Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccnc1SCc1ccccc1
Yield: 49.07 %

Procedure:
In a stirred suspension of 96.37 gm potassium carbonate in 700 gm dimethyl sulphoxide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 gm benzyl mercaptan in 300 gm dimethyl sulphoxide was added in a period of two hours maintaining reaction temperature 80-90 deg. c. The temperature of the reaction was raised up to 140 deg. c. and then maintained for another three hours. 500 gm water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 75.5 gm white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 49.07% yield (Assay by HPLC 99.16%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[C:17](/[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=3)\[C:18]#[N:19])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc3c(c2)CCO3)cc1OC
Yield: 49.5 %

Procedure:
2,3-Dihydrobenzofuran-5-carboxaldehyde (150 mg) was condensed with 3,4-dimethoxybenzyl cyanide (180 mg) through Method A (production step 2), to thereby yield the target product (yield: 154 mg, 50%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:6][C:5]=1[Cl:20].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:15])[CH3:16])=[CH:6][C:5]=1[Cl:20]
Reactant: CCC(C)(C)NCC(=O)c1cc(F)c(N)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 187°-188° C. (decomp.), was prepared from 4'-amino-3'-chloro-5'-fluoro-2-tert.pentylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20](O)=[O:21].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH:17][C:20](=[O:21])[CH2:19][C:18]([O:24][CH2:25][CH3:26])=[O:23])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1nc2ccccc2nc1-c1cc(N)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(-c2nc3ccccc3nc2C)n[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine (5.00 g, 22.2 mmol) and ethyl hydrogen malonate (2.88 mL, 24.4 mmol) in pyridine (89 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.38 g, 33.3 mmol) at 0° C. and stirred for 30 min. The reaction mixture was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was diluted with water (100 mL) and the resulting precipitate was collected and washed with water followed by diethyl ether to give ethyl 3-{[3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate. MS (APCI): m/z 340 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:20]2[C:15](=[N:16][C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=3)[CH:19]=2)[NH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]1([CH2:44][NH2:45])[CH2:43][CH2:42]1>>[CH:41]1([CH2:44][NH:45][C:23]2[N:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[N:13][NH:14][C:15]4=[N:16][C:17]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:26]=[CH:25][N:24]=2)[CH2:43][CH2:42]1
Reactant: CS(=O)(=O)c1nccc(-c2cc3c(NC(=O)OCc4ccccc4)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: NCC1CC1
Product: O=C(Nc1n[nH]c2nc(-c3cccc(C(F)(F)F)c3)c(-c3ccnc(NCC4CC4)n3)cc12)OCc1ccccc1

Procedure:
Following a similar procedure to that described in example 208, but starting from N-benzyloxycarbonyl-[5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine (obtained in section b) and (cyclopropylmethyl)amine, the desired compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[S:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CS(C)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:22]([O:1][C:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[S:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C2Sc3cc(C)ccc3NC(=O)C2O)cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C(c2ccc(C)cc2)Sc2cc(C)ccc2NC1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 70.6 %

Procedure:
A mixture of 2,3-dihydro-3-hydroxy-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one (30.0 g), acetic anhydride (50 ml), dimethylsulfoxide (100 ml), pyridine (3 ml) and toluene (100 ml) is stirred at room temperature for 4 days, and the mixture is treated in the same manner as in Reference Example 1-(1) to give 3-acetoxy-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one (24.0 g).
Reaction SMILES: [NH2:1][CH:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>C(Cl)Cl.CO.C(Cl)Cl>[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36]([NH:1][CH:2]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:3][C:4]2[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CCOC(=O)COc1ccc(CC(N)c2cccnc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)COc1ccc(CC(NS(=O)(=O)c2ccc(C)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.2 %

Procedure:
In 15 m of methylene chloride were dissolved 0.19 g of ethyl 4-[2-amino-2-(3-pyridyl)ethyl]phenoxyacetate and 0.09 g of triethylamine, followed by addition of 0.17 g of p-toluene sulfonylchloride, and stirred at room temperature for 15 hours. To the reaction mixture was added water, and the organic phase was then separated, which was extracted from aqueous phase with methanol-methylene chloride (5:95 v/v). The organic phases were combined and washed with 2N hydrogen chloride, followed by washing in aqueous saturated sodium chloride solution and drying over magnesium sulfate. Then, the solvent was evaporated off under reduced pressure. The residue obtained was subjected to preparative TLC on silica gel which was developed with methanol-methylene chloride (5:95 v/v). From the band at an Rf value of 0.35 to 0.45, 0.13 g of ethyl 4-[2-(4-toluene sulfonamido)-2-(3-pyridyl)ethyl]phenoxyacetate was obtained, which spectrometric data supports the structure of [18] as follows.
Reaction SMILES: C1(NN=[CH:9][C@@H:10]([C@@H:12]([C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])C=CC=CC=1.O.C(=[O:28])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C(O)C>[OH:19][C@@H:18]1[O:11][C@@H:10]([CH2:9][OH:28])[C@H:12]([OH:13])[C@@H:14]([OH:15])[C@H:16]1[OH:17]
Reactant: OC[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=NNc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCO
Solvent: O
Product: OC[C@@H]1O[C@@H](O)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The hydrazone (20 g.) was then refluxed for 3 hours with a solution containing water (200 ml.), ethanol (40 ml.), benzaldehyde (25 ml.) and benzoic acid (2.5 g.). The solution was cooled and then decanted from benzaldehyde phenylhydrazone, extracted three times with chloroform, decolorized with carbon and concentrated at reduced pressure. The resulting syrup was further evaporated with several portions of absolute ethanol to remove residual water and the resulting syrup (10 g.) was left to crystallize. The crystals were filtered with ethanol to give α-L-mannopyranose, m.p. 125°-126°, [α]D -26.9°→-14.4° (24 hr., c 2.0, water) compared to m.p. 128°-132°, [α]D -14.5° (equilibrium, c 3.4, water).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:20]([NH2:23])[C:21]#[CH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][NH:23][CH2:20][C:21]#[CH:22])[CH:19]=[CH:18][C:14]1=2
Reactant: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNCCOCCc1ccc2sccc2c1
Temperature: 80 °C

Procedure:
In 15 mL of N,N-dimethylformamide is dissolved 3.00 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-ethyl methanesulfonate, to which are added 1.40 mL of propargylamine and 2.76 g of potassium carbonate. The mixture is heated at 80° C. for 3 hours. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=30:1 to 20:1) to obtain 1.63 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-propynyl)amine as an oily product.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Si:27]([O:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]([C:44]2[N:45]=[CH:46][N:47]3[CH:51]=[C:50]([Sn](CCCC)(CCCC)CCCC)[S:49][C:48]=23)=[O:43])[CH:39]=[N:40][CH:41]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>>[Si:27]([O:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]([C:44]2[N:45]=[CH:46][N:47]3[CH:51]=[C:50]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:49][C:48]=23)=[O:43])[CH:39]=[N:40][CH:41]=1)([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(CO[Si](C)(C)C(C)(C)C)c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CO[Si](C)(C)C(C)(C)C)c5)c4s3)[C@H](C)[C@H]12
Yield: 70.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonylimidazo[5,1-b]-thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (707 mg) was prepared in the same manner as in step a) of Example 1, except that 509 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 926 mg of 7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Cl.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][CH2:28][O:27][C:26]4[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=4[O:24][CH3:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccccc1OCCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6-fluoro-3-[1-[3-(2-methoxyphenoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169°-170° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[CH2:34][CH2:33]2>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[C:35](=[O:39])[CH2:34][CH2:33]3)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1CCc2cc(O)ccc21
Product: O=C1CCc2cc(OCCCc3c[nH]cn3)ccc21

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 5-hydroxy-1-indanone are treated as described in Example 56.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[OH-].[Na+]>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([NH:4][C@H:5]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)[S:13][CH:14]=2)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:39])=[CH:33][CH:32]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)Cc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
To a solution of 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and of 35 mg (0.22 mmol) 4-fluorophenylacetic acid in DMF (2 ml) 121 mg (1.2 mmol) N-methyl morpholine and 114 mg (0.3 mmol) HBTU (O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) were added. The reaction was stirred over night at room temperature. The reaction was diluted with 2N aqueous NaOH solution (6 ml) and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 95 mg (94%) of 2-(4-fluoro-phenyl)-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-acetamide as a yellow solid. MS ISP (m/e): 508.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm) 10.38 (s, 1H), 8.30 (d, 1H), 7.96 (d, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.30-7.20 (m, 3H), 7.15-6.97 (m, 4H), 6.54 (s, 1H), 4.60 (m, 1H), 3.80 (s, 3H), 3.45 (m, 2H), 2.14 (s, 3H), 1.69-1.48 (m, 3H), 0.92 (d, 3H), 0.85 (d, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:25][CH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.7 %

Procedure:
To a solution of 2-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (3.20 g, 6.80 mmol) in ethanol (70.0 mL) was added hydrazine monohydrate (1.87 g, 37.0 mmol). The mixture was stirred at ambient temperature for 4 h. The solvent was removed under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with sodium bicarbonate and brine solution, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from hexane to yield the title compound (2.50 g) in 75% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.16-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.94-6.91 (m, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 5.82 (m, 2H), 4.90-4.87 (m, 1H), 4.61 (d, 1H), 3.98-3.71 (m, 2H), 2.77-2.73 (m, 2H), 1.97 (br, 2H), 1.84-1.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.9, 148.9, 142.3, 142.2, 132.4, 129.0, 124.0, 123.4, 119.4, 108.7, 103.0, 101.5, 93.6, 80.5, 58.2, 38.8, 37.5, 30.6; MS (ES+) m/z 339.3 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:15][CH2:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[C:10]([S:29][CH2:30][CH3:31])=[N:9][C:8]=2[C:7]1=[O:32]>C(O)=O>[CH2:30]([S:29][C:10]1[N:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:12](=[O:16])[C:13]2[CH2:14][CH2:15][NH:6][C:7](=[O:32])[C:8]=2[N:9]=1)[CH3:31]
Reactant: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCN(Cc1ccc(OC)cc1OC)C2=O
Solvent: O=CO
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCNC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
7-(2,4-Dimethoxybenzyl)-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,5,6,7-tetrahydropyrido[3,4-d]pyrimidine-4,8-dione (71 mg) was dissolved in formic acid (3 ml), and the solution was stirred at 100° C. for 1 hr, allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to azeotropic distillation with toluene. The obtained white solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (38 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-])=O>[Pd]>[NH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1])[CH:9]=[CH:10]1
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Agent: [Pd]
Product: Nc1cccc2cc[nH]c12
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Charge a 3-gal autoclave with 7-nitroindole (250 g, 1.542 moles), 2B-3 ethyl alcohol (5.0 L), and 10% Pd/C (50.0 g). Stir at 50 psi H2 for 2 h at <27° C. When the reaction is deemed complete, filter the reactor contents through Celite followed by concentration of the filtrate to dryness to yield 197.0 g (96.7%) of the title compound as purple solid. 1H-NMR(CD3OD, 300 MHz), δ 7.16 (d, 1H), 7.00 (dd, 1H), 6.81 (t, 1H), 6.50 (dd, 1H), 6.37 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][CH2:24][CH2:25][C:26]#[N:27])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]1CCC[CH2:29]1>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][N:17]=[C:18]3[C:19]=2[NH:20][C:29](=[O:28])[N:23]3[CH2:24][CH2:25][C:26]#[N:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(NCCC#N)c2[N+](=O)[O-])CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3CCC#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-[6-(2-Cyano-ethylamino)-5-nitro-pyrimidin-4-yl]piperazine-1-carboxylic acid t-butyl ester (1.0 g) was dissolved in tetrahydrofuran (12 mL), and then 10% palladium on carbon powder (wet type) (200 mg) was added to this solution. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 20 hours. Insoluble substances were then removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (30 mL), and then N,N′-disuccinimidyl carbonate (1.13 g) was added to this solution. The reaction solution was stirred at room temperature for five hours, then 40 mL of water was added. This reaction solution was then concentrated under reduced pressure to 40 mL. The precipitate was collected by filtration. The obtained solid was washed with water and hexane to give the title compound (623 mg). A portion of the obtained compound was purified by silica gel column chromatography for use in NMR analysis.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:22]=1)[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to 3-(3-amino-phenyl)-acrylic acid ethyl ester (60) (39 mg, 0.20 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH2:29])[CH2:23]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:22]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=2)[CH2:23]1
Reactant: NC1CCCCNC1
Reactant: Cc1ccccc1Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1Cn1c(N2CCCCC(N)C2)nc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.05 h

Procedure:
8-Bromo-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione (82A) (300 mg, 0,86 mmol) and azepan-3-ylamine (294 mg, 2,6 mmol), and triethylamine (0.6 ml, 4.3 mmol) were dissolved in 3 ml of DMSO and the mixture was subjected to microwaves (method F, 200° C., 300 W) for 3 minutes. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was washed with 1N NaOH, and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=6.93 min.). Evaporation of the solvent afforded the title compound as yellow crystals.