Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.C(O)C.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 400 parts of ethanol and 400 parts of 36 percent strength by weight hydrochloric acid are then added. A solution of 100 parts of NaNO2 in 150 parts of water is run in at 75° C., resulting in the evolution of nitrogen. The mixture is stirred for one hour at 75° C. and is then cooled, 1,500 parts of water are added and the product is filtered off. 183 parts (89% of theory) of 3,5-dichlorobenzoic acid of melting point 170°-175° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 8 h

Procedure:
6-Aminohexan-1-ol (11.7 g, 100 mmol) and potassium carbonate (16.58 g, 120 mmol) were dissolved in 100 mL water and 70 mL dichloromethane. Benzylchloroformate (14.27 mL, 100 mmol) was added dropwise over 30 minutes at a temperature of 25°-30° C. The resulting mixture stood overnight, then the dichloromethane layer was separated, washed with water (3×200 mL), 2N HCl (3×50 mL) and finally with water (3×100 mL), dried, and evaporated to give a white solid. The solid was recrystallized in hexane-ethylacetate (8:2) to give a solid, which was collected and dried under vacuum at room temperature. Yield: 23 g (91%).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 10.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>O1CCOCC1>[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:29][CH2:28]1
Reactant: NCC1CCC(CN)CC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: C1COCCO1
Product: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (78 mg, 0.21 mmol, 1 eq.) in 2 mL of dioxane was added [4-(aminomethyl)cyclohexyl]methanamine (89 mg, 0.62 mmol, 2 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 76 mg (76%) of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine which was carried forward. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85-1.13 (m, 2 H) 1.40-1.72 (m, 8 H) 1.74-2.01 (m, 2 H) 2.85-3.15 (m, 2H) 3.48-3.75 (m, 2H) 4.25-4.74 (m, 2 H) 5.98 (br. s., 1 H) 7.05-7.59 (m, 8 H) 8.44 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1.N1C(C)=CC=CC=1C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].Cl>ClCCl>[C:26]1([O:25][C:23](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1nnnc1-c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
In a dry flask of 1-methyl-5-(3-aminophenyl)-tetrazole (24.0 g, 137 mmol) was dissolved in dichloromethane (1.4 L) and 2,6-lutidine (44.1 g, 411 mmol) was added. Phenyl chloroformate (21.2 g, 136 mmol) was added in 4 portions over 15 minutes, then the reaction was stirred for 1.5 hours. The reaction was poured into 1N aqueous hydrochloric acid (200 mL) and the mixture was extracted with dichloromethane three times (200 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude brown material was dissolved in hot toluene, filtered, and allowed to precipitate at 0° C. to give 34.1 g of a white solid. The filtrate was concentrated and recrystallized from toluene again to give an additional crop of off-white crystals (3.44 g, 93% total). 1H NMR (300 MHz, CDCl3), δ: 10.51 (bs, 1H), 8.01 (s, 1H), 7.71 (dt, J=7, J′=2, 1H), 7.55 (m, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 4.14 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][NH:16]1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:24][C:23]1[NH:22][CH:21]=[C:20]3[C:19]=1[CH2:18][CH2:17][NH:16][C:15]3=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (35.4 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[N:26]1([CH2:2][C:3]2[N+:12]([O-:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]4[O:25][CH2:24][O:23][C:8]=4[CH:9]=3)[N:4]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: [O-][n+]1c(Cn2ccnc2)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (192 mg, 0.53 mmol), in dry DMF (3 mL), was added imidazole (142 mg, 2.1 mmol). The mixture was stirred at 85° C. for 1.5 h and left at rt for 15 h. DMF was removed and the mixture was poured into ice-water. The precipitated solid was extracted with EtOAc. The organic layer was washed with water, brine and dried over anhydrous MgSO4. It was filtered and the solvent was removed to yield the title compound as off white solid (100 mg); mp 212-217° C. 1H NMR (CDCl3) 7.76 (s, 1H), 7.00-7.21 (m, 5H), 6.80 (s 1H), 6.13 (s, 2H), 6.08 (s, 2H), 5.63 (s, 2H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16]>CS(C)=O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:15]2[CH2:2][O:16]2)[CH:17]=1
Reactant: C[S+](C)(C)=O
Reactant: O=Cc1cncc(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1cncc(C2CO2)c1
Yield: 31.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (7.10 g, 32.3 mmol) in DMSO (25 mL) were added, sodium hydride (0.774 g, 32.3 mmol, 95%) (portionwise) at ambient temperature, followed by 5-bromonicotinaldehyde (3.00 g, 16.1 mmol) in DMSO (15 mL). The reaction mixture was quenched by the addition of cold ice water (200 mL) and the resulting mixture extracted with ethyl acetate (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 31.0%). LCMS Condition B-26: retention time 1.83, [M+2]=202.2. 1H NMR (400 MHz, CDCl3) δ 2.79 (dd, J=2.4 Hz, J=5.2 Hz, 1H), 3.20 (dd, J=4.0 Hz, J=5.2 Hz, 1H), 3.87 (dd, J=2.4 Hz, J=4.0 Hz, 1H), 7.69 (dd, J=1.6 Hz, J=2.0 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:19]([C:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(CC)(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(Cc1ccc(C(=O)O)s1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(2-benzyloxycarbonyl-2-ethylbutyl)thiophene-2-carboxylic acid tert-butyl ester (24.9 g, 61.9 mmol) was added trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound (quantitative).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:25][C:24](=N)[NH:23][C:22]3=[O:27])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.C([OH:31])C>>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:25][C:24](=[O:31])[NH:23][C:22]3=[O:27])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2SC(=N)NC2=O)cc1
Agent: Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2SC(=O)NC2=O)cc1

Procedure:
To a suspension of 5-[4-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]phenyl]-2-iminothiazolidin-4-one (6.23 g) in ethanol was added concentrated hydrochloric acid (20 ml) to give a solution, which was stirred under reflux for 24 hrs. After the reaction, the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate-water, and the solution was neutralized with aqueous sodium bicarbonate. After partitioning and extraction, the extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated and concentrated, and the precipitated object compound (5.32 g) was collected by filtration melting point: 221-222° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH2:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CCCCCC.Cl[Si:34]([CH3:37])([CH3:36])[CH3:35]>CCOCC>[CH3:21][C:13]1[CH:12]([CH2:11][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([Si:34]([CH3:37])([CH3:36])[CH3:35])=[C:2]2[CH3:1])[C:20]2[C:15]([C:14]=1[Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: C[Si](C)(C)Cl
Reactant: CC1=Cc2ccccc2C1CC1C(C)=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=C([Si](C)(C)C)c2ccccc2C1CC1C(C)=C([Si](C)(C)C)c2ccccc21
Temperature: -50 °C
Yield: 96.8 %

Procedure:
6.32 g of bis(2-methyl-1-indenyl)methane (23.2 mmol) were dissolved in 70 ml Et2O in a 250 ml Schlenk tube, and the white suspension was cooled to −50° C. 19.5 ml of 2.5 M BuLi in hexane (48.8 mmol) were added dropwise over 20 minutes under stirring. The suspension was allowed to warm to room temperature and stirred for 3 hours. The final suspension was light yellow. 6.2 ml of chlorotrimethylsilane (48.8 mmol) were dissolved in 50 ml Et2O. The two mixtures were both cooled to −50° C. and the Li salt suspension in Et2O was added to the chlorotrimethylsilane solution in Et2O. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. Then the reaction mixture, colored in yellow, was quenched with a few ml of MeOH, filtered and concentrated, thus giving 9.36 g of an brown and viscous liquid (96.8% yield).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([CH2:20][CH2:21][C:22](OC)=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26]>ClCCl.CO>[CH3:1][NH:2][C:22](=[O:23])[CH2:21][CH2:20][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:26])[N:4]([CH3:3])[C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of gaseous methylamine is passed into a 250 ml round-bottomed flask containing a solution of 1.25 g (3.85 mmol) of methyl 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate in 20 ml of dichloromethane and 80 ml of methanol until saturation and the mixture is left stirring at room temperature for 3 days. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 80/20 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from acetonitrile, 0.85 g (2.65 mmol) of white crystalline solid is obtained. Melting point: 185°-186° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>O1CCCC1.ClCCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1O
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4-dihydroxybenzonitrile (4.33 g, 32.1 mmol) in tetrahydrofuran (50 mL) and 1,2-dichloroethane (400 mL) was added isopropylmagnesium chloride (17.7 mL, 2.0 M solution in tetrahydrofuran, 35.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione (8.58 g, 32.1 mmol) was added to the reaction mixture. The mixture was stirred at reflux for 18 h, cooled to 0° C. and 5% v/v hydrochloric acid was added. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.30 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.35 (s, 1H), 7.80 (s, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.14-7.08 (m, 1H), 6.88-6.84 (m, 4H), 6.75-6.72 (m, 1H), 6.63 (s, 1H), 6.30 (s, 1H), 4.79 (ABq, 2H), 3.70 (s, 3H); MS (ES+) m/z 384.8 (M−17).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.COC1C=CC([N+:19]#N)=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[C:10]([NH2:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Nc1cc2ccccn2n1
Reactant: COc1ccc([N+]#N)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1nn2ccccc2c1N

Procedure:
2.66 g. 2-Aminopyrazolo[1,5-a]pyridine (see Chem. Pharm. Bull., 21, 2146/1973) are reacted with p-methoxybenzenediazonium salt analogously to Example 12.3.1, the resultant azo compound is reduced with sodium dithionite and the crude product obtained is purified to give 2,3-diaminopyrazolo[1,5-a]pyridine; m.p. 190° C.; Rf =0.6 (silica gel, ligroin/acetone/glacial acetic acid 60:40:1 v/v/v).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].O.[OH-].[Li+]>CO.O>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-Biphenyl-4-ylmethyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (60 mg, 0.2 mmol) and lithiumhydroxide-hydrate (35 mg, 0.8 mmol) in 4 mL MeOH and 2 mL water was stirred at 80° C. for 2 h. The mixture was evaporated in vacuo, extracted with hexane and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4, and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 8.83 (s, 1H), 7.65-7.70 (m, 4H), 7.38-7.49 (m, 5H), 5.70 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10]O>>[CH3:10][O:6][C:5](=[O:7])[CH:4]1[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(O)C1CCNCC1
Product: COC(=O)C1CCNCC1
Reaction time: 0.17 h

Procedure:
Isonipecotic acid 2-3a (25 g, 0.19 mol; Aldrich) was suspended in MeOH (300 mL) at room temperature and HCl gas was bubbled through until saturated and a clear solution was obtained. After a further 10 minutes, the solvent was removed in vacuo to provide 2-3b as a solid (HCl salt).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH2:8])=[O:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>S(=O)(=O)(O)O.CCCCCC>[C:9]1([CH2:15][C:16]([NH:8][C:6](=[O:7])[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)SCC(N)=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)SCC(=O)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
A reaction mixture comprising 6.65 g. (0.05 mole) of 2-(acetylthio) acetamide, 10 ml. of 2-phenylacetyl chloride, and 1 drop of sulfuric acid was heated in a steam bath for 0.5 hour, and then allowed to stand overnight at room temperature, after which it solidified. There was then added 50 ml. of ether and 20 ml. of hexane, followed by stirring for 10 minutes and then filtering. A yield of 8.5 g. of a tan solid was obtained, which was then chromatographed on 100 g. of silica gel. eluting with 5% ether in dichloromethane, followed by concentration to dryness. The solid was suspended in 60 ml. of ethanol and stirred in an ice bath for 1 hour. The product of white crystals, m.p. 153°-155° C., was obtained in a 5.6 g. yield.
Reaction SMILES: [NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: Cc1c(C)c(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c(OCC(=O)N(C)C2CCN(CCc3ccccc3)CC2)c(C)c(C)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a mixture solution of 99 mg of the compound (1) obtained in the Example 1 and 42.3 μl of phenethyl bromide in 2 ml of acetonitrile was added 65 μl of triethylamine, and the mixture was stirred for 5 hours at 60° C. After the reaction, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saline, dried and concentrated under reduced pressure to give the residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.) column chromatography (dichloromethane : ether =1:1) to give 86 mg (65%) of the above-mentioned compound (6).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[C:13]([Cl:27])=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[NH:18][C:16]1[CH:17]=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[S:3][C:4]=3[N:5]=2)[C:13]([Cl:27])=[CH:14][C:15]=1[F:26])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc3nc(N)sc3n2)c(Cl)cc1F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-chloro-2-fluorophenyl}carbamate (470 mg, 1.14 mmol) in pyridine (10 mL) was added acetyl chloride (204 μL, 2.86 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-chloro-2-fluorophenyl)carbamate as a brown amorphous solid. The obtained compound was used for the next reaction without further purification.