of 1,2-epoxy-4-phenylindane as a pale yellow oil, 97% purity by gas chromatographic analysis.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[Br:12][C:13]1[C:14]([Cl:20])=[C:15](F)[CH:16]=[CH:17][CH:18]=1>>[Br:12][C:13]1[C:14]([Cl:20])=[C:15]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: Cc1cc2c(s1)C(O)CNC2
Product: Cc1cc2c(s1)C(Oc1cccc(Br)c1Cl)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1.O1CCOCC1>[Si:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: COc1ccc(OC)c(N)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(NCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Yield: 50 %

Procedure:
2,5-Dimethoxyaniline (352.3 mg) was dissolved in 20 ml of tetrahydrofuran, and then 2.3 ml of n-butyl lithium (1.0 M solution in hexane), 3 ml of a solution of (16-bromohexadecyloxy)-t-butyldimethylsilane in tetrahydrofuran, and 0.20 ml of 1,4-dioxane were added to this solution at 0° C. The reaction mixture was refluxed for 24 hours while stirring. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (heptane:ethyl acetate=7:3) gave [16-(t-butyldimethylsilanyloxy)hexadecyl]-(2,5-dimethoxyphenyl)amine as a yellow oil at a 50% yield.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH2:31][CH2:32][CH3:33])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:31][CH2:32][CH3:33])[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:34]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCOCC1
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[propyl-(tetrahydro-pyran-4-yl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.070 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.048 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1>ClCCl>[CH:1]1([C:5]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Cyclobutanecarbonylchloride (9 g, 76 mmol) was added to a solution of triethylamine (12.5 ml, 89.7 mmol) and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (12.87 g, 69 mmol) in dichloromethane (385 ml) at room temperature under nitrogen. After stirring for 18 hours at room temperature, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the title product as a light brown glass, (17.4 g, 94%)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)#[N:2].N.[H][H]>>[NH:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:1]1
Reactant: [H][H]
Reactant: N#CCCC1CCCCC1=O
Agent: N
Product: C1CCC2NCCCC2C1
Yield: 67.5 %

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed up-stream of the hydrogenation reactor and packed with 64.4 g (92 ml) of γ-aluminum oxide there were passed upwardly, per hour, 55.4 g of 2-(2-cyanoethyl)-cyclohexanone (purity 96%, 0.352 mole) and 875 ml of liquid ammonia (525 g, 30.9 moles) at a pressure of 250 bar and a temperature of 70° C. Hydrogen was then added to the stream at a rate of 200 standard liters (8.9 moles) per hour, and the effluent from the in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure of 250 bar and a temperature of 120° C. After an on-stream of 3.5 hours the separation and distillation measures as per Example 2 had yielded, besides 33.1 g of decahydroquinoline, 138.8 of 2-(3-aminopropyl)-cyclohexylamine, this corresponding to a yield of 2-(3-aminopropyl)-cyclohexylamine of 71.5% of theory.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([O:7][C:8]([CH3:11])(C)C)=[O:6])=[O:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC.C1(C)C=CC=CC=1>C(O)(C)(C)C>[C:5]([O:7][CH2:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])[CH2:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCO
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCCCCCCCOC(=O)CC(C)=O
Yield: 83.2 %

Procedure:
Another procedure involved heating the alcohol and tBAA, (or beta-ketoester) in solvent, in a round-bottom flask with magnetic stirrer, 5-plate Oldershaw column and still head for removal of the t-butanol co-product. For example: a solution of n-octanol (13 g, 0.1 mol), tBAA (16.6 g, 0.105 mol) and 50 mL toluene was heated at reflux until the theoretical amount of t-butyl alcohol was obtained (ca. 15 min. after reflux). The reaction mixture was subsequently concentrated and distilled to give 17.8 g (83.2%) octyl acetoacetate b.p. 95°-110° C. (1.0 mm Hg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:10][CH2:9][CH:7]3[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]3)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (150 mg) was carefully added to the solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (0.3 ml) in DMF (2 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. for 1 hour. The mixture was poured into 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 463(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)O)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(Cl)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 80.6 %

Procedure:
Using [1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.46 g) synthesized in Example 19(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.25 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.41 g, 57%) was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[S:15])[NH:11][N:12]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Solvent: c1ccncc1
Solvent: O
Product: S=c1ccc(-c2ccccn2)n[nH]1
Temperature: 25 °C
Yield: 92 %

Procedure:
500 mg (2.9 mmol) of pyridazinone 7 and 772 mg (3.5 mmol) of phosphorus pentasulfide are dissolved in 20 ml of anhydrous pyridine. The reaction mixture is brought to reflux for 18 h, and then cooled to ambient temperature. It is then poured into 200 ml of water, and the precipitate thus formed is filtered off and then washed with ice-cold water. The pyridazinethione 10 is obtained with a yield of 92%.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:17])[CH:8]=[C:7]([Cl:18])[C:5]=2[N:6]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+].[Cl-].[Na+]>O1CCCC1>[N:19]1([C:2]2[S:3][C:4]3[C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:17])[CH:8]=[C:7]([Cl:18])[C:5]=3[N:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(F)cc(Cl)c2nc(N3CCCCC3)sc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Under a nitrogen atmosphere a solution of 3.0 grams (9.7 mmole) of ethyl N-(2,4-dichloro-6-fluorobenzothiazol-7-yl)carbamate in 75 mL of tetrahydrofuran was stirred, and 1.7 grams (20 mmole) of piperidine was added. Upon completion of the addition the reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was then poured into a mixture of 75 mL of aqueous 10% ammonium chloride and 75 mL of an aqueous saturated sodium chloride solution. The resulting mixture was extracted with three 75 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding a brown solid, which was purified by column chromatography on silica gel. Elution was accomplished with 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated, yielding 2.6 grams of ethyl N-[2-(1-piperidinyl)-4-chloro-6-fluorobenzothiazol-7-yl]carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: OP([O-])(O)=O.[K+].[I:7][C:8]1[C:9]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][C:10]=2[CH:11]=[N:12][CH:13]=1.[O-:19]Cl=O.[Na+]>O.CS(C)=O>[I:7][C:8]1[C:9]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:10]=2[CH:11]=[N:12][CH:13]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc2cncc(I)c2o1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cncc(I)c2o1
Reaction time: 16 h

Procedure:
A solution of KH2PO4 (81 mg, 0.59 mmol) in H2O (3 mL) was added to a solution of 7-iodofuro[3,2-c]pyridine-2-carbaldehyde (578 mg, 2.12 mmol) in DMSO (16 mL). The stirred mixture was treated carefully with a solution of NaClO2 (335 mg, 2.96 mmol) in H2O (5 mL). After 16 h, more KH2PO4 (81 mg, 0.59 mmol) in H2O (3 mL) and NaClO2 (335 mg, 2.96 mmol) in H2O (5 mL) were added, then stirring was continued for a further 48 h. The precipitated solid was collected, washed with DMSO, H2O, i-PrOH, and EtOAc, and vacuum-dried to furnish the title compound: m/z (ES+)=289.9 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26]C2C=C(B(O)O)C=CC=2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:5]2[CH:6]=[C:1]([C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=3[C:14]=45)[CH:2]=[CH:3][CH:4]=2)=[CH:24][CH:23]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(Oc2ccc(F)cc2)c1
Product: O=C1NCCc2c(-c3cccc(Oc4ccc(F)cc4)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-(4-fluoro-phenoxy)-phenylboronic acid (213 mg, 0.83 mmol) were coupled to yield 2-[3-(4-fluoro-phenoxy)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 170 mg (60%) as a yellow crystalline solid: m.p. 240-241° C.; 1H NMR (300 MHz, d6-DMSO) δ3.01 (m, 2H), 3.38 (m, 2H), 6.99 (m, 2H), 7.21 (m, 6H), 7.42 (m, 1H), 7.54 (m, 2H), 7.68 (m, 1H), 8.09 (br t, 1H), 11.60 (br s, 1H). MS (FAB, MH+) 373. Anal. (C23H17N2O2 F.0.5 H2O) C, H, N.