Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[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.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:28])[CH3:29])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
To (S)-tert-butyl (4-(benzylamino)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)carbamate (8.0 g, 15.0 mmol) in MeOH (100 mL) was added ammonium formate (9.47 g, 150 mmol) and Pd(OH)2 (1.054 g, 1.502 mmol). The reaction mixture was stirred at 70° C. for 1.5 h then cooled to rt and filtered through a celite, eluting with MeOH/EtOAc (1:2, ˜800 mL). The filtrate was concentrated in vacuo to afford the title compound (7 g) of a light brown residue which was used as such without further purification. LCMS: Rt=0.95 min, m/z=443.2 (M+1) Method 2m_acidic.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:36]([O:35][C:34](=[O:40])[NH:33][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:24][CH:25]=1)=[O:18])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)pyridin-2-yl)-1-(4-(4-(hydroxyamino)-4-oxobutyl)phenylamino)-1-oxopropan-2-ylcarbamate (0.1 g, 0.19 mmol) and 10 mg of 10% Pd/C in 2 mL of methanol was vigorously stirred under H2 for 4 h at room temperature (monitored by TLC). It was filtered through Celite. The solvent was evaporated. The residue was purified by chromatography to give Compound 4 (0.09 g, 89%). Mp: 166-167° C.; NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.31 (s, 9H, Boc), 1.75 (m, 2H, CH2), 1.93 (t, 1H, CH2, J=7.10 Hz), 2.52 (t, 2H, CH2, J=7.10 Hz), 2.94 (m, 2H, CH2), 4.41 (m, 1H, CH), 6.94 (d, 1H, Ar—H, J=7.99 Hz), 7.05 (m, 1H, Ar—H), 7.08 (d, 2H, Ar—H, J=7.88 Hz), 7.21 (m, 1H, Ar—H), 7.46 (d, 2H, Ar—H, J=8.15 Hz), 8.03 (br, 1H, NH), 9.88 (br, 1H, NH), 10.32 (br, 1H, OH).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[S:16](=[O:19])(=[O:18])[NH2:17].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>O>[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[S:16](=[O:19])(=[O:18])[NH2:17])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)N2CCOCC2)ccc1Cl
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)N3CCOCC3)cc2S(N)(=O)=O)CC1

Procedure:
183 Grams of 4-chloro-3-sulfamoylbenzoic acid-morpholide (0.6 mole) were stirred with 0.3 l of N-methylpiperazine for 3 hours at 130° C. Subsequently the excess base was eliminated in vacuo, the residue was dissolved in 0.5 l of water, and the pH of the solution was adjusted to 7 by means of 5N HCl. After having stood in the refrigerator for several days, the reaction product which had separated in a crystalline form was suction-filtered and was recrystallized from ethanol of 90% strength.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39](OC2C=CC([N+]([O-])=O)=CC=2)=[O:40])=[CH:13][CH:12]=1)#[N:10].O>O1CCCC1>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:19](=[O:38])[N:18]2[C:39]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[O:40])=[CH:15][CH:16]=1)#[N:10]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) in dry tetrahydrofuran (1 mL) is cooled at −78° C. and treated with sodium hydride (60% in mineral oil, 5 mg, 0.11 mmol). After 20 min, a solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 60 mg, 0.10 mmol) in tetrahydrofuran (1 mL) is added and the mixture is stirred for 5 h at room temperature. Another portion of 2,2-dimethyl-1-propanol (9 mg, 0.10 mmol) is added and the mixture is stirred over night. Another portion of 2,2-dimethyl-1-propanol (18 mg, 0.20 mmol) is added and the mixture is heated at 50° C. for 2 h. Water is added and the mixture is extracted with dichlormethane. The organic layer is concentrated under reduced it) pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane to cyclohexane/ethyl acetate 1:1). Yield: 12 mg; ESI mass spectrum [M+H]+=526; Retention time HPLC: 0.76 min (X012_S01).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[Cl:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Cl:20][CH2:21][CH2:22][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:11][CH:10]=2)=[CH:14][CH:15]=1
Reactant: ClCCBr
Reactant: Oc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: ClCCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 98.3 %

Procedure:
A solution of 4-[[4-(2-oxazol yl)phenyl]methyl]phenol (2.2 g, 8.75 mmol) and 2-chloroethylbromide (10 g, 70 mmol) in acetonitrile as stirred as cesium carbonate (22.8 g, 70 mmol) was added. The reaction was heated at reflux for 3 days. The reaction was diluted with water. The product, 2-[4-[[4-(2-chloroethoxy)phenyl]methyl]phenyl]oxazole (2.7 g), was isolated by filtration, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.35 (m, 2H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 4.22 (t, 2H), 3.96 (s, 2H), 3.79 (t, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[C:13]=2[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.CC(C)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2ccc(OCc3ccccc3)c3sc4ccccc4c(=O)c23)cc1
Agent: B
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(OCc3ccccc3)c3c2Cc2ccccc2S3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) suspension of 4-benzyloxy-1-(4-methoxy-benzylamino)-thioxanthen-9-one (8.16 g, 18.00 mmol) in dry THF (150 ml) was added Borane-THF complex (90 mmol, 90 ml 1M in THF) in a dropwise fashion. The reaction was allowed to slowly warm to room temperature and stirred for a further 16 hours to give a homogeneous yellow solution. To mixture was then cooled (0° C.) and diluted slowly with acetone (150 ml) and then stirred for 60 minutes at room temperature. The solvent was removed in vacuo to give a crude residue that was diluted in CH2Cl2 (100 ml) and the washed with a saturated solution of NaHCO3 (100 ml), dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a mild amber oil (7.90 g, 99.8%) m/z (LC-MS, ESP): 438 [M+H]+, R/T=5.01 mins.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=O)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C(O)C.O>N1C=CC=CC=1>[CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=[S:18])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1NC2=S
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-one (21 g, 0.09 mol) and phosphorus pentasulfide (53 g, 0.12 mol) in pyridine (350 mL) and stir at room temperature overnight, heat at reflux for 5 h. Cool to room temperature to allow precipitate to settle, collect solid by filtration, wash cake with cold ethanol/water and air-dry for a few minutes to obtain 29 g of crude material. Take up solid in a small amount of pyridine, add a like volume of ethanol/water, sonicate for a few minutes and collect again by filtration. Air-dry cake, then place in the vacuum oven at 40° C. for 48 h to obtain 15.9 g of the title compound as an orange solid, which was used directly on the next step without further purification: melting point: 259.0-259.5° C.; Mass spectrum (APCI): m/z=247.0 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>CO.CCOC(C)=O>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([C@@H:26]3[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]3)[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC(=O)CC3)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn([C@H]3CC[C@@H](O)CC3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (3.39 mg, 0.09 mmol) was added to 4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanone (24.8 mg, 0.06 mmol) dissolved in methanol (0.5 mL). The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 80% ACN/Water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford cis-4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanol. MS ESI calcd. for C21H23F3N5O [M+F]+ 418. found 418. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.05 (s, 1H), 4.67 (s, 1H), 4.19-4.07 (m, 1H), 3.50-3.41 (m, 1H), 2.27 (s, 3H), 2.02-1.99 (m, 2H), 1.94-1.85 (m, 2H), 1.78 (q, J=11.7 Hz, 2H), 1.35 (q, J=11.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:16])[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:16])[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=c1c2cccc(Cl)c2oc2c(Cl)c(O)ccc12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3cccc(Cl)c3oc2c1Cl
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 4,5-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) was stirred at 60°-65° C. for 4 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.5 g of 4,5-dichloro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 283°-286° C. This compound gave a mass spectrum having a molecular ion peak at m/e 338.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)#[N:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:31]5[CH:30]=[C:29]([C:27]#[N:28])[CH:34]=[CH:33][C:32]=5[F:38])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(C#N)ccc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-cyano-2-fluoro-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.84 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1>C(O)=O>[O:2]=[CH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: COC=CC1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCCC(CC=O)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 59.6 %

Procedure:
tert-Butyl 3-(2-methoxyethenyl)-1-piperidinecarboxylate (1.16 g, 4.81 mmol) was dissolved in 90% formic acid (2 mL). The mixture was stirred at room temperature for 40 min. The mixture was then partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. Purification by column chromatography (hexane/ethyl acetate=4/1) gave tert-butyl 3-(2-oxoethyl)-1-piperidinecarboxylate as a colorless oil (652 mg, yield; 60%).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC1)O2
Yield: 51 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-nitrobenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 51%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1F)[O:15][CH2:14][CH2:13][CH:12]2[C:20]([O:22][CH3:23])=[O:21])#[N:8].[OH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][C:26]=1[CH3:38].Cl>CN1C(=O)CCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=1[CH3:38])[O:15][CH2:14][CH2:13][CH:12]2[C:20]([O:22][CH3:23])=[O:21])#[N:8]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1O
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Temperature: 120 °C

Procedure:
A mixture of K2CO3 (0.026 g, 0.19 mmol), methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (0.040 g, 0.17 mmol), and tert-butyl 4-hydroxy-3-methylbenzoate (0.039 g, 0.19 mmol) in 0.5 ml NMP was heated under argon at 120° C. for 24 hours. The reaction was cooled, poured into 10% aqueous HCl, and extracted with ethyl acetate. The organic extracts were dried with sodium sulfate and purified on silica gel. Elution with 25% ethyl acetate-hexanes provided material that still contained impurities. The mixture was deprotected with to 1:1 trifluoracetic acid-dichloromethane to provide the title compound (13 mg, still impure) which was used directly in the next step.
Reaction SMILES: CC([N:5]([C@@H:9]([C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:21][CH:22]=1)=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:11][C:10]([CH3:13])([CH3:12])[C@H:9]([C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:21][CH:22]=1)=[O:15])[NH2:5]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N(C(=O)[O-])C(C)(C)C)C(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-2,2-dimethyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 96, 8.2 mg) in dry dichloromethane (0.5 mL) cooled to 0° C., TFA (57 μl, 0.740 mmol) was added dropwise and the solution was stirred for 3 hours at that temperature. The volatiles were evaporated. The residue was dissolved with dichloromethane (2 mL) and an aqueous saturated solution of NaHCO3 was added (4 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The gathered organic layers were dried over sodium sulphate and evaporated to afford the title compound (6.2 mg).
Reaction SMILES: O[Li].O.[OH:4][C:5]1[C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8]=[CH:7][N:6]=1>O.O1CCCC1>[OH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cncnc1O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncnc1O
Reaction time: 0.75 h

Procedure:
The moist sodium salt of methyl 4-hydroxypyrimidine-5-carboxylate obtained as in Example 2a) was taken up in water/tetrahydrofuran=1:1, and 1.0 eq of LiOH.H2O was added. Following hydrolysis of the ester over 3.5 hours at 0° C. and 2 hours at room temperature, most of the tetrahydrofuran was evaporated and, at 0° C., a pH of 3 was adjusted using eq. HCl solution. After about 45 minutes at 0° C., the title product was filtered off. Drying gave the acid in a yield of 3.55 g (78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][CH:11]=[C:12](I)[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]#[N:16])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2nc(I)c[nH]2)cc1Cl
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2cnc(-c3ccc(Cl)c(Cl)c3)[nH]2)c1
Yield: 8.9 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-4-iodo-1H-imidazole (1.69 g, 5 mmol) and palladium tetrakis(triphenylphosphine) (0.29 g, 0.25 mmol) in toluene (25 ml) was stirred at r.t. for 15 min. 3-cyanophenylboronic acid (0.74 g, 5 mmol) and 2M K2CO3 solution (5 ml) was then added and the resulting mixture refluxed for 24 h. EtOAc (200 ml) was added and the organic phase was dried (Na2SO4), solvent eaporated and the residue chromatographed over SiO2 with EtOAc-hexane=1:1 to give 3-[2-(3,4-dichloro-phenyl)-3H-imidazol-4-yl]-benzonitrile (0.14 g, 9%) as a colorless mass. MS: m/e=313 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:29]1([C:35]2[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:38]3[CH:39]=[N:40][C:35]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:36][CH:37]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and [6-(4-morpholinyl)-3-pyridinyl]boronic acid (70 mg, 0.337 mmol). The final product was collected as a white solid (98 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (br. s., 1H) 8.68 (d, J=2.53 Hz, 2H) 8.37 (s, 1H) 8.07-8.12 (m, 2H) 7.84 (d, J=1.01 Hz, 1H) 6.98 (d, J=8.84 Hz, 1H) 5.91 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (d, J=4.80 Hz, 2H) 3.71-3.76 (m, 4H) 3.50-3.56 (m, 4H) 2.52-2.56 (m, 2H) 2.13 (s, 3H) 1.51-1.58 (m, 2H) 1.51 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=529.0 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:17]=[C:12]2[CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])C=C>>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])[C:13]3=[N:14][C:15]=2[C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1
Reactant: C=CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: C=CC(=O)OCC
Product: CCOC(=O)/C=C/CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
The title compound was prepared from 5-(hept-6-enyl)-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (step 1) and ethyl acrylate analogously to (E)-Methyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)hept-3-enoate (Example 10.1 step 2).