Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@@H:6]1[O:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])(=[O:3])[CH3:2].C1C(=O)N([O:34][C:35]([O:37][CH2:38][CH:39]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)=O)C(=O)C1>N1C=CC=CC=1>[CH:50]1[C:51]2[CH:39]([CH2:38][O:37][C:35]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][O:20][C@H:6]3[O:7][C@@H:8]([CH3:19])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]3[O:4][C:1](=[O:3])[CH3:2])=[O:34])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC[C@H](N)C(=O)O)O[C@@H](C)[C@H]1OC(C)=O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)O[C@@H](C)[C@H]1OC(C)=O
Yield: 59.8 %

Procedure:
A solution of 3-O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl)-L-serine (FIG. 1D) (209.6 mg, 0.82 mmol) and Fmoc N-hydroxysuccinimide ester (9-fluorenylmethyl-N-succinimidyl carbonate) (375.7 mg, 1.63 mmol) in dry pyridine (25 ml) was stirred for 15 h at room temperature. Evaporation and co-evaporation of the reaction mixture with toluene left a syrup which was purified by chromatography on silica gel using dichloromethane-methanol 95:5 as eluent. Pure N-(9-Fluorenylmethyloxycarbonyl)-3-O-(2,3,4-tri-O-acetyl-β-L-fucopyrano syl)-L-serine (294 mg, 88%) was obtained as a white powder, Rf =0.40 (9:1, dichloromethane:methanol). 1H-NMR (CD3OD): ε 7.82-7.25 (m, 8 H, aromatic), 5.18 (m, 1 H, sec. order, H-4), 5.08-4.98 (m, 2 H, sec. order, H-2, 3), 4.50 (d, 1 H, J1,2 =7.5 Hz, H-1), 4.44-3.95 (complex, 6 H, Fmoc-H and serine H's), 3.83 (q, J5,6 =6.25 Hz, H-6), 2.11, 1.99 and 1.92 (each s, 3 H, Ac), 1.10 (d, 3 H, H-6). 13C: ε 102.6 (C-1), 72.5, 71.8 and 70.3 (C-2, 3 and 4), 71.5 and 67.9 (FMOC and serine CH2), 56.5 (serine CHN), 20.8, 20.5 and 20.4 (COCH3), 16.3 (C-6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]([CH3:33])/[C:28](=[N:31]/[CH3:32])/[S:29][CH:30]=3)[CH2:21][CH:20]1[C:34]([O:36]C(C)(C)C)=[O:35])=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2>Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]([CH3:33])/[C:28](=[N:31]/[CH3:32])/[S:29][CH:30]=3)[CH2:21][CH:20]1[C:34]([OH:36])=[O:35])=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C/N=c1\scc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C(C(=O)OC(C)(C)C)C2)n1C
Agent: Cl
Product: C/N=c1\scc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C(C(=O)O)C2)n1C
Yield: 299 %

Procedure:
tert-Butyl 1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate (4.1 g) obtained in Example 23b) was dissolved in concentrated hydrochloric acid (15 mL) and mixed at room temperature for 1 hour. The reaction solution was concentrated, and then water was removed from the residue by azeotropy with toluene (30 mL), to give the title compound (4.2 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 24 h
Yield: 105.2 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O=[C:10]([CH2:16][C:17](=O)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Na]>O.CCOCC.C1C=CC=CC=1>[CH3:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][CH2:18][C:17]1[CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)C(=O)CC(=O)COc1cccc(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OCC)[nH]1
Temperature: 5 °C

Procedure:
To a stirred, refluxing mixture of ethyl glycinate hydrochloride (100 g, 0.71 m), ethyl 2,4-dioxo-5-(3-methylphenoxy)pentanoate (187 g, 0.71 m) and benzene (650 ml) under a nitrogen atmosphere is added finely powdered anhydrous potassium carbonate (50 g, 0.36 m) in five portions over one hour, the eliminated water being collected in a Dean-Stark trap until the theoretical amount (12.6 ml) is collected. The mixture is cooled to 5° C., then 750 ml dry ethanol is added and sodium metal (16.5 g, 0.71 mol) is added in small pieces at a rate which permits the internal reaction temperature to be maintained at less than 40° with cooling. Stirring is continued in the ice bath for an additional 1/2 hour, and the reaction mixture is then poured into a 5-liter separatory funnel containing ether (1 liter) and water (2 liters). The layers are separated and the aqueous layer is re-extracted with ether. The combined ether layers are washed with water and saturated brine. The organic layer is dried over sodium sulfate and concentrated to give a residue which is purified by preparative HPLC to afford diethyl 4-(3-methylphenoxy)methylpyrrole-2,5-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])(=O)=O)=CC=1>CCO.O>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Solvent: O
Product: CCCC(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
To a stirred solution of aniline 12 (1.0 g, 6.1 mmol) in EtOH:H2O (9:1) was added 2-propylpentyl 4-methylbenzenesulfonate (0.87 g, 3.08 mmol). The reaction mixture was heated under reflux for 4 days, concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc three times. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by flash chromatography (25% EtOAc—hexanes) gave 3-hydroxy-3-(3-(2-propylpentylamino)phenyl)propanenitrile as a colorless semi-solid. Yield (0.3 g, 18%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.66 (d, J7.6 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.0, 8.0 Hz, 1H), 4.95 (dt, J=3.2, 6.0 Hz, 1H), 3.72 (bs, 1H), 3.02 (d, J=6.0 Hz, 2H), 2.80 (d, J=6.8 Hz, 2H), 2.89 (d, J=3.2 Hz, 1H), 1.64-1.57 (m, 1H), 1.37-1.20 (m, 8H), 0.84 (t, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[O:11][C:7]=2[CH:6]=[C:5]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C@H:30]([CH3:37])[CH2:31][C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=2)=[O:22])[CH:4]=1.[OH-].[Li+].Cl>CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[O:11][C:7]=2[CH:6]=[C:5]([CH2:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:37])[CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=2)=[O:22])[CH:4]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(OC)c3nc(Nc4ccccc4C)oc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)O)cc2)cc2oc(Nc3ccccc3C)nc12
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A solution of ethyl (R) 3-{4-[2-(4-methoxy-2-o-tolylaminobenzoxazol-6-yl)acetylamino]phenyl}butanoate (0.17 g, Reference Example 8) in methanol was treated with aqueous lithium hydroxide solution (5 mL, 1M) and left to stand for five hours under argon. The mixture was acidified to pH 1 by addition of dilute hydrochloric acid, then partially evaporated, then diluted with more water and then partially evaporated again. The residue was diluted with water to afford a tan solid which was filtered, then dissolved in saturated sodium bicarbonate solution. The solution was washed with ethyl acetate, then acidified to pH1 and then extracted with ethyl acetate several times. The combined ethyl acetate extracts were washed with brine and then evaporated to give the title compound (0.12 g) as a white powder. LC-MS: RT=3.29 minutes (100% by ELSD); MS (ES+), 474 (MH+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:13][CH3:14])([CH3:12])[CH3:11])=[CH:6][CH:5]=1>O>[CH3:14][O:13][C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=1)([CH3:12])[CH3:11]
Reactant: COC(OC)c1ccc(C(C)(C)OC)cc1
Solvent: O
Product: COC(C)(C)c1ccc(C=O)cc1
Temperature: 87 °C
Yield: 91.9 %

Procedure:
4-(1-Methoxy-1-methylethyl)benzaldehyde dimethyl acetal (1.8 kg) and water (1.8 kg) are heated in a stirred flask for about 1 h under reflux at 87° C. The mixture is cooled to about 25° C., and the two phases are separated. The organic phase is distilled with a head pressure of 4 mbar and head temperature of 105°-108° C. 4-(1-Methoxy-1-methylethyl)benzaldehyde (1314.6 g) is obtained. HNMR: (CH3)2C-- 1.55 ppm (s), --OCH3 3.1 ppm (s), ArH 7.6 ppm (d), 7.90 ppm (d), --CHO 10.0 ppm (s). nD25 =1.5264. The yield is 97.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25]C2.C(NC1C=CC=CC=1)C>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:27]([CH2:26][CH3:25])[C:28]1[CH:29]=[CH:30][CH:21]=[CH:22][CH:23]=1)=[O:9]
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: CCNc1ccccc1
Product: CCN(C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)c1ccccc1

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (Example 80, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with ethyl-phenyl-amine ([CAS RN 103-69-5]). MS (ISP): 405.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>C(Cl)Cl.N1C=CC=CC=1>[O:12]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16])[CH3:11]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nc3ccccc3s2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2-amino-1,3-benzthiazole (700 mg, 4.7 mmol) in methylene chloride (20 ml) and pyridine (800 μl) was treated with 2,4-dimethoxybenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with HCl (10 ml of 5 wt %) and the resulting precipitated collected by filtration. The solid was recrystallized from methanol to give 2-(2,4-dimethoxylbenzamido)-1,3-benzthiazole as colorless needles. (1.185 mg, 80% yield)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].O.[NH2:18][NH2:19]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([NH:18][NH2:19])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
113 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 470 cc of hydrazine hydrate are stirred at reflux at a bath temperature of 110° for 1 hour. The title compound has a M.P. of 145°-147° (decomp., from absolute ethanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH2:14]([O:16][C:17](=[O:31])[C:18](=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30])[C:19]([CH3:21])=O)[CH3:15].[ClH:32].C(OCC)C>C(OCC)C>[ClH:32].[CH2:14]([O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[CH3:30])[C:5]2[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:19]=1[CH3:21])=[O:31])[CH3:15]
Reactant: CCOC(=O)C(=Cc1cc(C)ccc1C)C(C)=O
Reactant: Cn1nc(-c2ccccc2)cc1N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2C)C1c1cc(C)ccc1C

Procedure:
Starting from 1-methyl-3-phenyl-5-pyrazolamine and ethyl-2-(2,5-dimethylbenzyliden)acetoacetate in equimolar proportions. The crude reaction product is taken up with ethyl ether, washed with 2% H2SO4, water, and then 5% NaHCO3 until neutralization of the mother liquors. After drying over Na2SO4 the hydrochloride of the title compound is obtained by reacting with HCl/ethyl ether. Crystallization from isopropanol/ethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O.[CH3:25]C(C)([O-])C.[K+].CI>CN(C)C=O>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[N:6]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:25]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(N(C)c2ccccc2N)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
Ethyl 2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.0 g) was dissolved in N,N-dimethylformamide (120 ml) and the mixture was stirred at 0° C., during which potassium tert-butoxide (3.0 g) was added portionwise. Methyl iodide (12.4 g) was added dropwise under ice-cooling and the mixture was stirred at 0° C. for 5 min and heated to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (hexane:ethyl acetate=4:1) to give crude crystals (2.8 g) of ethyl 2-(N-methyl-2-nitroanflino)benzo[b]thiophene-3-carboxylate. Without purification, the crystals were treated in the same manner as in Starting Material Synthesis Example 21 using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin(II) chlorihe.dihydrate (12.6 g) to give ethyl 2-(2-amino-N-methylanilino)benzo[b]thiophene-3-carboxylate (3.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH:24]5[CH2:25][CH2:26][N:27]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28][CH2:29]5)=[CH:22][CH:23]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Product: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12

Procedure:
2-(4-{4-[8-(4-Chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.046 g, 0.110 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.016 mL, 0.159 mmol) in a manner analogous to Example 313 to give product (0.010 g, 18%). MP=104-107° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.79 (d, 1H), 7.58 (m, 4H), 7.25 (s, 1H), 7.15 (m, 3H), 7.05 (m, 1H), 3.78 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.92 (m, 2H), 2.85 (s, 3H), 2.35 (m, 1H), 2.12 (m, 2H), 1.65 (m, 4H): MS=520 (MH)+.
Reaction SMILES: [C:1]([CH:3]([CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=O)[C:4]([O:6][CH3:7])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:25].O>C(OCC)(=O)C>[Cl:25][C:1]1[NH:2][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[C:8]([CH3:18])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: COC(=O)C(C#N)C(C)C(=O)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)[nH]c(-c2ccccc2F)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a solution of methyl 2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate (31.0 g) in ethyl acetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with water, and then washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as white crystals (yield 19.3 g, 58%).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:20])=[CH:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])C1C=C2C(C=CN2)=CC=1>>[I:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(F)cc21
Product: FC(F)(F)c1ccc2c(I)c[nH]c2c1
Yield: 98 %

Procedure:
Following the general method as outlined in Intermediate 3, starting from 6-(trifluoromethyl)-1H-indole (0.97 g; 5.24 mmol), 1.60 g (98%) of the title compound was obtained as a red solid, which was used directly without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:33]=[CH:32][C:9]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:8][C:7]=1[OH:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:5][C:6]1[CH:33]=[CH:32][C:9]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:8][C:7]=1[O:34][CH2:2][CH2:3][OH:4]
Reactant: OCCBr
Reactant: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)c(OCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromoethanol (0.012 mL) was added to a mixture of the compound prepared in Example 55 (50 mg) and potassium carbonate (49 mg) in N,N-dimethylformamide (0.8 mL). The mixture was stirred at room temperature overnight, then 50° C. for six hours. The reaction was cooled to room temperature and was adjusted to pH 7 via the addition of aqueous 3% hydrochloric acid. The mixture was extracted twice with ethyl acetate and the organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methanol:ethyl acetate=1:19) to obtain the title compound (10 mg) having the following physical data.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)[CH2:6]2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)[CH2:6]2
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4=O)nc2n(CCC)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4O)nc2n(CCC)c1=O

Procedure:
8-(8-Oxo-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (25 mg) was reduced using NaBH4 (30 mg) in MeOH at 0° C. The product was purified by HPLC. Yield (7 mg). Mass (ES+ 361).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.CCOC(C)=O.O.[NH2:22][NH2:23]>CCO>[NH:22]([C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1)[NH2:23]
Reactant: NN
Reactant: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Yield: 100 %

Procedure:
To a solution of 6-chloro-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (2.0 g 9.3 mmol) in EtOH (8 mL), hydrazine monohydrate (1.3 mL) in EtOH (3 mL) is added slowly. The reaction mixture is refluxed for 5 hours, and then cooled. A large amount of AcOEt is added into the reaction mixture, and then cooled and filtered to give 1.95 g of product as yellowish solids (Yield: 100%).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:29])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:5].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:15]([C:12]2[CH:13]=[C:14]3[C:6]([C:4](=[O:5])[C:3]4[C:18]([F:29])=[CH:19][CH:20]=[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[C:2]=4[F:1])=[CH:7][NH:8][C:9]3=[N:10][CH:11]=2)=[O:16])[CH:31]=1
Reactant: Nc1cccnc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)Nc4cccnc4)cc23)c1F

Procedure:
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid pyridin-3-ylamide P-1801 is prepared in one step from 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 41 and pyridin-3-ylamine 42 as shown in Scheme 6.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([I:13])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(N)c(I)c1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Silver sulphate (103 g, 0.33 mol) was added over 5 minutes to a stirred suspension of 4,5-dimethyl-2-nitroaniline (50.0 g, 0.30 mol) in ethanol (1500 mL) at 20° C. Iodine (84.0 g, 0.33 mol) was added in portions, and the resulting mixture was stirred for 30 minutes at 20° C. The mixture was filtered, and the filter cake washed thoroughly with ethanol (1 L) and dichloromethane (1 L). The filtrate was concentrated under reduced pressure, and the residue was redissolved in dichloromethane (500 mL), and washed with 10% aqueous sodium metabisulphite (2×500 mL), and brine (250 mL). The solution was dried (MgSO4) and concentrated under reduced pressure to give 4,5-dimethyl-6-iodo-2-nitroaniline (82.1 g, 93%) as an orange solid.