Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:29])[N:24]=[C:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:29])[N:24]=[C:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Temperature: 78 °C
Yield: 70.9 %

Procedure:
4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.167 g, 0.409 mmol) and ethyl formate (0.098 mL, 1.23 mmol) were dissolved in anhydrous ethanol (0.810 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.76 mL, 2.05 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.127 g, 0.290 mmol, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.[C:26]1([C:32]2[O:36][C:35](=[S:37])[NH:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[S:37][C:35]1[O:36][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:33][N:34]=1
Reactant: O=c1cnn(-c2cc(Cl)c(C(O)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: S=c1[nH]nc(-c2ccccc2)o1
Agent: CS(=O)(=O)O
Product: O=c1cnn(-c2cc(Cl)c(C(Sc3nnc(-c4ccccc4)o3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
A mixture of 2-[3,5-dichloro-4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.005 mol) and 5-phenyl-1,3,4-oxadiazole-2(3H)-thione (0.006 mol) in methanesulfonic acid (20 ml) was stirred for 18 hours at RT. The reaction mixture was poured out into water/ice (150 ml), and the resulting precipitate was filtered off, stirred in water, treated with NaHCO3 and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97.5/2.5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 1 g of (±)-2-[3,5-dichloro-4-[(4-chlorophenyl)[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (comp. 406).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C:39]([CH3:41])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:40])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 81 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and cumylamine: yield 81%.
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[CH2:49][CH:48]([N:53]([CH3:55])[CH3:54])[CH2:47]2.Cl.C(OCC)C>CC(O)C>[CH3:54][N:53]([CH3:55])[CH:48]1[CH2:47][C:46]2[C:50](=[CH:51][CH:52]=[C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:45]=2)[CH2:49]1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: CN(C)C1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Temperature: 180 °C

Procedure:
The title compound was synthesized by combining N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (147 mg, 0.33 mmol) (see Example 2, step B) and (5-amino-2,3-dihydro-1H-inden-2-yl)dimethylamine (70 mg, 0.40 mmol) in i-PrOH (2 mL) and adding 1M hydrochloric acid in diethyl ether (33 uL, 0.03 mmol). The reaction was heated to 180° C. in the microwave for 20 min. repeatedly until LC/MS analysis of the reaction mixture showed consumption of starting material. The reaction product was concentrated to a residue, partitioned between chloroform and saturated aqueous NaHCO3 and the organic fraction was washed with brine. The crude organic solution was dried with Na2SO4 and concentrated. The crude product was purified by silica gel flash column chromatography (DCM: 0-100% 90:9:1 DCM:MeOH:NH4OH(aq)). Purification yielded 43 mg (22%) of a brown powder. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.41 (s, 1H), 8.81 (d, J=6.9 Hz, 1H), 8.46 (m, 1H), 8.21 (dd, J=5.2, 4.1 Hz, 1H), 7.90-7.87 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.4 Hz, 1H), 7.48-7.35 (m, 4H), 7.25 (d, J=7.7 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 7.06-7.02 (m, 1H), 6.97-6.94 (m, 1H), 6.45 (dd, J=8.6, 5.4 Hz, 1H), 3.86 (s, 2H), 3.30 (s, 6H), 3.02-2.86 (m, 2H), 2.70-2.63 (m, 1H), 2.17 (s, 2H). ES-LC/MS m/z=586 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2.B(O[O-])=[O:30].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([OH:30])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2
Reactant: O=BO[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2C1=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(O)cc(F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 144g (16.0 g, 40.9 mmol) in THF (200 mL) and H2O (200 mL) was added sodium perborate (26.4 g, 171.8 mmol) in one portion at RT under N2. See FIG. 3. The mixture was stirred at room temperature for 8 h. The mixture was filtered and the filtration was extracted with EtOAc (400 mL×5). The combined organic phase was washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=30/1, 5/1) to afford 9.50 g (82.6%) of tert-butyl 8-fluoro-6-hydroxy-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate 144h. 1H NMR (400 MHz, CDCl3) δ 6.56-6.60 (d, J=13.6 Hz, 1H), 6.49 (s, 1H), 3.83-3.86 (m, 2H), 2.82-2.84 (m, 2H), 1.49 (s, 9H), 1.20 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:22]=[C:21]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][C:26]=2[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:35])[CH3:33])[N:22]=[C:21]3[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(F)cc3)cc12

Procedure:
470 mg of 4-fluorophenylboronic acid, 593 mg of sodium carbonate in 40 cm3 of water and 155 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 40 cm3 of dioxane. The mixture is refluxed for 18 hours and the reaction medium is filtered through a sinter funnel packed with Celite. 60 cm3 of ethyl acetate and 50 cm3 of distilled water are added to the filtrate. The organic phase is washed with 2×20 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.75 g of N-[5-(4-fluorophenyl)-6-chloro-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: [CH2:1]([N:5]1[C:17]([CH2:18][CH2:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[C:16]2[C:7]([C:8]([NH2:26])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.[Pt](=O)=O>[CH2:1]([N:5]1[C:17]([CH2:18][CH2:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])=[C:16]2[C:7]([C:8]([NH2:26])=[N:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=32)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc2c(N)nc3ccccc3c2c1CCS(=O)(=O)CCC
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1nc2c(N)nc3c(c2c1CCS(=O)(=O)CCC)CCCC3
Reaction time: 20 h
Yield: 81.3 %

Procedure:
A solution of 2-butyl-1-[2-(propylsulfonyl)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 60, 0.50 g, 1.3 mmol) in trifluoroacetic acid (6 mL) was treated with platinum (IV) oxide (0.5 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 20 hours on a Parr apparatus. The reaction mixture was filtered through a layer of CELITE filter agent, and the CELITE filter agent was rinsed with dichloromethane (100 mL) until the rinses were clear. The filtrate was concentrated under reduced pressure. The oil was suspended in water (20 mL) and treated with 50% aqueous sodium hydroxide to adjust the mixture to pH 14, causing a precipitate to form. The mixture was stirred for 1 hour, then the precipitate was isolated by filtration and washed with water. The white powder was recrystallized from acetonitrile (5 mL). The crystals were isolated by filtration, washed with acetonitrile, and dried under vacuum at 65° C. to afford 0.40 g of 2-butyl-1-[2-(propylsulfonyl)ethyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as white crystals, mp 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ 6.02 (bs, 2H), 4.28 (t, J=7.5 Hz, 2H), 3.43-3.37 (m, 4H), 3.19-3.14 (m, 2H), 2.85 (bs, 2H) 2.56 (bs, 2H), 1.85 (pentet, J=7.5 Hz, 2H), 1.77-1.70 (m, 6H), 1.33 (sextet, J=7.5 Hz, 2H), 1.00 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H);
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2>>[N:33]1[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Clc1ncnc2[nH]cnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ncnc5[nH]cnc45)c3)ncnc12
Reaction time: 3 h

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 6-Chloro-9H-purine. Reaction conditions: 120° C. in the microwave for 3 h:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[CH:11]=[C:10]2[C:12]([C:14]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[C:15]=3[C:16](=[O:17])[C:9]2=[CH:8][CH:7]=1)=[O:13]>[O-2].[O-2].[Mn+4].O>[CH:6]1[CH:7]=[CH:8][C:9]2[C:16](=[O:17])[C:15]3[C:18]([OH:23])=[C:19]([OH:22])[CH:20]=[C:21]([OH:2])[C:14]=3[C:12](=[O:13])[C:10]=2[CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(O)c2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(O)c(O)cc(O)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A suspension of 17.5 g of manganese dioxide/40 g of concentrated sulfuric acid, that had been prepared by putting 9.0 g of water and 130 g of 96% sulfuric acid into 30 g of alizarin (manufactured by Sigma-Aldrich Corporation), followed by ice-cooling, was added over 1 hour to a reaction liquid while maintaining it at 10° C. or lower. After 2 hours, the reaction liquid was poured into 1 L of water, with the inside of the container being washed with 400 mL of water, and filtered. The crystal collected by filtration was washed with 300 mL of methanol and dried to obtain 32.4 g of purpurin.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([N:14]1[C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:22]=[CH:23][C:18]=2[C:17](=[O:30])[CH:16]=[CH:15]1)[CH2:11][CH2:12][CH3:13].[OH-].[NH4+]>O>[CH2:10]([N:14]1[C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[N:22]=[CH:23][C:18]=2[C:17](=[O:30])[C:16]([N+:6]([O-:9])=[O:7])=[CH:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CCCCn1ccc(=O)c2cnc(-c3ccncc3)nc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCCn1cc([N+](=O)[O-])c(=O)c2cnc(-c3ccncc3)nc21
Temperature: 30 °C
Reaction time: 1 h

Procedure:
C-8. 8-n-Butyl-6-nitro-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one--To 7.2 g of concentrated sulfuric acid was added, with stirring and cooling keeping the temperature below 30° C., 10.8 ml of fuming sulfuric acid. To the resulting mixture was added 6.0 ml of fuming nitric acid with stirring, and cooling as necessary to keep the temperature below 30° C. To the stirred mixture of acids at room temperature was added 6.6 g of 8-n-butyl-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one. The reaction mixture was heated with stirring, gradually raising the temperature to 90° over a twenty minute period and then maintaining the reaction mixture at 90°-95° C. for ten minutes. The reaction mixture was cooled to 30° C. and added to 500 ml of a mixture of ice and water. The resulting mixture was made basic by adding concentrated ammonium hydroxide and the resulting mixture was allowed to stand for one hour. The separated solid was collected, washed with water, dried at 65° C. in vacuo to produce 6.3 g of 8-n-butyl-6-nitro-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 240°-241° C. The product was dissolved in 50 ml of boiling dimethylformamide, the solution treated with decolorizing charcoal and filtered, and the filtrate concentrated to a volume of about 30 ml and cooled to complete precipitation of the product. The product was collected, washed with a small quantity of cold ethanol, and dried at 65° C. in vacuo to produce 5.25 g of 8-n-butyl-6-nitro-2-(4-pyridinyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 241°-243° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2].[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C(O)(=O)C>[CH2:1]([NH:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:23])[CH3:2]
Reactant: NCC(=O)O
Reactant: CCNC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Yield: 34.4 %

Procedure:
To a slurry of ˜1.0 mmol ethyl benzamide from Step 3 in 3 mL acetic acid was added 0.15 g (2.0 mmol) glycine. The reaction was mixed at 90-102° C. for 5.5 hr and allowed to cool. The solution was concentrated and and the residue was purified by 6Gilson preparative HPLC to afford 120 mg of [2-(4-ethylcarbamoyl-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid [5LC-MS data molecular ion and retention time): m/z 349 (M+H); 2.36 min] as a brown solid.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([C:10]1[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:11]=1)=O.O>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:2]([S@@:5](/[N:7]=[CH:8]/[C:10]1[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:11]=1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a 500-mL round-bottom flask was added (S)-(−)-2-methyl-2-propanesulfinamide (1.62 g, 13.4 mmol), and tert-butyl 5-formylthiophene-2-carboxylate (2.37 g, 11.2 mmol), and DCM (100 mL). The mixture was cooled to 0° C., then titanium tetraisopropoxide (19.8 mL, 67.0 mmol) was added. After the solution was warmed to rt and stirred for 16 h, the reaction mixture was diluted with DCM (200 mL). To the flask was added water (19.8 mL) slowly. The mixture was vigorously stirred at rt for 30 min, then filtered through a pad of Celite. The filtrate was concentrated to give a solid. Purification via flash chromatography (hexanes to 10% EtOAc-hexanes) afforded (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)thiophene-2-carboxylate (3.07 g, 87%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.65 (d, J=3.8 Hz, 1H), 1.58 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[CH3:9][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7](=[NH:8])[O:13][CH2:11][CH3:12]
Reactant: Cc1cccc(C#N)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccc(C)c1

Procedure:
Ethyl 3-methylbenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, m-tolunitrile (25.2 g, 0.215 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 41.7 g (97%) of the target compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][CH2:25][Cl:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][CH2:25][Cl:26])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(CCl)CCCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: ClCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,4-dichloro-2-butanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(2-chloroethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].N[C:11]1N=C(O)C=CC=1.BrBr>C(O)(=O)C.O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:11])=[CH:5][CH:4]=1
Reactant: Nc1cccc(O)n1
Reactant: Nc1nc(O)ccc1Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(N)n1
Reaction time: 0.25 h

Procedure:
In accordance with scheme 1, the compound of formula V (6-amino-5-bromo-pyridin-2-ol) may be prepared as described in Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Letters 1991, 32, 4263-4266) as follows: To a solution of 6-amino-pyridin-2-ol in acetic acid at room temperature is added bromine and stirred for 15 min. The mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted and the combined organic layers are dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridin-2-ol is treated with KOH pellets and dimethylsulfate. The mixture is stirred for 4 h at room temperature and evaporated to dryness. The residue is purified and 3-bromo-6-methoxy-pyridin-2-yl-amine (IV) is obtained. Furthermore, a mixture of 3-bromo-6-methoxy-pyridin-2-yl-amine, phenylboronic acid (wherein the phenyl ring may be substituted by R1), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium II) dichloromethane adduct in dioxane is heated to 110° C. for 2 h. The mixture is concentrated, diluted Na2CO3 aq. is added and extracted. The combined organic phases are dried and evaporated. The residue is purified to yield the corresponding compound of formula II, for example 6-methoxy-3-phenyl-pyridin-2-yl-amine. A mixture 6-methoxy-3-phenyl-pyridin-2-yl-amine (II) and ethoxycarbonyl isothiocyanate is stirred at room temperature for 2 h and afterwards evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiisopropylamine (DIPEA). The mixture is heated to 80° C. for 16 h, evaporate to dryness, taken up in water and extracted with diethyl ether. The combined organic phases are dried and evaporated to yield, for example, 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine (Ia). A mixture of 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and a compound of formula R2Cl, for example 3-fluorophenyl carboxylic acid chloride, and NEt3 in dioxane is heated to 90° C. for 16 h. The mixture is purified to give a compound of formula I, for example 3-fluoro-N-(5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42]>CO.C1COCC1>[CH3:40][N:41]([CH2:28][C@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), dimethylamine in MeOH (2 M, 2 mL) and THF (5 mL) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, purified by prep TLC (eluting with 5% MeOH in DCM). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=0.65 min (polar—5 min).