Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])=[C:46]([CH:57]=2)[CH2:47][N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:40])=[CH:32][CH:31]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.B(O)O>>[C:51]([O:50][C:49]([N:48]([CH2:47][C:46]1[CH:57]=[C:42]([NH:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][CH:32]=2)[CH:43]=[CH:44][C:45]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:56])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: OBO
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 18B (0.660 g, 1.17 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (0.290 g, 1.28 mmol) and then hydrolyzed to the free boronic acid to give 18C (0.476 g, 80%) as a white solid. MS (ESI) m/z 533.0 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:26])[C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)cc1
Yield: 50.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (268 mg) described in Preparation Example 18 and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (235 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.Br[CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1.O>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:28][CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: COc1ccc(C(=O)C2CCNCC2)c(OC)c1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)C2CCN(CCc3c[nH]c4ccccc34)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 8.0 g of 4-(2,4-dimethoxybenzoyl)piperidine hydrochloride and 6 ml of triethylamine in 250 ml of dimethylformamide is added a solution of 6.4 g of 3-(2-bromoethyl)indole in 50 ml of dimethylformamide. The reaction mixture is permitted to stir at ambient temperature for 72 hours and then 500 ml of water is added dropwise and extracted with chloroform. The combined extracts are dried and most of the chloroform removed leaving a dark oil. The oil is subjected to column chromotography on a silica gel column and eluting with a 3% methanol in chloroform solution to give 3-{2-[4-(2,4-dimethoxybenzoyl)piperidyl]ethyl}indole. The indole is recrystallized thrice from an ethanol-water mixture to give the pure indole, mp 110°-112° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[CH:13]2[N:16](C)[CH:10]([CH2:11][CH2:12]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([N:8]1[CH2:14][CH:13]2[NH:16][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: c1ccc(CN2CC3CCC(C2)N3)cc1

Procedure:
A solution of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo (3.2.1)octane (2.05 g, 8.91 mmoles) in dry ether (100 mL) was treated gradually with lithium aluminum hydride (1.52 g, 4 mmoles), heated under reflux for one hour, and hydrolyzed successively with 50 mL of water-saturated ether and then 10 mL of water. This mixture was filtered on a celite pad. The filtrate was dried over magnesium sulfate and then evaporated to give the crude titled product which was used without any purification for further uses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[C:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[Cl:22].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:29]O>C(OCC)(=O)C>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[NH:1]1[C:9]2[C:4](=[C:5]([O:25][CH2:24][C@@H:23]([OH:28])[CH2:29][N:18]3[CH2:17][CH2:16][C:15]4[CH:14]=[CH:13][C:12]([Cl:22])=[C:11]([Cl:10])[C:21]=4[CH2:20][CH2:19]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CO
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589=−6.87 (c=0.44, methanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: Nc1cc(C=O)nc(CC2CC2)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Product: Nc1c(F)c(CC2CC2)nc(C=O)c1Cl
Yield: 42.7 %

Procedure:
Using the procedure for Example 15, 4-amino-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (0.5 g, 2.57 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.279 g, 1.416 mmol) and CH3CN (26 mL) gave 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (138 mg, 0.604 mmol, 23.44%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.83 (s, 3H), 2.75 (dd, J=7.0, 2.8 Hz, 3H), 1.26 (t, J=7.1 Hz, 1H), 0.50 (m, 3H), 0.28 (dt, J=6.2, 4.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.49; 13C NMR (101 MHz, CDCl3) δ 190.47, 148.35, 147.05, 145.79, 143.11, 139.40, 116.45, 36.23, 10.04, 4.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[S:8](=[O:16])(=[O:15])[C:7]=2[CH:17]=1.[BH4-].[Na+].Cl>CS(C)=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:10][CH:9]([S:11](=[O:13])(=[O:14])[NH2:12])[S:8](=[O:15])(=[O:16])[C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(S(N)(=O)=O)=C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: COc1ccc2c(c1)S(=O)(=O)C(S(N)(=O)=O)C2
Reaction time: 0.5 h

Procedure:
The product from Step A (200 mg) was dissolved in 1.5 ml of DMSO and was added rapidly dropwise to a solution of 200 mg of NaBH4 in 5 ml of 95% ethanol. After 30 minutes, the mixture was poured into dilute HCl and extracted with ethyl acetate. The extract was washed with water, and brine and dried (Na2SO4) and evaporated to dryness. The residue was pure by TLC and the structure was not contraindicated by 'H-NMR. Mass spectrum shows m/e=277. Calc'd for C9H11NO5S2 : C, 38.98; N, 5.05; H, 4.00%. Found: C, 39.34; N, 5.15; H, 3.95%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=2.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2
Reactant: COC(=O)c1ccc2cc(-c3c(C)cccc3C)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylate (490 mg, 1.75 mmol) and 1N sodium hydroxide (3.5 mL, 3.5 mmol) in ethanol (25 mL) was heated at 80° C. for 18 h. The solution was poured into ethyl acetate and extracted with 1N HCl. The organic phase was dried, filtered, and solvent was removed under reduced pressure to afford 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:14]([C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])[CH2:15][S:16][C@H:11]12)=[O:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCCOC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCOC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
Benzhydryl 7-thienylacetamido- 3-(n-propoxycarbonyl)-3-cephem-4-carboxylate was deesterified (65%) with a trifluoroacetic acid-anisole mixture as described in Example 10 to give the title acid as a white solid. The product exhibited biological activity against both gram-positive and gram-negative organisms.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].CO.O>O1CCCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[N:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([CH2:11][C:5]4([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)(=[O:13])=[O:14])[CH2:16][CH2:17]3)=[N:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Yield: 69.5 %

Procedure:
1-{4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-cyclohexanecarboxylic acid methyl ester (0.40 g) and lithium hydroxide monohydrate (0.20 g) were combined in tetrahydrofuran (20 ml), methanol (10 ml) and water (5 ml) and heated to reflux for 10 h. The organic solvents were then removed under reduced pressure. The aqueous residue was diluted with water (20 ml), acidified with citric acid to approximately pH 4, and a white precipitate filtered off. After drying, the precipitated solid was triturated with hot ethyl acetate (30 ml) to provide the title compound as a white solid (0.27 g, 69%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:4][C@@H:3]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34]>CN(C=O)C>[CH2:34]([O:1][C@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:4][C@@H:3]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCOCC2)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1CN(C2CCOCC2)C[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
To a solution of N-(2-((3S,4S)-4-hydroxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.1 mmol) in DMF (1 mL), was added NaH (17 mg, 0.4 mmol) at 0° C. The mixture was stirred at 0° C. for 10 min., followed by addition of allyl bromide (0.011 mL, 0.13 mmol). The mixture was stirred at 0° C. for 30 min., and the organic phase was washed with water, dried over MgSO4, concentrated, and subjected to flash chromatography (EtOAc:MeOH:Et3N 9:1:0.1) to generate the title compound (6 mg, 10% yield). 1H-NMR (CDCl3) δ: 1.40-1.57 (m, 2H), 1.70-1.90 (m, 2H), 2.27-2.40 (m, 2H), 2.70-2.82 (m, 2H), 3.30-3.42 (m, 3H), 3.77-3.85 (m, 1H), 3.90-4.05 (m, 3H), 4.06-4.22 (m, 3H), 4.29-4.32 (m, 1H), 5.10-5.30 (m, 2H), 5.80-5.98 (m, 1H), 6.60 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 8.08 (s, 1H). MS m/z: 456 (M+1)
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Temperature: 90 °C

Procedure:
2,6-Dichloro-4-(trifluoromethyl)benzaldehyde (3.2 g, 13.2 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (1.5 g, 4.4 mmol), Pd(dppf)Cl2 (320 mg, 0.4 mmol) and K3Pa4hydrate (3.0 g, 13.2 mmol) were dissolved in 1,4-dioxane (200 mL) and the resulting mixture was heated to 90° C. After 10 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]2[CH3:27])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B.[ClH:29]>C1COCC1>[ClH:29].[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]1[CH3:27])([O-:3])=[O:2]
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1cccc([N+](=O)[O-])c1)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C)N(CCc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(3-Nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (22.0 g, 0.059 m) was added portionwise to 190 ml of 1 M borane in THF which was maintained under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 15 minutes, then heated to reflux for 4 hours. The mixture was cooled in an ice bath, treated carefully with 20% HCl (250 ml), and then refluxed for 1 hour. After cooling, the solvents were removed on an aspirator and the residue treated with 250 ml 20% NaOH and extracted with chloroform (3×200 ml). The extracts were dried over MgSO6 and evaporated to an oily residue. The residue was dissolved in methanol (100 ml) and treated with HCl gas until acidic. Upon cooling, a yellow solid was obtained which was collected by filtration and dried to give 23.2 g N-(3-nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride, m.p. 139°-140°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=O)[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.Cl.NO.[N:41]1C=CC=CC=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]#[N:41])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: c1ccncc1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(COc2cc(C#N)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 86 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (990 mg), hydroxylamine hydrochloride (200 mg), pyridine (1 mL) and ethanol (10 mL) was refluxed for 3 hrs. After concentration of the reaction mixture, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in acetic anhydride (20 mL), and the mixture was refluxed for 5 hrs. After concentration of the reaction mixture, The residue was subjected to silica gel column chromatography to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbonitrile (850 mg, yield 86%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]O)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][I:42])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C[C@H](CO)CN1C(=O)COc2cc(F)ccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Yield: 86.2 %

Procedure:
The compound (S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF18) (2.57 g, 11.0 mmol), triphenylphosphine (6.61 g, 23.7 mmol), imidazole (1.76 g, 25.8 mmol) and I2 (7.64 g, 30.1 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF20) (3.31 g, 89%). 1H NMR (CDCl3) δ 7.00-6.96 (m, 1H), 6.78-6.74 (m, 2H), 4.65-4.56 (m, 2H), 3.92 (d, J=7.6 Hz, 2H), 3.21-3.13 (m, 2H), 2.13-2.03 (m, 1H), 1.04 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 164.3, 159.0 (d, J=244.4 Hz), 146.6 (d, J=12.0 Hz), 125.0 (d, J=3.0 Hz), 115.9 (d, J=9.7 Hz), 109.4 (d, J=22.5 Hz), 105.5 (d, J=26.0 Hz), 67.8, 46.3, 33.6, 18.9, 11.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[C:20]([O:32][CH3:33])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH:34](O)=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[CH:34]=[O:35])=[C:20]([O:32][CH3:33])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NCCN1CCCC1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(C=O)CCN1CCCC1

Procedure:
A solution of 6-(4-Chlorophenyl)3-{3-methoxy-4-[(2-pyrrolidin-1-ylethyl)amino]phenyl}thieno[3,2-d]pyrimidin-4(3H)-one (0.050 g, 0.1 mmol) in formic acid (88%, 2 mL) was heated to reflux, concentrated, and then diluted with aqueous sodium hydroxide (0.1N, 2 mL) to precipitate the product as a white solid (0.051 g, 100%). LCMS m/z 509 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.60 (d, 2H), 7.43 (d, 1H), 7.42 (s, 1H), 7.20 (d, 1H), 3.82 (s, 3H), 3.78 (t, 2H), 3.30-3.50 (m, 2H), 2.40 (m, 4H), 1.70 (m, 4H) ppm.
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C>>[C:9]1([C:1]2[CH:2]=[CH:11][CH:10]=[CH:9][CH:14]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccccc1
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
The procedure of Example 4 was repeated except that 0.874 mol of acetic acid was used in place of the lauric acid. The reaction was carried out at about 85° C. for 3 hours. Analysis showed that only a trace amount of phenyl acetate formed and 8 millimols of biphenyl were formed.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:13])([CH3:12])[C:8](=[CH2:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([SiH2:5][O:6][C:7]([CH3:13])([CH3:12])[C:8](=[CH2:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CO)C(C)(C)O[SiH2]C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C=C(C=O)C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 1 h

Procedure:
2-(Tert-butyl-dimethyl-silanyloxymethyl)-prop-2-en-1-ol (6 g, 29.7 mmol) prepared in example 99a was dissolved in dichloromethane (296 mL) containing both the molecular sieves (4 A) (Aldrich) and N-methyl morpholine oxide (5.2 g, 44.47 mmol). After stirring the mixture for 1 h, (Tetra-n-butyl ammonium perruthenate) (0.47 g, 1.48 mmol) (Aldrich) was added and the reaction mixture was stirred at room temperature for 1 h. Then another batch of (Tetra-n-butyl ammonium per-ruthenate) (0.23 g, 0.74 mmol) was added and the mixture was stirred at room temperature for another 1 h. The reaction mixture was diluted with dichloromethane. The organic layer was washed with Na2S2O3 solution, brine and saturated copper (II) sulfate solution, then dried over dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give 2-(tert-butyl-dimethyl-silanyloxymethyl)-propenal to as colorless oil (Yield 1.3 g, 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-n2ccc(-c3cccc(Cl)c3)n2)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccn(-c3ccc(Cl)c(CBr)c3)n2)c1

Procedure:
A mixture of 1-(3-methyl-4-chlorophenyl)-3-(3-chlorophenyl)-1H-pyrazole (i.e. the product of Step A) (1.7 g, 5.61 mmol), N-bromosuccinimide (1.1 g, 6.17 mmol) and benzoyl peroxide (30 mg, 0.12 mmol) in 100 mL of carbon tetrachloride was irradiated with a sun lamp for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (10 to 20% gradient of ethyl acetate in hexanes as eluant) to give the title compound as a white solid (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\[OH:10])[CH:5]=[CH:4][N:3]=1.[Cl:29]C1C(NS(C2C(F)=CC=CC=2F)(=O)=O)=CC=CC=1C(OC)=O.ClC1N=C(C)C=CN=1>>[Cl:29][C:12]1[C:11](/[C:9](/[OH:10])=[CH:8]\[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][S:18]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])(=[O:19])=[O:20]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cc1ccnc(Cl)n1
Product: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Yield: 73.5 %

Procedure:
Following a procedure analogous to Intermediate 5, Step B using methyl 2-chloro-3-(2,6-difluorophenylsulfonamido)benzoate (31 g, 85.9 mmol) and 2-chloro-4-methylpyrimidine (12.2 g, 94.5 mmol) the title compound was obtained (33 g, 73.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.47-13.52 (br, 0.96H), 8.50-8.56 (m, 0.13H), 8.38 (d, J=5.3 Hz, 1H), 7.78-7.82 (m, 0.15H), 7.62-7.73 (m, 2H), 7.40-7.50 (m, 1.18H), 7.17-7.30 (m, 1.77H), 6.90-6.97 (m, 2.29H), 6.83 (d, J=5.3 Hz, 1H), 5.65 (s, 1H), 4.28 (s, 0.26H). MS (ES+): 458 [M+H]+.