Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:30])=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH2:18][F:19])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9]3)[CH:7]=1.C(OC[C@@H]1OC[C:43]2(C3C=C(C#N)C(F)=CC=3F)[N:44]=C(NC(=O)C3C=CC=CC=3)SCC2C1)C1C=CC=CC=1>>[C:43]([C:2]1[C:3]([F:30])=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH2:18][F:19])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:9]3)[CH:7]=1)#[N:44]
Reactant: N#Cc1cc(C23CO[C@@H](COCc4ccccc4)CC2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Product: N#Cc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C13) was converted to the product using the method described for the synthesis of N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C10) in Example 1. Yield: 98.5 mg, 0.220 mmol, 44%. LCMS m/z 446.2 [M+H+]. 1H NMR (400 MHz, CD3OD), δ 8.06 (d, J=7.2 Hz, 2H), 7.85 (t, J=7.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.45-7.49 (m, 2H), 7.37 (dd, J=12.1, 9.2 Hz, 1H), 4.44-4.51 (m, 1H), 4.32-4.39 (m, 1H), 4.06-4.10 (m, 1H), 3.89-4.0 (m, 2H), 3.11-3.19 (m, 1H), 2.96 (dd, J=13.3, 4.1 Hz, 1H), 2.75 (dd, J=13.3, 2.9 Hz, 1H), 1.83-1.93 (m, 1H), 1.64-1.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH2:27][CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(N1CCN(c2ccccn2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 81.1 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-(2-pyridyl)piperazine (0.56 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.16 g of the title product was obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>O.C(O)C>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:16][OH:17])[CH3:2]
Reactant: CCC1CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1CCCCC1=NO
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of 2-ethylcyclohexanone (104.3 mmol) in water and ethanol, and sodium acetate (125.1 mmol) were added hydroxylamine hydrochloride (156.4 mmol), the reaction was heated at 70° C. overnight. The ethanol was removed under reduced pressure, and the reaction mixture was dissolved in water. The aqueous layer was extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give 2-ethyl-1-(hydroxyimino)cyclohexane (52%) as a thick oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCn1nccc1C(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCn1nccc1C(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine and tetrahydrofuran were combined and cooled to −20° C. n-Butyl lithium (2.5M in hexanes) was slowly added and the resulting mixture stirred at this temperature for 30 minutes. The temperature was lowered to −78° C. and neat 5-bromo-2-fluoropyridine was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The resulting mixture was added to a solution of 2-ethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide in tetrahydro-furan. The combined reaction mixture was stirred at −78° C. for 1 hour before the reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride solution. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel to afford (5-bromo-2-fluoro-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone. MS: m/z 298.1+300.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C3C=CC=CC=3)=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)Oc3ccccc3)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a solution of phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (2.00 g, 4.65 mmol) in tetrahydrofuran (50 mL) and water (10 mL) was added lithium hydroxide monohydrate (1.00 g, 23.8 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was neutralized to pH 4-5 with 10% w/v hydrochloric acid. The resultant precipitate was filtered and washed with diethyl ether to afford 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid (1.40 g, 85%): mp 297-299° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.43 (m, 3H), 7.32-7.28 (m, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.77 (ABq, 2H), 4.12-4.02 (m, 4H), 3.15 (s, 3H); MS (ES+) m/z 376.0 (M+23).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C1(=O)[NH:25]C(=O)C2=CC=CC=C12.[K].CN(C)C=O.C1C=CC=CC=1>O>[NH2:25][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Temperature: 100 °C
Yield: 96.9 %

Procedure:
A mixture of ethyl 3-(4-(2-bromethoxy)phenyl)-2-ethoxypropanoate (3.05 g, 8.8 mmol), potassium phtalimide (2.0 g, 10.8 mmol) and dimethylformamide (20 ml) was heated to 100° C. for 16 h, benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was dissolved in ethanol (60 mL), hydrazine hydrate (1.3 ml) was added and the mixture was refluxed for 2 h, filtered and the solvent evaporated to give 2.4 g (96%) of ethyl 3-(4-(2-aminoethoxy)phenyl)-2-ethoxypropanoate as an oil. Hydrogen oxalate hemihydrate was prepared for characterization by neutralization with oxalic acid in acetone. M.p. 146-148° C. A mixture of dibenzo[b,f]-1,4-thiazepin-11(10H)-thione (2.20 g, 9 mmol; prepared as described in Coll.Czech.Chem.Commun. 48, 1465 (1983), 3-(4-(2-aminoethoxy)phenyl)-2-ethoxypropanoic acid ethyl ester (2.60 g, 8.9 mmol) and 3-methyl-1-butanol (70 ml) was stirred and heated at 150° C. for 16 h. The solvent was evaporated in vacuo, dichloromethane (50 ml) and water (50 ml) were added, the mixture was filtered and the phases were separated. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with chloroform. This afforded 0.7 g of the starting thione and then 1.7 g (38%) of the title compound as an oil. 1H NMR (250 MHz, CDCl3) δ7.05-7.50 (m, 9 H), 6.85-6.95 (m, 3 H), 5.15 (bs, 1 H), 4.25 (m, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 3.96 (t+m, 3 H), 3.59 (m, 1 H), 3.34 (m, 1 H), 2.95 (d, J=6.4 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H), 1.16 (t, J=7.2 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([OH:23])[C:21]#[CH:22]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][CH2:20][OH:23])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CCO)c1

Procedure:
Sonogashira reaction of bromide 39 with propargyl alcohol gave tert-butyl 3-hydroxy-3-(3-(3-hydroxyprop-1-ynyl)phenyl)propylcarbamate as brown oil. Yield (0.880 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.28-7.36 (m, 3H), 4.85-4.87 (bs, 1H), 4.70-4.72 (m, 1H), 4.49 (d, J=5.2 Hz, 2H), 3.47-3.50 (m, 1H), 3.44 (bs, 1H), 3.12-3.17 (m, 1H), 1.93-1.99 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][CH2:5][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8].C=O.[C:19](=O)([O-])[OH:20].[K+]>>[OH:20][CH2:19][C:6]([C:11]([O:13][CH3:14])=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:15][CH3:16]
Reactant: O=C([O-])O
Reactant: COC(=O)C(CCC(OC)OC)C(=O)OC
Agent: C=O
Agent: [K+]
Product: COC(=O)C(CO)(CCC(OC)OC)C(=O)OC
Yield: 95 %

Procedure:
The hydroxymethylation of dimethyl 4,4-dimethoxybutane-1,1-dicarboxylate was carried out. The diester (23.4 g, 0.10 mol) was added dropwise to a mixture of formalin (8.1 ml, 0.10 mol) and potassium hydrogen carbonate (0.8 g, 8 mmol) over 20 min. The mixture was stirred at room temperature for 6 hours until the starting ester was completely consumed. A saturated aqueous solution of ammonium sulfate (35 ml) was added to the reaction mixture. The mixture was then extracted with three 60 ml portions of ethyl ether and the combined extracts were dried over anhydrous magnesium sulfate. The salt was filtered off and rotary evaporation of the solvent from the filtrate gave the product, at 95% yield, as viscous oil.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 4-aminobutanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 2 of European Patent Application 136,883 to give (±)-4-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]butanoic acid, methyl ester.
Reaction SMILES: C(OC(N1C2C=CC=C(C(C3C([N:26]([S:30]([C:33]4[CH:38]=[CH:37][C:36](Cl)=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=4)(=[O:32])=[O:31])COC)=CC(Cl)=CN=3)=O)C=2OCC1)=O)(C)(C)C>Cl.O>[F:43][C:40]([F:41])([F:42])[C:35]1[CH:34]=[C:33]([S:30]([NH2:26])(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 123.8 %

Procedure:
A solution of 8-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-2,3-dihydro-benzo [1,4]oxazine-4-carboxylic acid tert-butyl ester (510.2 mg) in 3 mL HCl (4 M in dioxane) and water (1 mL) was heated at 80 OC for overnight. Upon cooling to room temperature, the mixture was concentrated and the residue was purified by flash column chromatography on silica gel to afford 4-chloro-NJ5-chloro-2-(3,4-dihydro-2H-benzo[1,4]oxazine-8-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (210.2 mg) as white solid. MS m/z: 531.9 (M+H)+.
Reaction SMILES: [C:1]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: O=[N+]([O-])c1ccccc1C(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C(O)c1cccc2ccccc12
Yield: 89.1 %

Procedure:
To a solution of product (4-B) (0.5 g 1.8 mmol) in MeOH (20 mL) was added Pd(OH)2/C (0.5 g) at rt. The reaction mixture was stirred at rt under H2 for about 1 h until complete consumption of product (4-B) by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated to give crude product (5-B) (0.4 g, 90%) as a yellow solid. LC-MS (M-OH)+=232.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[CH2:10](I)[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[CH2:11][CH2:12][CH3:13]
Reactant: OCCC1CCCCN1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCCCC1CCO
Yield: 72.9 %

Procedure:
2-Piperidineethanol (15 g, 0.12 mol), n-butyl iodide (23.5 g, 0.13 mol) and potassium carbonate (32.1 g, 0.23 mol) in actonitrile (250 ml), as described in example 3 above, gave 1-butyl-2-piperidineethanol (16.2 g, 75%).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH2:14][C:15](OCC)=[O:16])=O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:16][C:15]1[CH:14]=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:21][CH:20]=2)[N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2cc(O)nc(C)n2)cc1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
1.89 g of acetamidine hydrochloride and 4.44 g of etyl paramethoxybenzoylacetate were dissolved in 40 ml of ethanol. After addition of 5.52 g of potassium carbonate, the solution was refluxed with stirring for 8 hours, and then evaporated in vacuo. 5 g of sodium hydroxide was dissolved in 30 ml of water and this was added to the evaporated residue. Add ether, then extract, the aqueous layer was neutralized with acetic acid. The resulting precipitations were filtered off, washed with water and dried. Then 1.1 g of crystals were obtained. Melting point is 270° to 272° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[C@H:18]([C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]2)[N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCN(C(=O)OCc4ccccc4)[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc2nc(N3CCN[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC

Procedure:
A solution of (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(benzyloxy)carbonyl]-3-(1,1-dimethylethylamino)carbonyl piperazine (1.11 g, 2.124 mmol) and 10% Pd-C (111 mg, 10 weight %) in dry EtOH (8 mL) was evacuated under high vacuum and purged to a H2 balloon (14 h). The mixture was filtered through Celite (30 mm×30 mm), the filter cake washed with EtOH and concentrated in vacuo. PCTLC (SiO2, 4 mm, 0-10% CH3OH/CH2 Cl2) provided the title compound.
Reaction SMILES: CC(=C(C)C)C.[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]#[N:17])[CH2:9][CH2:8]1.[OH-].[Na+].OO.C([O:25]C(C)C)(C)C>O1CCCC1.O>[OH:25][CH:8]1[CH2:7][C:15]2[C:14]([C:16]#[N:17])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1cccc2c1CCC2
Reactant: CC(C)OC(C)C
Agent: CC(C)=C(C)C
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc2c1CC(O)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
42 ml of a 1M solution of boran-tetrahydrofuran complex is cooled to 0° C., 3.7 ml of 2,3-dimethyl-2-butene in 20 ml of tetrahydrofuran is added and agitation is carried out for one hour 15 minutes at 0° C. 1.98 g of product obtained in Stage A in 20 ml of tetrahydrofuran is introduced at 0° C. over 40 minutes, with agitation for 1/4 hour at 0° C., and the temperature is allowed to rise to +14° C. over 3 hours. After cooling to 0° C., 5 ml of water is added drop by drop with agitation for 5 minutes, then 18 ml of 2N sodium hydroxide is introduced at +2° C., and the temperature is allowed to rise to +15° C. 18 ml of hydrogen peroxide at 30% is added slowly and the mixture is left under agitation for 17 hours. The reaction mixture is poured into 100 ml of water and 100 ml of isopropyl ether and decanted; the aqueous phase is extracted with isopropyl ether. The reunited organic phases are washed with water, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica in a hexane-ethyl acetate mixture (6-4), and 0.15 g of expected product is obtained, and 1.15 g of impure product is obtained which is chromatographed again on silica in a hexane-ethyl acetate mixture (65-35) so as to obtain 0.74 g of expected product, M.p.=60° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (171 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661 (M, M+2)+.
Reaction SMILES: CO[N:3]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1)[CH2:4][C:5](NC)=[O:6].[CH2:33]([Mg]Cl)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O.C(OCC)(=O)C>C1COCC1>[C:34]1([CH2:33][C:5](=[O:6])[CH2:4][NH:3][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:10]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CNC(=O)CN(OC)c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(NCC(=O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reaction time: 2 h

Procedure:
To a solution of 2-(N′-methoxy-N′-methylaminocarbonylmethylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.46 g, 3.4 mmol) in THF (30 mL) at 0° C. was slowly added benzylmagnesium chloride (Aldrich, 2.5M in THF, 20 mL). After 2 h, water (100 mL) and ethyl acetate (200 mL) were added. The layers were separated. The organic layer was washed with brine (3×80 mL), dried, and evaporated to give the crude product. Column chromatograph purification (silica gel, 1-2% MeOH/CH2Cl2) gave the final product. M+1=491.2.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([OH:56])[C:15](=[O:55])[N:16]([CH:28]([CH3:54])[CH:29]([C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)[CH2:30][C:31]1[O:32][C:33]([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:35]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8](=[C:14]([OH:56])[C:15](=[O:55])[N:16]([CH:28]([CH3:54])[CH:29]([C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)[CH2:30][C:31]1[O:32][C:33]([C:36](=[O:44])[NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:35]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
40 mg of methyl 3-tert-butoxycarbonyl-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]butanoate was dissolved in 5 ml of chloroform, and 68 mg of Dess-Martin reagent was added thereto, followed by stirring at room temperature for one hour. The reaction solution was poured into a mixed solution of a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (Kieselgel™60F254, Art™5744; hexane/ethyl acetate=3/2) to obtain 16 mg (yield: 40%) of the above-identified compound as a colorless oily substance.