Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cccc(OCCc2ccccc2)c1

Procedure:
3-Hydroxybenzamide (500 mg; 3.6 mM) was dissolved in dry acetonitrile (36 ml), and to this was added potassium carbonate (0.503 g; 3.6mmol) and 2-(bromoethyl)benzene (0.498 ml; 3.6 mmol). The mixture was heated under reflux for two days. The acetonitrile was removed under reduced pressure to yield a white solid. This was dissolved in water and extracted into dichloromethane (3×30 ml). The organics were pooled, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to yield a white solid. This was recrystallised from boiling ethyl acetate and petrol (0.459 g; 12.51%). MPt: 132-136° C. 1H: 200 MHz CDCl3 3.05 (2H, t, H8); 4.2 (2H, t, H7); 6.00 (1H, br s, NH); 7.04 (1H, m, H4); 7.27 (9H, m, NH; aromatic). IR cm-1 3300 (NH2); 1666 (CO); 2930 (C=C). M/Z (EI); 241 (M+ ; 18%); 105 (--COHN2 ; 100%). Elemental Analysis: Expected % C15H15O2N C: 74.4, H: 6.20, N: 5.79; Found: % C: 74.7, H:6.2, N:5.8.
Reaction SMILES: C([O:9][C:10]1[CH:70]=[CH:69][C:13]([C:14]([O:16][C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:36]C(=O)C4C=CC=CC=4)=[CH:23][C:24]=3[O:27]C(=O)C3C=CC=CC=3)[O:19][C@@H:18]2[C:45]2[CH:50]=[CH:49][C:48]([O:51]C(=O)C3C=CC=CC=3)=[C:47]([O:60]C(=O)C3C=CC=CC=3)[CH:46]=2)=[O:15])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C1COCC1.CO>[OH-].[OH-].[Pd+2].CO.C(Cl)Cl>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:36])=[CH:23][C:24]=3[OH:27])[O:19][C@@H:18]2[C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([OH:60])[CH:46]=2)=[O:15])=[CH:69][CH:70]=1
Reactant: O=C(Oc1ccc(C(=O)O[C@H]2Cc3c(OC(=O)c4ccccc4)cc(OC(=O)c4ccccc4)cc3O[C@@H]2c2ccc(OC(=O)c3ccccc3)c(OC(=O)c3ccccc3)c2)cc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O[C@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1ccc(O)c(O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Under an H2 atmosphere, Pd(OH)2/C (20%, 100 mg) was added to a solution of 102 (200 mg, 0.23 mmol) in a solvent mixture of THF/MeOH (1:1 v/v, 20 mL). The resulting reaction mixture was stirred at r.t. under H2 for 6 h, TLC showed that the reaction was completed. The reaction mixture was filtered to remove the catalyst. The filtrate was evaporated, and the residue was rapidly purified by flash chromatograph on silica gel (10% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2) to afford 11 (82 mg, 87% yield): mp 220-222° C. (decomposed); [α]D=+87.2 (c=2.0, EtOH); 1H NMR (acetone-d6, 400 MHz): δ 7.98 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.99-6.96 (m, 2H), 6.27 (d, J=2.2 Hz, 1H), 6.19 (d, J=2.2 Hz, 1H), 5.62 (dd, J=11.8, 6.3 Hz, 1H), 5.34 (d, J=6.3 Hz), 3.15 (A of ABq, J=16.5, 5.2 Hz, 1H), 3.00 (B of ABq, J=16.5, 6.4 Hz, 1H); 13C NMR (acetone-d6, 400 MHz): δ 163.3, 160.0, 155.2, 154.5, 153.6, 143.1, 129.9, 128.7, 119.6, 116.6, 113.4, 113.3, 111.8, 111.7, 96.7, 93.8, 93.0, 76.2, 67.9, 21.9; HRMS (ESI) calcd for O22H18O8Na (M+Na) 433.0899. found 433.0909.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3]>O.O.O.[Rh](Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]([C@@H:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][C@H:5]1[CH3:12])=[O:3]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: Cl[Rh](Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C

Procedure:
In a 200-ml four-necked flask equipped with a thermometer, condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, ethyl alcohol (40 ml) and rhodium trichloride trihydrate (0.9 g). Under stirring, they were reacted at 90° C. for 24 hours. The reaction mixture at this time was sampled and analyzed by gas chromatography, resulting in that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 11%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 87% and 2%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].O[CH:11]([CH2:23][CH3:24])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH3:20][C:17]([O:16][C:15](=[O:21])[N:14]([CH2:13][CH2:12][CH:11]([O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:23][CH3:24])[CH3:22])([CH3:18])[CH3:19]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.7 %

Procedure:
2,5-Dichlorophenol (325 mg, 2.00 mmol) and (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester (217 mg, 1.00 mmol) were dissolved in tetrahydrofuran (10 ml). To the resulting solution was added triphenylphosphine (393 mg, 1.50 mmol) and then diethyl azodicarboxylate (0.240 ml, 1.52 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted three times with diethyl ether. The combined organic fractions were washed with 1N sodium hydroxide solution twice and then brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 180 mg (50%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([O:22][C:23](=[O:34])[NH:24][CH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(O)C>[CH2:15]([O:22][C:23](=[O:34])[NH:24][CH2:25][CH2:26][C@H:27]1[CH2:28][CH2:29][C@@H:30]([NH:33][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:31][CH2:32]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CCNC(=O)OCc3ccccc3)CC2)nc2ccccc12
Temperature: 170 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (2.45 g, 10.2 mmol) and cis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.3 g, 10.2 mmol) and triethylamine (1.65 mL, 10.2 mmol) in 2-propanol (15 mL) was heated at 170° C. for 45 min using a Smith Microwave Synthesizer. The mixture was concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give cis{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamic acid benzyl ester (4.48 g, 85%) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([CH2:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([CH2:15][CH3:16])=[N:13][N:12]3[C:18]([OH:23])=[CH:19][C:20]([CH3:22])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution of 2.9 g (11.5 mmol) of 4-benzenesulphonyl-5-ethyl-2H-pyrazol-3-ylamine and 1.8 ml (13.8 mmol) of ethyl acetoacetate in 10 ml of acetic acid was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was partitioned between CH2Cl2 and H2O and the aqueous phase was washed three times with 150 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Crystallization from ethyl acetate yielded 2.6 g (71%) of 3-benzenesulphonyl-2-ethyl-5-methyl-pyrazolo[1,5-a]pyrimidin-7-ol as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:5]=2[C:25](O)=[O:26])[CH2:3][CH2:2]1.Cl.Cl.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41][OH:42])[CH2:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:5]=2[C:25]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[CH2:41][OH:42])[CH2:34][CH2:35]2)=[O:26])[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: O=C(O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Agent: Cl
Product: O=C(c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1)N1CCC(N2CCC[C@H]2CO)CC1
Yield: 54 %

Procedure:
In analogy to the procedure described in Example 160E), 5-cyclopropyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 165B]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride (Example 161A]) gave the title compound as a light yellow solid (54%). MS: 539.8 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(Cc2ccc(-c3c[nH]nc3N)cc2)c1

Procedure:
To a solution of 3-amino-2-carbamoyl-4-[4-(3-methylphenylmethyl) phenyl]pyrazole (2.0 g) in methanol (20 ml) was added 5N sodium hydroxide solution (10 ml), and the mixture was refluxed for 4 hours. Methanol was distilled away under reduced pressure. To the residue was added water (100 ml), and the mixture was neutralized (pH 7 to 8) with conc. hydrochloric acid, and extracted with chloroform. The extadt was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:1 followed by chloroform:methanol=10:1) to give a mixture containing the title compound. This mixture was used in the subsequent reaction without isolation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][O:12][C:25]1[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][C:20]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2ccccc2OCc2ccccc2)c(F)c1
Reaction time: 2 h
Yield: 44.2 %

Procedure:
2-(Benzyloxy)benzaldehyde (274 mg, 1.3 mmol) dissolved in methanol (20 mL), sodium borohydride (73 mg, 1.9 mmol) was added thereto, and then the mixture was stirred with ice cooling for 2 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). Ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (200 mg, 0.86 mmol), tributylphosphine (0.23 mL, 1.1 mmol) and azodicarbonyldipiperidine (282 mg, 1.1 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction solution was purified with alumina column chromatography (ethyl acetate) and silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (162 mg, yield 29%) as an oily matter.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:5]=1[C:6]([O:8]CC)=O.C[O-].[Na+].[OH-].[Na+]>CO>[NH2:3][C:4]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:5]=1[C:6]([NH:2][CH3:1])=[O:8]
Reactant: CCOC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Methylamine (117 g, 3.77 mol) is introduced into a solution of ethyl 2-amino-5-cyano-3-methylbenzoate (50 g, 0.251 mol) in methanol (175 mL), sodium methoxide (1.13 g, 30% strength in methanol, 6.28 mmol) is added and the reaction mixture is stirred overnight at room temperature. Thereafter, 100 ml of 22% strength NaOH are added and the batch is cooled down to 10° C. The suspension obtained is filtered and the solid obtained is washed once with 1:1 methanol:water and then with 50 mL of water. The solid is dried at 50° C. in a vacuum drying cabinet. 2-Amino-5-cyano-N,3-dimethylbenzamide is isolated as a slightly beige solid. Yield: 80.3% of theory, purity: 94.9% quantitative LC, 73 ppm Cu).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1/[C:25](=[CH:20]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])/[C:26](=[O:32])[NH:27]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 60.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 49 (40 mg, yield 60.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and 3-fluorobenzyl bromide according to General Procedure B. Yield 113 mg (8%), MP 113° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.90 (m, 4H), 4.33 (q, J=7.2 Hz, 2H), 5.55 (s, 2H), 7.08 (m, 3H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.34 (m, 1H), 7.46 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.17 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 539 (M+1). Anal. (C27H24F2N4O4S) C, H, N.
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)[N:5]=1)([CH3:3])[CH3:2].IC.[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([C:4]1[C:8]([C:9]([O:11][CH3:35])=[O:10])=[CH:7][N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(C(C)C)n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (10.09 g), iodomethane (2 ml), potassium carbonate (4.83 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylate (9.80 g, yield: 94%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 90–91° C.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.Cl[C:31]([O:33][CH3:34])=[O:32]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH3:34])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30.5 g (87.0 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A are dissolved in 30 ml of pyridine. The resulting solution is cooled to 0° C. 8.22 g (87.0 mmol) of methyl chloroformate are added, and the mixture is stirred at 0° C. for a further 2 hours. It is subsequently allowed to warm to room temperature and is stirred for a further 12 hours. After concentration in vacuo, the residue is washed with water and dried. Further purification is effected by stirring in 300 ml of boiling diethyl ether. The precipitated product is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=O)[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:22]([C:24]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:25])[NH2:23].CN(C)C=O>Cl.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18](=[N:23][NH:22][C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[S:25])[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 75.7 %

Procedure:
1-[5-(4-n-Pentylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2381 mmol, HPLC purity 86.3%, 79.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2381 mmol, 50.3 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (86.4 mg, yield 76%).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH3:31])[CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[Si:14]([O:13][CH2:12][C@@H:11]([NH2:10])[CH3:31])([C:27]([CH3:29])([CH3:30])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 83.6 %

Procedure:
A solution of [(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethyl]carbamic acid benzyl ester (6.71 g, 15.0 mmol) (obtained as described in Reference Example 35(1)) in methanol (340 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (6.71 g) at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride→methylene chloride:methanol (85:15) as the eluant to afford (1S)-2-(t-butyldiphenylsilyloxy)-1-methyl-ethylamine (3.93 g, yield 84%) as a pale yellow oil.
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[C:19]([C:24]#[N:25])=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[NH2:25][CH2:24][C:19]1[C:16]2[CH2:17][CH2:18][N:12]([C:10]([O:9][C:5]([CH3:7])([CH3:6])[CH3:8])=[O:11])[CH2:13][CH2:14][C:15]=2[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#N)c2CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CN)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Add borane-methyl sulfide complex (40 mL, 80 mmol, 2M solution in THF) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.79 g, 10.2 mmol) in anhydrous THF (120 mL). Reflux the mixture overnight under nitrogen. Cool the mixture to room temperature and quench with methanol. Add KHSO4 (20 g in water) and stir for 1 h. Remove the organic solvent in vacuo and basify by addition of solid K2CO3. Extract with DCM and wash with brine. Collect the organic layer, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1), DCM and DCM/(chloroform:methanol:concentrated ammonium hydroxide 88:18: 2) (20:1, 10:1 and 5:1) to give the title compound (2.56 g, 81% over 2 steps). MS (ES+) m/z: 311 (M+H)+.