Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:4].CCN(CC)CC.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.O>[CH3:1][N:2]([C@@H:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:4])[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: CN[C@H](C)c1oc2ccccc2c1C
Reactant: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)[C@H](C)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an ice cold mixture of (R)-methyl-[1-(3-methyl-benzofuran-2-yl)-ethyl]amine (7.5 mL of a 0.46 M solution in DMF, 3.5 mmol) and Et3N (0.6 mL, 4.1 mmol) was added acryloyl chloride (0.3 mL, 3.8 mmol) drop-wise. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was diluted with H2O and extracted with Et2O (3×). The combined organics were washed with H2O and satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica, gel, 7:3 hexanes/EtOAc) gave the title compound (630 mg, 75%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ7.50-7.47 (m, 1H), 7.44-7.41 (m, 1H), 7.30-7.20 (m, 2H), 6.81-6.52 (m, 1H), 6.40-6.25 (m, 2H), 5.74-5.70 (m, 1H), 2.99-2:90 (m, 3H), 2.23 (s, 3H), 1.69-1.58 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:20](=[O:22])[CH3:21])=[CH:4][C:5]2[CH:11]([CH3:12])[CH2:10][N:9]([C:13](=[O:18])C(F)(F)F)[CH2:8][CH2:7][C:6]=2[CH:19]=1.[OH-:23].[Na+]>CO>[C:20]([C:3]1[C:2]([OH:1])=[CH:19][C:6]2[CH2:7][CH2:8][N:9]([C:13]([O:23][C:3]([CH3:20])([CH3:4])[CH3:2])=[O:18])[CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)(=[O:22])[CH3:21]
Reactant: [OH-]
Reactant: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2C
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc2c(cc1O)CCN(C(=O)OC(C)(C)C)CC2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5.13 g of 1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanone in 50 ml of MeOH was added 50 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to a half of the amount, and to the residue were added 50 ml of dioxane and 4.27 g of di-t-butyl dicarbonate, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized by the addition of 1 M hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 4.385 g of t-butyl 8-acetyl-7-hydroxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a yellow viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11](Br)[CH2:12][CH3:13])=[CH:5]2.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([N:15]=[N+:16]=[N-:17])[CH2:12][CH3:13])=[CH:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(Br)c1cc2cc(F)ccc2[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(N=[N+]=[N-])c1cc2cc(F)ccc2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 5-fluoro-indolyl-3-propylbromide (10.67 g, 41 mmol) and sodium azide (3.9 g, 60 mmol) in anhydrous N,N-dimethylformamide (60 ml) was allowed to stir at 60° C. for 18 hours. The mixture was poured into water (150 ml), extracted with methylene chloride (3×150 ml), washed with water (3×100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under vacuurml Chromatography (30% ethyl acetate-hexanes) afforded 8.10 g (89%) of product as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)#[N:2].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:48]2[CH:49]=[N:50][C:51]([F:54])=[CH:52][CH:53]=2)(N)[C@@H:44]([NH2:46])[CH3:45])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:46][C@@H:44]([CH3:45])[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)([C:48]3[CH:49]=[N:50][C:51]([F:54])=[CH:52][CH:53]=3)[N:2]=2)[CH:8]=1)#[N:10]
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Reactant: N#Cc1ccnc(C#N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1NC(c2cc(C#N)ccn2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
2,4-Dicyanopyridine (46.5 mg) and ytterbium trifluoromethanesulfonate (24 mg) were added to a solution of the optical active (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (100 mg) described in Reference Example 5-1 in toluene (0.25 mL), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:3) to give the objective compound (106 mg) as a white solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH3:22])[C@@H:10]1[CH2:23][O:24]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:32]>[Pd].C(O)C>[ClH:32].[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH3:22])[C@@H:10]1[CH2:23][OH:24]
Reactant: CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1C[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 20 h
Yield: 88 %

Procedure:
A mixture of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-methylpyrrolidine (Compound 3) (38 mg, 0.067 mmol), 10% Pd/C (30 mg), 4 N HCl (0.1ml) and 99.9% ethanol (5 ml) was reduced in a Parr apparatus at 40 psi for 20 hours. The mixture was filtered and evaporated in vacuo to give (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine, hydrochloride (15 mg, yield 88%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:39][C:36]4[CH:35]=[CH:34][C:33]([N:30]5[CH2:29][CH2:28][N:27]([C:24](=[O:26])[CH3:25])[CH2:32][CH2:31]5)=[CH:38][CH:37]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Oc3ncnc4c3cnn4C3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1

Procedure:
4-{4-[4-(4-Acetyl-piperazin-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 1-acetyl-4-(4-hydroxyphenyl)piperazine (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.01 (m, 4H), 2.05 (s, 3H), 2.93-3.02 (m, 2H), 3.10-3.20 (m, 4H), 3.55-3.65 (m, 4H), 4.08-4.11 (m, 2H), 4.96-5.01 (m, 1H), 7.04-7.08 (m, 2H), 7.17-7.20 (m, 2H), 7.95 (s, 1H), 8.53 (s, 1H). Mass spectrum M+Na=544, MH+=522.
Reaction SMILES: ClC1C=CC=C([C:8]([O:10]O)=[O:9])C=1.[C:12]1([S:18]([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](C=O)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH:8]([O:10][C:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:22]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Solvent: ClCCl
Product: O=COc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
Into a 250 mL 3-necked round bottom flask was placed dichloromethane (30 mL). To the mixture was added mCPBA (m-chloroperbenzoic acid) (2.78 g, 13.69 mmol), while cooling to a temperature of 0° C. This was followed by the addition of a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3 g, 10.49 mmol) in dichloromethane (100 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, 2 hours while the temperature was maintained at 0° C. Then the resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 30° C. in a bath of oil. The reaction progress was monitored by LC-MS. The residue was purified by eluting through a column with a 1:10 ethyl acetate/petroleum ether solvent system. This resulted in 2 g (63%) of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate as a light yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16](Cl)=[O:17].O>CN(C)C=O>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17]
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31](O)=O)[CH:27]=[CH:26]2.O=O.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Reactant: Nc1ccccc1S
Agent: O=O
Agent: Oc1cccc2cccnc12
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: Oc1cccc2ccc(-c3nc4ccccc4s3)nc12
Temperature: 40 °C

Procedure:
To introduce a benzo[d]thiazol group into an 8-hydroxyquinoline compound, 2-aminothiophenol (123 mg, 1.1 mmol) and 8-hydroxyquinoline-2-carboxylic acid (189 mg, 2 mmol) were dissolved in dry toluene (30 ml) with blown nitrogen to prevent oxidation which is caused by oxygen in air. The solution was heated to 40° C. and phosphorus trichloride (0.1 ml, 1.1 mmol) was slowly added thereto. Then, the reaction solution was heated at 100° C. for 24 hours and allowed to cool. The reaction mixture was extracted with a 20% aqueous sodium carbonate solution, distilled water and dichloromethane, dried and recrystallized with dichloromethane and hexane to yield 2-(benzo[d]thiazol-2-yl)quinolin-8-ol, the compound of Formula 1 as a light green solid (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:10](/[CH:12]=[N:13]\O)[N:11]=1)=[O:5].CCN(CC)CC>C(Cl)Cl>[C:12]([C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:2]=2[F:1])[S:8][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1)#[N:13]
Reactant: O=C(Nc1nc(/C=N\O)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1

Procedure:
Into a solution of Compound 72 (90 mg, 0.21 mmol) in 10 mL of CH2Cl2 was added 2-chloro-1-methylpyridium iodide (128 mg, 0.5 mmol) and NEt3 (0.1 mL).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:40][C:36]1[CH:37]=[N:38][CH:39]=[C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH:35]=1)=[C:3]([CH3:27])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (85.0 mg, 0.210 mmol) and 5-morpholinopyridin-3-amine in toluene to give tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.70 (1H, d, J=2.2 Hz), 7.29 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.90 (1H, d, J=12.9 Hz), 6.80 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.57 (1H, t, J=2.3 Hz), 3.85 (4H, dd, J=5.6, 4.0 Hz), 3.52-3.63 (4H, m), 3.27-3.35 (4H, m), 3.10-3.17 (4H, m), 2.07 (3H, s), 1.50 (9H, s). Mass Spectrum (ESI) m/e=541.3 (M+1).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[C:8]([C:10]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:22].[CH3:23]I>CN(C=O)C>[I:3][C:4]1[CH:9]=[C:8]([C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[O:22][CH3:23]
Reactant: CI
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
NaH (60% in mineral oil, 60 mg, 1.50 mmol) was added an ice-cooled solution of 2-iodo-4-(1-phenyl-cyclohexyl)-phenol (400 mg, 1.06 mmol) in DMF (10 mL). Methyl iodide (125 μL, 2.0 mmol) was added. The reaction temperature was allowed to reach room temperature. The mixture was stirred for 2 h, then quenched with water 10 mL and extracted with dichloromethane (2×20 mL). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was taken up in water (20 mL) and extracted with dichloromethane. The organic phase was dried (Na2SO4) and concentrated in vacuo. 1H-nmr of the syrup (430 mg) indicated full conversion to the methyl ether. 1H NMR (400 MHz, CDCl3): 7.71 (d, 1H, J=2.1 Hz), 7.32-7.25 (m, 4H), 7.18 (dd, 1H, J=2.1 Hz, J=8.8 Hz), 7.17-7.13 (m, 1H), 6.72 (d, 1H, J=8.8 Hz), 3.83 (s, 3H), 2.32-2.18 (m, 4H), 1.62-1.44 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8](S)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2cccc(Cl)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Clc1cccc2ncsc12

Procedure:
Following the same procedure in step 2 of Example 337 using 7-chloro-1,3-benzothiazole-2-thiol (700 mg, 3.47 mmol, 1.00 equiv) and iron powder (1.94 g, 10.00 equiv) in acetic acid (20.0 mL) (gray white solid).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1)#[N:2].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:12][CH2:13][CH2:14][OH:15])[C:1]#[N:2]
Reactant: OCCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCO)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 4-cyano-2-fluoro phenol (5 g, 0.0365 mol; from prep N(iv) above), 3-bromopropanol (10.15 g, 0.073 mol) and potassium carbonate (7.6 g, 0.054 mol) in dry acetone (50 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5% ethyl acetate in petroleum ether to yield (5.5 g) of the sub-title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[CH:3]=1.[CH3:19]N(C)C=O.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([O:1][CH3:19])[N:6]([CH3:7])[N:5]=2)=[CH:9][C:10]=1[CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: Cc1cc(-c2cc(O)n(C)n2)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 1 h

Procedure:
At room temperature, to mixture of 5-hydroxy-3-(4 isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 95) 9.5 g, and N,N-dimethylformamide 70 ml was added 55%-sodium hydride 2.5 g and was stirred for one hour, and thereto was then added dimethyl sulfate 9.7 g and stirred at 100° C. for 12 hours. Thereto was added water 50 ml and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 5.8 g.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](Cl)=[O:5].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.Cl.[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-]>CC(C)=O.O>[CH2:9]1[C:10]2=[C:15]3[C:14](=[CH:13][CH:12]=[CH:11]2)[CH2:2][CH2:3][C:4](=[O:5])[N:7]3[CH2:8]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCc2cccc3c2N1CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A solution of 3-chloropropanoyl chloride (9.1 ml, 95.0 mmol) in 20 ml dry acetone was added dropwise to a solution of indoline (20.5 g, 0.21 mol) in 80 ml dry acetone and the mixture was refluxed for 1 h. After cooling to ambient temperature the solution was poured into 500 ml stirred 2N HCl and extracted with ethyl acetate (3×150 ml). After washing with 1N HCl and brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. This was added portionwise to a molten mixture of AlCl3 (60.0 g, 0.45 mol) and NaCl (17.5 g, 300 mmol) at 150° C. and stirred for additional 30 min. On cooling, excess aluminum chloride was decomposed by the addition of a chilled mixture of 20 ml concentrated hydrochloric acid and 500 ml water. Extraction with ethyl acetate (3×200 ml), followed by drying over MgSO4 and removal of the solvent gave a yellow solid, which was purified by crystallization from acetone/ether yielding 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (11.8 g, 65.8 mmol, 69%) as colorless needles.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.C([O-])(=[O:23])C.[Na+].[OH-].[Na+].Cl>C1COCC1.CO.C(O)C.O.C(OCC)(=O)C.CN(C=O)C>[CH3:18][C:16]1[CH:17]=[C:12]([NH:11][C:6]2[N:5]=[C:4]([S:19][CH3:20])[NH:3][C:2](=[O:23])[C:7]=2[C:8]([NH2:10])=[O:9])[CH:13]=[N:14][CH:15]=1
Reactant: CC(=O)[O-]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cncc(C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Nc2cncc(C)c2)c(C(N)=O)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 5 h
Yield: 14.8 %

Procedure:
To a mixture of 4-chloro-6-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 359) (194 mg) and DMF (5 mL), sodium acetate (257 mg) was added and stirred at 100° C. for 5 hours. After the reaction liquid was cooled, ethyl acetate and water were added, and the precipitated powder was collected by filtration and dried to give a light yellow solid. To a mixture of the solid, ethanol (5 mL), methanol (20 mL) and THF (5 mL), 1M aqueous sodium hydroxide (3 mL) was added and stirred at room temperature for 1 hour, at 60° C. for 1 hour, and at 80° C. for 1 hour. After the reaction liquid was cooled, 1M hydrochloric acid (3 mL) was added, and the reaction liquid was extracted with chloroform-isopropanol. Silica gel was added to the organic layer, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 20:1) to give a crude product. This crude product was washed with a small amount of methanol to give 4-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (27 mg) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][CH:5]=1.[O-:27][C:28]#[N:29].[Na+]>O.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:28]([NH2:29])=[O:27])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CNC(N)=O)cc2)cc1

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150 mg) in water (8 ml) and ethanol (4 ml) was added sodium cyanate (100 mg) under ice cooling.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7]C(=O)[C:5]2=[O:13].[OH:14]O.C>[OH-].[Na+]>[NH2:7][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:13])=[O:14]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)c(F)cc1C(=O)O
Temperature: 80 °C

Procedure:
A solution of 20 g of 5,6-difluoro-1H-indole-2,3-dione in 200 ml of 2.5N sodium hydroxide was treated dropwise with 35.7 ml of 31.4% hydrogen peroxide. The reaction mixture was warmed to 80° C. for 15 minutes, then treated with charcoal and filtered. The filtrate was cooled in an ice bath and acidified with hydrochloric acid to pH 3.5. The resulting precipitate was crystallized from xylene, giving 14.18 g of the desired compound mp 176°-178° C.