Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-:34])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCc1ccccc1
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A solution of N-benzyl-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.01 g, 3.04 mmol) in 50 mL of CH2Cl2 was treated with MCPBA (77% max., 1.02 g, 4.56 mmol). After stirring for 3 h, the reaction mixture was quenched with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (0.99 g) as a light-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=2[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH2:22][CH2:21][N:20]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Oc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(O)cccc32)nc(N2CCOCC2)cc1=O
Yield: 23 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of indolin-4-ol and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 85 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18]O)=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: OCCCc1c(-c2ccccc2)n(-c2ccccc2)c2ccccc12
Product: CCC(=O)Nc1ccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 3-(1,2-diphenyl-1H-indol-3-yl)-1-propanol and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 542.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[OH:13][C:12]1[C:11]([OH:17])=[N:10][C:4]2[C:5](=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)cc1N
Product: Oc1nc2cc(F)c(F)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 11.3 g. (0.0784 mole) of 4,5-difluoro-o-phenylenediamine (U.S. Pat. No. 4,264,600) and 80 ml. (0.589 mole) of diethyl oxalate was refluxed for a period of four hours to give a thick precipitate of product. The spent reaction mixture was then cooled to room temperature (~20° C.) overnight, filtered and the solid product so obtained was thereafter washed several times with diethyl ether and air-dried to constant weight to ultimately afford 15.5 g of pure 2,3-dihydroxy-6,7-difluoroquinoxaline, m.p. >310° C. Mass Spectrum: m/e, 198 (P+).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])I>CS(C)=O.O.[Cu]>[F:19][C:4]1[CH:3]=[C:2]([C:22]([F:25])([F:24])[C:21]([F:27])([F:26])[F:20])[CH:18]=[CH:17][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: FC(F)(F)C(F)(F)I
Reactant: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a pressure vessel was bubbled in 1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) The vessel was sealed and heated at 120° C. for 16 hours. The reaction mixture was diluted with water and filtered through a plug of silica and then extracted with ethyl acetate (4×). The organics combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a crude mixture that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-40%) to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06, found 365.3 (M+1)+; Retention time: 1.39 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4 Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CCCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-butyl-cinnoline-3-carboxamide (200.0 mg, 0.62 mmol) and 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (987.9 mg, 3.72 mmol) according to Method B to afford a white solid (162.1 mg, 69%). 1H NMR (300.132 MHz, CDCl3) δ 8.49 (t, J=5.5 Hz, 1H), 8.33 (s, 1H), 7.90 (dd, J=7.6, 2.1 Hz, 1H), 7.77-7.69 (m, 3H), 4.07 (s, 3H), 3.93 (s, 3H), 3.50 (q, J=6.6 Hz, 2H), 1.63 (quintet, J=7.2 Hz, 2H), 1.44 (sextet, J=7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H). MS APCI, m/z=383.1 (M+H). HPLC 2.52 min.
Reaction SMILES: Cl.Cl.[CH:3]1([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.O.NN>C(O)C>[CH:3]1([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:17][CH2:18]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(C2CCCc3ccccc32)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCN(C2CCCc3ccccc32)CC1

Procedure:
Batch size: 52 g (106 mmol) 2-{4-[4-(1,2,3,4-tetrahydronaphthalin-1-yl)-piperazin-1-yl]-butyl}-isoindolin-1,3-dione-dihydrochloride and 14.6 ml (300 mmol) hydrazine-hydrate in 500 ml ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:9]=2[CH:10]=1.[F:32][C:33]([F:48])([F:47])[C:34]1[N:39]=[N:38][C:37]([C:40]2[CH:45]=[CH:44][NH:43][C:42](=[O:46])[CH:41]=2)=[CH:36][CH:35]=1>>[O:46]=[C:42]1[CH:41]=[C:40]([C:37]2[N:38]=[N:39][C:34]([C:33]([F:48])([F:47])[F:32])=[CH:35][CH:36]=2)[CH:45]=[CH:44][N:43]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:22][CH2:21][C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)ccc3c2C1
Yield: 30.7 %

Procedure:
tert-Butyl 7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (260 mg, 0.51 mmol) and 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (123 mg, 0.510 mmol) were reacted according to the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a yellow solid: ESI MS m/z 512 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2ccc(C)nc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (6-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(Cl)cc1

Procedure:
A mixture containing 2,2-diphenyl-5methylaminopentanamide (0.3 g--see Preparation 3), 4-chlorophenethyl bromide (0.234 g--see Preparation 7), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.306 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCOCCCl
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
3-Methoxyphenylacetonitrile (10 g, 67.9 mmol) in DMF (50 ml) was added slowly to a suspension of NaH (5.04 g, 150 mmol) in DMF (50 ml) at 0° C. under N2. The reaction was allowed to warm to room temperature and stirred for 30 nms. The reaction was cooled to 0° C. and bis(2-chloroethyl)ether (10.7 g, 74.7 mmol) in DMF (100 ml) was added dropwise over 80 min. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (3×50 ml), dried over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo. The crude mixture was purified by column chromatography, eluting with heptane increasing the polarity to heptane:ethyl acetate (90:10), to give 4-(3-methoxyphenyl)tetrahydro-pyran-4-carbonitrile (4.1 g, 28%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OC)cc1O
Yield: 86.7 %

Procedure:
6.00 g of 2′,4′-dihydroxypropiophenone was dissolved in 70 ml of acetone. Thereafter, 7.09 g of potassium carbonate and 3.03 ml of methyl iodide were successively added to the reaction solution. The reaction solution was then heated to reflux. Approximately 3 hours later, the reaction solution was stood to cool and then filtered. The filtrate was concentrated under a reduced pressure. A saturated sodium chloride solution and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with 2 N hydrochloric acid and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was solidified from hexane-ethyl acetate, so as to obtain 5.64 g of the subject compound. 1H-NMR (CDCl3) δ (ppm): 1.23 (t, J=7.2 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 6.40-6.45 (m, 2H), 7.65 (dd, J=1.6 Hz, 8.0 Hz, 1H), 12.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si](C(C)(C)C)(C)C)[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:3]([C:17]([OH:20])([CH3:18])[CH3:19])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: CC(C)(O)c1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 2-[3-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2-propanol (328 mg, 1.038 mmol) in THF (10 ml) was added TBAF (1.557 ml, 1.557 mmol). The solution was stirred at room temperature for 3 h. The mixture was concentrated under vacuum and the residue was purified by Flashmaster chromatography on a 40 g Merk silica gel cartridge using DCM/MeOH 95:5 as eluent to obtain 2-[3-chloro-5-(hydroxymethyl)-2-pyridinyl]-2-propanol (210 mg, 95%) as colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)Oc1ccccc1

Procedure:
(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester, shown below, from Example 1, Step C, and toluene-4-sulfonic acid 2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (S)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (41%). 1H NMR (300 MHz, CDCl3): δ 7.96 (m, 2H), 7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H), 6.93 (t, 1H), 6.82 (m, 4H), 4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H), 3.06 (d, 1H), 2.95 (t, 2H), 2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486 (M+H)+, [EI−] 484 (M−H)+.
Reaction SMILES: I[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1)=[CH2:27])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)ncnc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
[10 g, 25 mmol] of 4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was dissolved/suspended in 200 mL of dry toluene along with [2.0 g, 2.85 mmol] of palladium (II) bis-triphenylphosphine dichloride. The mixture was purged with nitrogen gas for ˜5 minutes before mixture was heated to 90° C. in an oil bath under an atmosphere of nitrogen gas. Added slowly dropwise over 2 hours, was [12.66 mL, 13.54 g, 37.5 mmol] of tri-n-butyl(1-ethoxyvinyl) tin in 100 mL of dry toluene. After completing the addition, the mixture was heated for an additional 6 hours under nitrogen. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure until the remaining volume was ⅕ the original. Added to this slurry was 160 mL of petroleum ether and the mixture was stirred for 1 hour, the solid being isolated via suction filtration and washed with petroleum ether. The damp solid was slurried in acetonitrile, stirred for one hour and the solid re-isolated via suction filtration and airdried. The resulting pale yellow solid, 7.2 g representing an 82% yield was utilized without further treatment.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(OC)(C)(C)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
L-phenylalanine methyl ester hydrochloride (120.00 g), benzaldehyde (56.5 ml), anhydrous sodium sulfate (158.07 g) and triethylamine (77.5 ml) were added to tert-butylmethyl ether (480 ml), and the mixture was stirred overnight at 5° C. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, n-hexane was added, and the solvent was distilled off again under reduced pressure. To the concentrate was added n-hexane, and the crystallization was conducted by cooling with ice to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (126.01 g) in a yield of 85.0%. Further, the mother liquor was concentrated under reduced pressure, and the concentrate was crystallized by cooling with ice to obtain N-(phenylmethylene)-L-phenylalanine methyl ester (13.86 g) in a yield of 9%. Thus, the crystals of N-(phenylmethylene)-L-phenylalanine methyl ester were obtained in a total yield of 94%. A part of the resulting crystals were converted into a phenylalanine methyl ester. It was analyzed by HPLC using an optically active column, and identified to have the optical purity of >99.5%e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11](#[N:13])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:11]#[N:13]
Reactant: CC#N
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: N#CC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
Orthochlorobenzoyl chloride (17.5 g, 0.1 mol), cuprous cyanide (11.65 g, 0.13 mol), and acetonitrile (8 mL) were refluxed in toluene (15 mL) for 3 hours, and were cooled to room temperature. Then, insoluble substances were removed through filtration, and the residue was washed with toluene. Solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to obtain orthochlorophenyloxoacetonitrile (12.3 g, 75% yield).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.CO.C[O-].[Na+].[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=[O:30])[CH:27]=2)[NH:22][N:21]=1>O>[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][CH:12]=[N:11][CH:10]=3)[CH:27]=2)[NH:22][N:21]=1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1n[nH]c2ccc(-c3cnco3)cc12
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a 150 mL round-bottom flask was added p-toluenesulfonylmethyl isocyanide (1.46 g, 7.5 mmol) and MeOH, followed by sodium methoxide (4.60 mL, 21.2 mmol) and a MeOH solution of 3-methyl-1H-indazole-5-carbaldehyde (1.00 g, 6.24 mmol) (prepared as described in WO 2007/124288). The solution was stirred at reflux for about 1 hour and followed by LCMS. Water was added (50 mL) and the MeOH was removed in vacuo. The suspension was cooled to 0° C. and the resulting precipitate was filtered and dried in the vacuum oven overnight to give 3-methyl-5-(oxazol-5-yl)-1H-indazole (1.01 g, 81% yield) as a tan powder. LCMS (API-ES) m/z (%): 200 (100%, M++H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[NH:7]1[CH:14]=[CH:13][C:11]([NH2:12])=[N:10][C:8]1=[S:9]>CCO.[OH-].[Na+]>[NH2:12][C:11]1[CH:13]=[CH:14][N:7]=[C:8]([S:9][CH2:2][CH2:3][CH2:4][C:5]#[N:6])[N:10]=1
Reactant: N#CCCCCl
Reactant: Nc1cc[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCCSc1nccc(N)n1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
4-Chlorobutyronitrile (0.23 g.) in EtOH (2 ml.) was added to a solution of 2-thiocytosine (0.25 g.) in 0.5N aqueous NaOH (5 ml.) and the mixture stirred for 18 hours. A further portion of 4-chlorobutyronitrile (0.23 g.) was added and the mixture stirred a further 24 hours. The solution was concentrated in vacuo to 2 ml. and cooled and the crystalline precipitate collected to give 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.3 g.) m.p. 99°-100°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[C:33]([CH3:32])=[N:34][O:35][C:36]=3[CH3:41])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1noc(C)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3,5-dimethylisoxazol-4-yl)boronic acid gave 234. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.47 (s, 1H), 7.78 (s, 1H), 4.82 (dd, J=10.8, 3.6 Hz, 1H), 4.56-4.32 (m, 1H), 4.25-3.93 (m, 2H), 3.79 (s, 3H), 3.27-3.13 (m, 1H), 2.74 (s, 3H), 2.53 (s, 3H), 2.13-2.01 (m, 1H), 1.93-1.78 (m, 1H), 1.77-1.64 (m, 2H). LCMS (ES+) m/z 435 (M+1).