Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.CCCCCCC.[C:17](OCC)(=[O:19])C>ClC(OC(Cl)(Cl)Cl)=O>[O:1]1[CH:5]=[C:4]([C:6]2[O:7][C:17](=[O:19])[NH:9][N:8]=2)[N:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: NNC(=O)c1cocn1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: O=c1[nH]nc(-c2cocn2)o1

Procedure:
After suspending oxazole-4-carboxylic acid hydrazide (CAS 885274-12-4) (1.06 g) in ethyl acetate (10 ml), trichloromethyl chloroformate (1.21 ml) was added dropwise while stirring on ice. Upon completion of the dropwise addition, the mixture was heated to reflux for 2 hours and 20 minutes. It was then allowed to cool, n-heptane was added to the reaction mixture, and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure and the residue was recrystallized with toluene-ethyl acetate. This was combined with the previously filtered substance to obtain the title compound (1.38 g).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:3].[C-:14]#[N:15].[Na+]>CS(C)=O>[C:14]([CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:3])#[N:15]
Reactant: CC(C)Cc1ccccc1C(C)Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Cc1ccccc1C(C)C#N
Temperature: 80 °C

Procedure:
Crude 1-chloro-1-(isobutylphenyl)ethane containing 47g of 1-chloro-1-(isobutylphenyl)ethane was added to a mixture of 17g of sodium cyanide in 126g of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 80° C. with agitation for 10 hours, after which the DMSO and inorganic salts were removed by water washing to yield 1-cyano-1-(isobutylphenyl)ethane. The crude nitrile was reacted with excess 50% sodium hydroxide at 135.C for four hours to form the sodium salt of 2-(isobutylphenyl)propionic acid, which was then acidified and crystallized from hexane at -10.C. The para/ortho ratio of the resultant 2-(isobutylphenyl)propionic acid in hexane solution was approximately 200/1.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[OH:36])=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3O)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (45 mg, yield 93%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[N:31](COCC[Si](C)(C)C)[C:30]3=[O:46])[CH2:25][CH2:24]2)=[O:22])[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:47]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH2:47][C@@H:10]1[C:11]2=[N:16][CH:15]=[CH:14][N:13]=[C:12]2[C@H:17]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:46])[CH2:27][CH2:28]2)=[O:22])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](NC(=O)N2CCC(n3c(=O)n(COCC[Si](C)(C)C)c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2nccnc2[C@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
In a 50 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(4-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamido)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (31 mg, 0.041 mmol) in methylene chloride (1 mL) to give a colorless solution. trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h: LCMS showed complete conversion. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (12 mg, 55%) as a white solid: MS (ESI) [M+H]+=535.3; 1H NMR (400 MHz, CDCl3) δ 10.98-9.87 (m, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.07 (dd, J=5.3, 1.2 Hz, 1H), 7.35 (dd, J=7.9, 1.2 Hz, 1H), 7.21-7.05 (m, 4H), 6.98 (dd, J=7.9, 5.3 Hz, 1H), 5.29 (dd, J=10.4, 5.1 Hz, 1H), 4.71-4.55 (m, 2H), 4.35 (d, J=13.6 Hz, 2H), 3.05 (1, J=13.0 Hz, 2H), 2.94 (t, J=9.3 Hz, 1H), 2.53 (t, J=11.7 Hz, 2H), 2.41-2.23 (m, 2H), 2.16-1.69 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −137.32 (ddd, J=21.4, 9.6, 4.5 Hz), −142.66 (d, J=19.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:41]=[CH:40][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:29][CH3:30])[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:42]>O1CCOCC1>[ClH:42].[NH2:31][C@@H:28]([CH2:29][CH3:30])[C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]2[S:20][C:16]3[CH:15]=[C:14]([C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[O:13])[CH:41]=[CH:40][C:17]=3[N:18]=2)[CH2:22][CH2:23]1)=[O:39]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2nc3ccc(C(=O)Nc4ccc(OC)c(OC)c4)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)C(=O)N1CCN(c2nc3ccc(C(=O)Nc4ccc(OC)c(OC)c4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The (S)-tert-butyl 1-(4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxobutan-2-ylcarbamate (142.8 mg, 0.245 mmol) was dissolved in p-dioxane (3 mL), treated with 4N hydrogen chloride in 1,4-dioxane (3 mL, 12.0 mmol) and the resulting mixture was stirred at room temperature for 5.5 h. The resulting heterogenous mixture was concentrated under high vacuum, then covered with diethyl ether and placed under high vacuum for 2 d to yield the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCCCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 62 %

Procedure:
A mixture of 4.8 g of the product of Step B, 50 ml of ethyl acetate, 1 ml of quinoline, 1 g of 10% palladium hydroxide on barium sulfate in 50 ml of ethyl acetate was hydrogenated and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 70-30-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 3 g of (1R,cis) 2,2-dimethyl-3-[Z-2-(pentyloxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[NH2:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:34]
Reactant: Cc1ccc(CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)c2ccc(C)c(C)c2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(CCN(C(=O)[C@@H](N)c2ccccc2)c2ccc(C)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 50 mg (0.11 mmol) ((S)-{(3,4-dimethyl-phenyl)-[2-(5-methyl-pyridin-2-yl)-ethyl]-carbamoyl}-phenyl-methyl)-carbamic acid tert-butyl ester in 0.2 mL dioxane was added 265 uL (1.06 mmol) of a 4 M HCl solution in dioxane. The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo. Ethylacetate was added and the mixture was stirred slowly at ambient temperature. The solid was filtered, rinsed with ether and dried under vacum to provide 0.044 g (94%) of the title compound as a light yellow solid MS (m/e): 374.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:25])[CH2:10][C:11]2[CH:12]=[C:13]([P:17](=[O:24])([O:21]CC)[O:18]CC)[CH:14]=[CH:15][CH:16]=2)=[CH:6][N:5]=[C:4]([C:26]2[N:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]([NH:8][C:9](=[O:25])[CH2:10][C:11]2[CH:12]=[C:13]([P:17](=[O:18])([OH:24])[OH:21])[CH:14]=[CH:15][CH:16]=2)=[CH:6][N:5]=[C:4]([C:26]2[N:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1cccc(CC(=O)Nc2cnc(-c3cccnn3)nc2O)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(Cc1cccc(P(=O)(O)O)c1)Nc1cnc(-c2cccnn2)nc1O
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A solution of diethyl 3-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidin-5-ylamino)-2-oxoethyl)phenyl-phosphonate (35i, 280 mg, 0.63 mmol) in DCM (20 mL) was added with TMSBr (1.9 g, 12.6 mmol) and stirred at 30° C. for overnight. The reaction mixture was concentrated in vacuum. The residue was added with MeOH (50 mL), stirred for 20 min, and concentrated. The residue was added with water (20 mL) and MeCN (0.5 mL). The solids were filtered to afford the pure product, 35-1, as a white solid (70 mg, 29%). 1H NMR (300 MHz, DMSO) δ 3.9 (s, 2H), 7.39-7.58 (m, 3H), 7.70 (d, J=12.9 Hz, 1H), 7.93 (m, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.86 (m, 1H), 9.40 (d, J=4.2 Hz, 1H), 9.84 (m, 1H), LC-MS (M+H)+ 388.1
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[S:32]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[N:33]1>>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:37]([C:34]5[CH:35]=[CH:36][S:32][N:33]=5)=[O:38])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: O=C(O)c1ccsn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccsn3)C4)n[nH]c2c1
Yield: 19.7 %

Procedure:
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and isothiazole-3-carboxylic acid (11 mg, 80 μmol) using the same method as described in Example 1. The crude material was purified by HPLC Method A to afford 7.7 mg of the title compound.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][C@H:28]1[N:32]([CH3:33])[C:31](=[O:34])[CH2:30][CH2:29]1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C@H:28]1[N:32]([CH3:33])[C:31](=[O:34])[CH2:30][CH2:29]1
Reactant: CN1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Bu4NF (1 mol THF solution, 17.5 ml, 17.5 mmols) was added to a THF (100 ml) solution of the (5S)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (3.84 g, 15.8 mmols), and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 150 g, MeOH—CHCl3 1:9 v/v) to obtain (5S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one as a mixture (2.46 g) with inseparable impurities.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[N:34]1N[N:36]=[C:37]([CH2:39][OH:40])[CH:38]=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:36]=[C:37]([CH2:39][OH:40])[CH:38]=[N:34]3)[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: OCc1cn[nH]n1
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (Step AA4) by replacing di-t-butyliminodicarboxylate (Step AA3) with (2H-[1,2,3]triazol-4-yl)-methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([NH:31][C@@H:32]([C:35]([OH:37])=O)[CH2:33][OH:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.[NH3:47]>>[NH2:47][C:35](=[O:37])[C@H:32]([NH:31][C:29](=[O:30])[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:45][CH3:46])([CH3:44])[CH3:43])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH2:33][OH:34]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(=O)O)c1)C(F)(F)F
Reactant: N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-D-serine and ammonia.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C1(NC(C2C=CC(N3C(=O)CC(=O)NC4C5C(C=CC3=4)=CC=CC=5)=CC=2)=O)C=CC=CC=1>>[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:14]([C:13]1[CH:17]=[CH:18][C:10]([N:6]2[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]3[C:26]4[C:21]([CH:20]=[CH:19][C:5]2=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:11][CH:12]=1)=[O:15]
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: Nc1ccccc1Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 15 %

Procedure:
By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and 2-chloroaniline, the title compound (yield 15%) was obtained in the same manner as that of Example 102, (5).
Reaction SMILES: O[C:2]1([C:8]2[N:9]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=3)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[O:5]1[CH2:6][CH2:7][C:2]([C:8]2[N:9]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=3)=[CH:3][CH2:4]1
Reactant: CSc1ccc2c(c1)cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CSc1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Yield: 90.4 %

Procedure:
To a solution of the compound obtained in Example 14 (1) (39 mg) in benzene (10 ml), p-toluenesulfonic acid monohydrate (3.7 mg) was added and the mixture was heated under reflux for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 33.7 mg of the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:31]>P(Cl)(Cl)(Cl)=O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:31])=[N:7][C:2]=3[N:1]=2)=[CH:16][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Yield: 30.2 %

Procedure:
The above N-(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide (1.0 g, 0.0025 mol) and phosphorous pentachloride (0.64 g, 0.0025 mol) were taken in phosphorous oxy chloride (25 ml) and refluxed for 20 hours The mixture was cooled and solvent was removed. The residue was dissolved in water (20 ml) and extracted with DCM. (3×5 ml). The organic layer was washed with sat. NaHCO3 (30 ml) followed by saturated brine solution (2×30 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 30%) as a yellow solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[C:25]([CH3:33])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH3:35].CC[O-].[Na+].[Na]>C(O)C.CN(C)C=O>[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:5][C:4]1[C:25]([CH3:33])=[C:26]([CH3:32])[C:27]([O:30][CH3:31])=[C:28]([CH3:29])[C:3]=1[Cl:2])[CH3:35]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: COc1c(C)c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(C)c(OC)c(C)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
9.9 g. of 2-chloro-4-methoxy-3,5,6-trimethyl-benzyl-triphenylphosphonium chloride are dissolved in 50 ml. of dimethylformamide. After the addition of 4.16 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester, the solution is treated dropwise at 20° C. with 10 ml. of a solution of sodium ethylate freshly prepared from 0.460 g. of sodium and 10 ml. of absolute ethanol. The mixture is stirred at room temperature for 12 hours, then introduced into 100 ml. of water and extracted with hexane. The hexane extract is shaken out three times with methanol/water, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by absorption on silica gel using methylene chloride/hexane (8:2 parts by volume) for the elution. The 9-(2-chloro-4-methoxy-3,5,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester obtained from the eluate melts at 90° C. after recrystallisation from hexane.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH:17]=[O:18])=[CH:11][NH:12]2.I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH:17]=[O:18])=[CH:11][N:12]2[CH:20]([CH3:22])[CH3:21]
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
Cesium carbonate (873 mg, 12.68 mmol) was added to a solution of 4-bromo-1H-indole-3-carboxaldehyde (200 mg, 0.893 mmol) in DMF (2.0 mL) and the mixture was stirred at room temperature for 10 minutes. Then 2-iodopropane (0.179 ml, 1.785 mmol) was added and the solution was stirred for 80° C. for 2 hours. The solution was cooled to room temperature and then partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic layers were washed twice with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title intermediate (175 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:39]=[C:22]3[CH:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=4)[CH2:24][CH2:25][CH2:26][N:21]3[N:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.C(OCC)(=O)C>CO.[Cl-].[Na+].O>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:39]=[C:22]3[CH:23]([C:27]4[CH:28]=[CH:29][C:30]([CH:33]([OH:38])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:31][CH:32]=4)[CH2:24][CH2:25][CH2:26][N:21]3[N:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: CCCCC(=O)c1ccc(C2CCCn3nc(/C=C/c4ccc(-n5cnc(C)c5)c(OC)c4)nc32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(O)c1ccc(C2CCCn3nc(/C=C/c4ccc(-n5cnc(C)c5)c(OC)c4)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Sodium tetrahydroborate (0.166 mg) was added to a solution of (−)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one obtained in Example 3 (2 mg) in methanol (0.5 mL), and the reaction solution was stirred in a nitrogen atmosphere at room temperature for one hour. Brine and ethyl acetate were added to the reaction solution and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 1.19 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([C:32](=[O:34])[CH3:33])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(Cc3ccccc3F)c2C1
Yield: 12 %

Procedure:
1-(4-(2-Fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12 mg, 12%) was prepared from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 457 (M+H)+