Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=1>CO.[Pt](=O)=O>[NH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([CH:8]2[C:9]3=[N:10][NH:11][C:12](=[O:20])[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:18]=43)[NH:19][CH:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:22]1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2c1cccnc1
Agent: O=[Pt]=O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2C1CCCNC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 3.3 %

Procedure:
A suspension of 8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol) and platinum (IV) oxide (60 mg) in methanol (20 mL) was purged in 20 atm hydrogen and stirred at 50° C. for 24 hr. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (4 mg, yield: 4%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) 1.19-1.32 (m, 2H), 1.60-1.65 (m, 2H), 1.94-1.97 (d, J=10.0 Hz, 1H), 2.31-2.43 (m, 2H), 2.82-2.85 (d, J=12.4 Hz, 1H), 3.02-3.05 (d, J=12 Hz, 1H), 3.29-3.32 (dd, J1=2.8 Hz, J2=8.4 Hz, 1H), 4.25-4.26 (d, J=2.8 Hz, 1H), 7.02-7.05 (dd, J1=0.8 Hz, J2=8.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.40-7.53 (m, 3H), 8.25-8.29 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([N:15]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]4[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:30]1[CH:31]=[C:32]([C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[N:37]=2)[CH:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[C:41]1([N:40]2[C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[N:37]=[C:36]2[C:32]2[CH:31]=[C:30]([C:13]3[CH:12]=[C:11]([N:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22]5[C:27]4=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:10]=[CH:9][CH:14]=3)[CH:35]=[N:34][CH:33]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-n2c(-c3cncc(-c4cccc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 80 °C
Yield: 56 %

Procedure:
A mixture of compound 1C (3.0 g, 8.15 mmol), compound 1F (2.85 g, 8.15 mmol), tetrakistriphenylphosphine palladium (471 mg, 0.408 mmol), and sodium carbonate (3.09 g, 29.2 mmol) in tetrahydrofuran (THF)/water (50 mL/30 mL) was degassed for about 45 minutes. The mixture then heated to reflux (about 80° C.) overnight under argon. After cooling to RT, the reaction mixture was poured into DCM (300 mL) then washed with saturated sodium bicarbonate (200 mL), water (200 mL), and brine (200 mL). The organic phase was then collected, dried over magnesium sulfate, and loaded onto silica gel. A flash column (gradient of 25% to 40% ethyl acetate in DCM) and precipitation from ethyl acetate/methanol gave 2.34 g of HTH-1; 56% yield, pure by HNMR.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[NH3:13].CO>O>[CH:11]([N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:13])=[CH2:12]
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: N
Solvent: O
Solvent: CO
Product: C=Cn1cnc2c(N)ncnc21
Temperature: 50 °C

Procedure:
6-Chloro-9-vinylpurine (0.48 g, 3 mmol) was added to saturated ammonia/methanol (20 mL) and the mixture was heated at 50° C. for 15 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:28])[C:14]=3[NH:18][C:19](=[O:27])[CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:3]1.[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:28][C:13]1[C:14]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:3]1)[CH:17]=[CH:16]2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: N[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a), using N-[2-[(3S)-3-amino-1-piperidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 60) (200 mg), (tert-butyldimethylsilyloxy)acetaldehyde (0.086 mL) and sodium triacetoxyborohydride (0.212 g) to afford the sub-title compound (0.2 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br>>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCCCCBr
Reactant: NC1CCC(O)CC1
Product: OC1CCC(N2CCCC2)CC1

Procedure:
Prepared from 4-amino-cyclohexanol and 1,4-dibromo-butane.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3Cl)nc1)CCO2
Yield: 59.8 %

Procedure:
Similarly, (2-chlorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (164) (13.1 mg, yield: 59.8%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) and 2-chlorobenzoyl chloride (23 μl).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[N:2]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>>[Cl:19][C:18]1[C:13]([O:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: Oc1cc2ccccc2cn1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cnc(Oc2cc3ccccc3cn2)c(Cl)c1

Procedure:
Isoquinolin-3-ol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 3-(3-chloro-5-nitropyridin-2-yloxy)isoquinoline which was further converted to 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine as per the procedure described in preparation 1, step iii and iv.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH:3]=1>CC(O)C.[Pd].CCCCCC>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)C1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@@H]1CC(=O)C[C@H](C)C1
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A solution of 3,5-dimethyl-2-cyclohexenone (2.0 g, 16.1 mmol) in 2-propanol (32 ml) was hydrogenated over 5% palladium on charcoal (200 mg) at room temperature and 103 kPa (14.7 psi) for 4 hours, then diluted with 1:1 hexane:ether (150 ml) and filtered using a filter aid. The filtrate was evaporated under reduced pressure to provided the substantially stereochemically pure title compound (1.56 g) as a yellow oil. 13C NMR spectroscopy revealed a cis:trans ratio of 150:3.
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:23]1[N:24]=[C:25]([S:31][CH3:32])[N:26]=[N:27][C:28]=1[C:29]#[N:30]>C(O)C>[CH3:32][S:31][C:25]1[N:26]=[N:27][C:28]([C:29]#[N:30])=[C:23]([N:4]2[CH2:3][CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5]2)[N:24]=1
Reactant: CSc1nnc(C#N)c(Cl)n1
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of 395 mg (2.7 mmol) of 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride [J. Heterocycl. Chem. 1971, 8(5), 779-83] in 5 ml of ethanol was treated at room temperature with 0.92 ml (5.4 mmol) of Huenig's base and, thereupon, with a solution of 501 mg (2.7 mmol) of crude 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile in 5 ml of ethanol. The dark brown reaction mixture was stirred during 18 h at room temperature. For the working-up, the product, partially precipitated in pure form, was filtered and the resulting mother liquor evaporated under reduced pressure. The residue was chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent. In total, 470 mg (58.5% of theory) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile were obtained in the form of a beige powder; MS: 298 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH:12](C)[CH2:13][CH2:14][N:15]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:23]=3)[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-].O.Cl.[CH2:39]1COCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:39])[CH2:12][CH2:13][CH2:14][N:15]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:23]=3)[CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CN(CCC(C)NCc1ccc2c(c1)OCO2)c1cc(C)nc(-n2ccnc2)n1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N(CCCN(C)Cc2ccc3c(c2)OCO3)CC(=O)O)nc(-n2ccnc2)n1
Reaction time: 16 h

Procedure:
To 2-[[3-[(1,3-benzodioxol-5-ylmethyl)amino](methyl)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, ethyl ester (2.2 g, 4.6 mmol) (a compound of formula (Yc10)) dissolved in THF (50 mL) was added LiOH (0.34 g, 8.1 mmol) and water (10 mL). After stirring for 16 hours, the solvent was removed in vacuo and 1 N HCl (8.1 mL, 8.1 mmol) was added. The solvent was removed in vacuo to give 2-[[3-[(1,3-benzodioxol-5-ylmethyl)(methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, a compound of formula (Yc11).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]([CH:22]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([CH:38]2[O:42][N:41]=[C:40]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:39]2)=[O:37])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C(=O)OC(C)(C)C)=O)C>C(Cl)Cl>[NH2:14][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([CH:38]2[O:42][N:41]=[C:40]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:39]2)=[O:37])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
) Trifluoroacetic acid (50 ml) was added dropwise to a solution of compound (125) (0.037 mol) in CH2Cl2 (500 ml), stirred at RT. The reaction mixture was stirred overnight at RT. The solvent was evaporated under reduced pressure. Toluene was added and azeotroped on the rotary evaporator (2×). The residue (crude oil) was dissolved in CH2Cl2. The organic solution was washed with 1 N NaOH (2×), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc, filtered off, washed with EtOAc, then dried, yielding 7.4 g (54%) of (±)-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 126)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:34]([NH:33][CH2:31][CH3:32])=[S:35])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: CCN=C=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 34.6 %

Procedure:
188 mg (0.5 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 326 mg (1 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.1 ml (1.1 mmol) of ethyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid and extracted three times with 10 ml of dichloromethane each time. The combined organic phases were washed with water until neutral, dried over sodium sulfate and filtered after addition of activated carbon. The crude product obtained after removal of the solvent was recrystallized from methanol/water. 80 mg (35%) of the title compound were obtained as a colorless solid.
Reaction SMILES: C(O[C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH2:6]1)C=C.I([O-])(=O)(=O)=O.[Na+].[C:32]([O:36]C)(C)(C)[CH3:33]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][C@@H:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([CH2:33][CH:32]=[O:36])[CH2:6]3)[N:14]=2)=[CH:24][CH:23]=1
Reactant: C=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1
Reactant: COC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](CC=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyl-oxazole are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 hours, 100 ml of methyl tert-butyl ether are added, and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5). This gives 1.4 g of [cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde as a colorless oil. C20H25NO4 (343.42), MS (ESI): 344 (M+H+), Rf(n-heptane:ethylacetate=1:1)=0.25.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[S:21]1[C:25]2([CH2:29][C@@H:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[NH:27][CH2:26]2)[S:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:17])[C:18]([N:27]1[C@H:28]([C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:29][C:25]2([S:21][CH2:22][CH2:23][S:24]2)[CH2:26]1)=[O:20])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1)SCCS2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2

Procedure:
To a cold (0°) solution of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine (720 mg., 2.57 mmole) and (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester, p-toluenesulfonate (1.06 g., 1.1 eq.) in 8 ml. of dry dimethylformamide under argon is added dropwise a solution of 0.61 ml. (1.1 eq.) of diphenylphosphoryl azide in 1 ml. of dimethylformamide. The reaction mixture is worked up according to the procedure of Example 95(f) to yield (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].N1C=CN=C1>CN(C)C=O>[Si:1]([O:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
Tert-butyldimethylsilyl chloride (22.5 g) was added to a mixture of 3-hydroxypropiophenone (18.7 g), imidazole (21.3 g) and dimethylformamide (100 ml) and the solution was stirred at ambient temperature for 6 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with an aqueous sodium chloride solution, dried (Na2SO4) and evaporated. Petrol (b.p. 60°-80° C., 250 ml) was added to the residue, the resulting mixture was filtered and the filtrate was evaporated to give 3-(tert-butyldimethylsilyloxy)propiophenone as a pale yellow oil (31 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)[N:36]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(N4CCN(C)CC4)n3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 32 %

Procedure:
A stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide, 3 (200 mg, 0.464 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (154 mg, 0.510 mmol) and Na2CO3 (123 mg, 1.160 mmol) in a mixture of water (3 mL) and DMF (15 mL) was degassed with argon gas for 30 min. Then PdCl2(PPh3)2 (16.28 mg, 0.023 mmol) was added and heated to 120° C. for 3 h. Then the reaction mixture was filtered through Celite bed and the Celite bed was washed with ice cold water (2×100 mL). The filtrate was extracted with EtOAc (20 mL), dried over anhydrous sodium sulphate, filtered, and concentrated to afford 150 mg of crude product. The crude product was purified by silica gel chromatography over (eluent: 5% MeOH/DCM) to afford the title compound as an off-white solid (85 mg, 32%). 1HNMR (DMSO-d6, 400 MHz): 0.889 (t, J=14.4 Hz, 3H), 1.554-1.483 (m, 8H), 2.134 (s, 3H), 2.55 (s, 3H), 4.411 (d, J=1.6 Hz, 2H), 5.059 (m, 1H), 5.913 (s, 1H), 7.830 (s, 1H), 8.047 (s, 1H), 8.08 (s, 1H), 8.306 (s, 1H), 8.462 (s, 1H), 11.53 (s, 1H), 13 (brs, 1H). LCMS (ES+) m/z=528.2.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:14]=[CH2:15])=[N:9]2)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd]>[CH2:14]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH2:1])[N:9]=1)[CH3:15]
Reactant: C=Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ccc2c(N)cccc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.0 g (5.0 mmol) of 5-nitro-2-vinylquinoline is dissolved in 30 ml of ethyl acetate. After 100 mg of palladium on carbon and 50 mg of sodium carbonate are added, the reaction mixture is allowed to stir for 20 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (0-100%), then with ethyl acetate-methanol (0-30%), 720 mg (84% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)CC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)CC)C(=O)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Dissolve heptane-3,5-dione (2.5 g, 19.5 mmol) in dry tetrahydrofuran (10 mL) and add the resulting solution dropwise to a chilled (0° C.) suspension of sodium hydride (0.94 g, 23.4 mmol, 60% dispersion in oil) in tetrahydrofuran (20 mL). Stir at 0° C. for 1 hr., then add bromoacetic acid ethyl ester (2.6 mL, 23.4 mmol) dropwise. Stir for 16 hr. at 0° C. and warm to room temperature. Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate the organic layer and wash with saturated aqueous sodium chloride solution (50 mL), dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give 4-oxo-3-propionyl-hexanoic acid ethyl ester as an oil (3.2 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 4.08 (m, 3H), 2.83 (d, 2H), 2.55 (q, 2H), 1.21 (t, 3H), 1.02 (t, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCCCC1
Yield: 87.3 %

Procedure:
Using an analogous procedure to that described in Example 292, (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), was reacted with piperidine (211 mg, 2.49 mmol) to give (2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (325 mg, 86%).