Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[C:6]2[CH3:14]>Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[C:6]2[CH3:14]
Reactant: COc1ccc2c(=O)[nH]cc(C)c2c1
Agent: Cl
Product: Cc1c[nH]c(=O)c2ccc(O)cc12
Yield: 67.5 %

Procedure:
A suspension of 6-methoxy-4-methyl-2H-isoquinolin-1-one (215 mg, 1.1 mmol) in 5N hydrochloric acid (1 ml) was was irradiated in a microwave at 180° C. for 40 minutes. After removing solvent in vacuo the crude residue was purified by flash chromatography on silica (eluent: 1% methanol in DCM) to give 6-hydroxy-4-methyl-2H-isoquinolin-1-one (130 mg, 67%)., El-MS: m/z=174.3 [M-H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)c2)n1
Yield: 97.7 %

Procedure:
A mixture of 6-methyl-2′-(3-nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example 306) (6.6 g, 15.15 mmol) in THF-MeOH 1:1 (300 mL) and 10% palladium on carbon (10 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was triturated with diethyl ether and dried in HV to give the title compound as a light brown solid (6.0 g, 97%). MS (ISP) 406.3 [(M+H)+]; mp 162° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2]>C(NCC)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:6]=[C:7]([N:8]([CH2:9][CH3:10])[CH2:7][CH3:6])[N:8]=[C:9]([Cl:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)c1
Solvent: CCNCC
Product: CCOC(=O)c1cc(Cl)nc(N(CC)CC)c1

Procedure:
A solution of 2,6-dichloroisonicotinic acid ethyl ester (14.0 g, 63.6 mmol) in diethylamine (25 mL) is stirred at 100° C. for 7 h. The volatile compounds are evaporated and the residue is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-chloro-6-diethylamino-isonicotinic acid ethyl ester (10.1 g, contains 2-chloro-6-diethylamino-isonicotinic acid methyl ester which forms during the transfer of the reaction mixture into a round bottom flask using methanol); LC-MS: tR=1.09 min.
Reaction SMILES: C(OC([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=O)(C)(C)C.C([BH3-])#N.[Na+].[ClH:20]>O1CCCC1.CO>[ClH:20].[O:13]1[CH2:14][CH2:15][CH:10]([NH:9][NH2:8])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NN=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NNC1CCOCC1
Temperature: 25 °C
Yield: 60 %

Procedure:
N′-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 mL) and dry methanol (30 mL). Sodium cyanoborohydride was added to the solution resulting in effervescence. When the effervescence subsided, the mixture was heated to reflux for 5-10 minutes. After cooling to room temperature 6N HCl (10.5 mL) was slowly added and then the mixture was heated to reflux for 20 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and chilled. The solid was collected by filtration and was found to be the reduced material but not completely deprotected. The solid was dissolved in the same THF-methanol mixture and treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and solid quickly began to crystallize out of solution. After chilling overnight, ether was added followed by additional chilling. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (2.22 g, 60%).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.[CH3:32][OH:33]>>[ClH:1].[ClH:1].[OH:33][CH2:32][C:4]1[CH:3]=[CH:31][C:7]2[CH2:8][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[C:6]=2[CH:5]=1
Reactant: CO
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(CO)ccc2C1

Procedure:
Example 274 was prepared as an off white solid from Compound B as described for Compound F of Example 41, with chromatography using 5% MeOH/0.5% NH4OH/methylene chloride, and Compound D of Example 1, with purification by prep HPLC before formation of the HCl salt. MS (M+H) 413.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 160 mg (0.47 mmol) of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 116 mg (0.57 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 1.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%), 110 mg (45% of theory) of the product is obtained.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2].[C:14]([C:16]1[CH:29]=[CH:28][C:19]2[O:20][C:21]([CH3:27])([CH3:26])[C@@H:22]([OH:25])[C@H:23]([NH2:24])[C:18]=2[CH:17]=1)#[N:15]>CN(C)C=O.C(OCC)(=O)C>[C:14]([C:16]1[CH:29]=[CH:28][C:19]2[O:20][C:21]([CH3:27])([CH3:26])[C@@H:22]([OH:25])[C@H:23]([NH:24][C:4](=[N:3][C:1]#[N:2])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:18]=2[CH:17]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(=NC#N)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)c2ccccc2)[C@@H]1O

Procedure:
1.89 g of ethyl N-cyanobenzimidate was dissolved in 5 ml of dimethylformamide, and 2.15 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added thereto. The mixture was reacted at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed four times with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 1.32 g of the above identified compound in the form of crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=[C:29]([F:28])[CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield from 2-(5-hydroxy-4′-chloro-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) and 3-fluoro-5-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH:26]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1/[CH:26]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 72 %

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (43 g, 0.26 mol) and 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (66 g, 0.26 mol) in methanol (700 mL) was added pyrrolidine (22 g, 0.31 mol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give the title compound as a yellow solid (76 g).
Reaction SMILES: [C:1]1([OH:12])([C:6]2(O)[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:7]1[C:6]2([CH2:2][CH2:3][CH2:4][CH2:5][C:1]2=[O:12])[CH2:10][CH2:9][CH2:8]1
Reactant: OC1(C2(O)CCCC2)CCCC1
Agent: FB(F)F
Solvent: COC(OC)OC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCCCC12CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bi(cyclopentane)-1,1′-diol (5.16 g, 29.4 mmol) in CH2Cl2 (80 mL), cooled to −20° C., was added trimethoxymethane (3.22 mL, 29.4 mmol), followed by boron trifluoride etherate (2.98 mL, 23.52 mmol). The cold bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The mixture was then diluted with CH2Cl2 (100 mL), washed with saturated NaHCO3, dried with MgSO4, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (100% hexane to 15:85 EtOAc/hexane, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.40 (t, 2H), 2.00-2.11 (m, 2 H), 1.78-1.87 (m, 2 H), 1.71 (t, 4H), 1.59 (t, 4H), 1.39 (t, 2 H). MS (DCI+) m/z 153 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:29]1(S(N)(=O)=O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.C(Cl)(=O)C1C=CC=CC=1>>[C:18]1([C:17]([NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH3:20])=[O:19])[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: C[C@H](CCCNC(=O)c1ccccc1)NS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
4-chloro-N-2,5-dichlorophenyl)-N-(4-[[(phenyl)carbonyl]amino]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with benzoyl chloride. Yield=84%; MS (ESI+), 525 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]=1.[C:33]([C:37]1[O:41][N:40]=[C:39]([OH:42])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:33]([C:37]1[O:41][N:40]([C:2]2[CH:3]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[C:39](=[O:42])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CCCCCCCCCCCCCCCCOc1cc(Cl)c([N+](=O)[O-])cc1C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOc1cc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])cc1C(=O)OCC
Yield: 37.9 %

Procedure:
In 300 ml of dimethyl sulfoxide were dissolved 65 g of ethyl 4-chloro-2-hexadecyloxy-5-nitrobenzoate and 24 g of 5-t-butyl-3-hydroxyisoxazole and after adding thereto 24 g of potassium carbonate, the reaction was performed for 8 hours at 75° C. After the reaction was over, the reaction mixture obtained was poured into diluted hydrochloric acid and the product formed was extracted with ethyl acetate. After recovering and drying the organic phase thus formed, the solvent was distilled off from the organic phase and the residue thus formed was carefully applied to silica gel column chromatography, whereby the aforesaid compound was obtained as the main product. The product thus obtained was recrystallized from a mixture of methanol and acetonitrile to provide 30.1 g of the desired compound with a yield of 37.9%. The melting point thereof was 35° C. to 36° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:46])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:14]([C:27]3[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([NH:36][CH3:37])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:47]=[C:48]1[CH2:53][CH2:52][CH2:51][CH2:50][N:49]1[CH2:54][C:55]([OH:57])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH3:46])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:14]([C:27]3[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([N:36]([CH3:37])[C:55](=[O:57])[CH2:54][N:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:48]3=[O:47])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(COCc3ccccc3)C4)n(COCC[Si](C)(C)C)c2c1
Reactant: O=C(O)CN1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(COCc3ccccc3)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (150 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added (2-oxopiperidin-1-yl)acetic acid obtained in Reference Example 6 (43 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27% mmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg). Under a nitrogen atmosphere, to a solution of the obtained N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran (0.8 ml) was added 20% palladium hydroxide-carbon (150 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, yield 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[ClH:14].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: COC(=O)c1ccc(C)c(CN)c1

Procedure:
Methyl 3-(aminomethyl)-4-methylbenzoate hydrochloride was prepared from methyl 3-cyano-4-methylbenzoate in an analogous manner to Intermediate 2.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][N:33]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:34]>>[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][N:33]([C:35]1[CH:36]=[CH:37][C:38]([NH:39]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:40][CH:41]=1)[CH3:34]
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=20:1) C29H32N4O3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].[Cl-].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]#[N:24])=[CH:19][CH:18]=1>O.C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH2:9])[N:5]=[C:6]([NH2:8])[C:7]=1[N:24]=[N:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: N#[N+]c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=Nc2ccc(Cl)cc2)c(Cl)n1
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a suspension of 4-chloro-2,6-diaminopyrimidine (21.68 g, 0.150 mol) in water (750 ml) and acetic acid (750 ml) was added sodium acetate (300 g). Solution occurred after stirring for 20 minutes, and then the solution of 4-chlorobenzenediazonium chloride (0.166 mol) was added with cooling over 30 minutes at a rate that kept the reaction at 18°. The reaction was stirred overnight at room temperature, and the orange crystals were filtered, washed with water (4×400 ml), and dried in vacuo to give 17.6 g of 6-chloro-5-[(4-chlorophenyl)azo]-2,4-pyrimidinediamine. The mother liquors were cooled to 5° for 20 hours, and the crystals were collected and dried in vacuo to give 6.94 g of additional 6-chloro-5-[(4-chlorophenyl)-azo]-2,4-pyrimidineadiamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:56])[N:7]([CH:9]([C:11](=[O:55])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:41](=[O:54])[CH2:42][NH:43]C(OCC3C=CC=CC=3)=O)[CH2:26][CH:27]([C:28](=[O:40])[NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:56])[N:7]([CH:9]([C:11](=[O:55])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:41](=[O:54])[CH2:42][NH2:43])[CH2:26][CH:27]([C:28](=[O:40])[NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:15])([CH3:17])[CH3:16])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CN)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of 59 (430 mg, 0.56 mmol) in 1:1 MeOH/EtOAc (4 mL) was treated with Pd/C (5% wet, ca. 100 mg) and placed under H2 (35 psi) using a Parr apparatus. After 3 h, the reaction mixture was filtered through syringe filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford crude 60 (350 mg) which was concentrated twice from anhydrous toluene (50 mL) and then used without further purification. Mass spectrum, m/z [637.5] (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([I:14])=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[I:14][C:11]1[N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]2=[N:13][CH:12]=1
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccn2c(I)cnc2c1
Yield: 90.3 %

Procedure:
To a suspension of Methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.4 g, 1.32 mmol) in MeOH (6 ml) was added hydrazine hydrate (0.25 ml, 5.28 mmol). The mixture was refluxed for 4 h then further hydrazine hydrate (0.25 ml, 5.28 mmol) was added, the mixture heated o/n, allowed to cool, solid was filtered off and washed with MeOH and dried to afford 0.36 g of product. MS: [M+H]+ 303.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5].[N-:18]=[C:19]=[O:20].[K+]>C(O)(=O)C>[C:19]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])(=[O:20])[NH2:18]
Reactant: [N-]=C=O
Reactant: CCOC(=O)C(NC(=O)CN)C(=O)OCC
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(NC(=O)CNC(N)=O)C(=O)OCC
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To an aqueous solution of diethyl 2-(glycylamino)malonate hydrochloride (2.7 g) is added potassium isocyanate (1.6 g), and the mixture is stirred for 10 minutes. To the reaction mixture is added acetic acid (0.7 ml), and the mixture is further stirred for 5 hours. The reaction mixture is extracted with chloroform, and the extract is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give diethyl 2-(N-carbamoylglycyl)aminomalonate (1.58 g), m.p. 140°-141.5° C.