Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To methyl (2-(1-indolinyl)-6-benzoxazolyl)acetate (200 mg, 0.649 mmol) were added THF/methanol (6/3 ml) and 1N NaOH (3 ml). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 1N HCl to acidify the residue therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-indolinyl)-6-benzoxazolyl)acetic acid (161 mg, 84%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]
Reactant: NCCCN1CCCC1=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 1-(3-aminopropyl)pyrrolidin-2-one (35.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a beige solid, 63.5 mg, (65% yield) MS (ES+): 392.2, (M+H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].CC(O[C:38]1[CH:39]=[C:40]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1)C>>[F:22][C:19]([F:21])([F:20])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:40]4[CH:39]=[CH:38][C:43]([O:27][CH:18]([CH3:19])[CH3:15])=[CH:42][CH:41]=4)([CH3:51])[NH:48][C:47]3=[O:49])[CH2:6][CH2:7]2)=[C:13]([CH2:31][CH2:32][CH3:33])[CH:14]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)Oc1cccc(C2(C)NC(=O)NC2=O)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(3-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:10][C:11]=2[C:12](Cl)=[CH:13][CH:14]=1)=[O:4].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(Cl)c2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(=O)c2c(C(=O)OC)cccc2[nH]1
Temperature: 50 °C

Procedure:
To a suspension of 24 (4.50 g, 14.5 mmol) in EtOAc (100 mL) was added Et3N (50 mL). The reaction mixture was heated to 50° C. to generate a clear solution. 10% Pd/C (0.500 g) was added carefully. The reaction mixture was hydrogenated (50 psi) on a Parr hydrogenation apparatus at room temperature for 4 h. Then the catalyst was filtered off on a pad of celite and the filtrate washed with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was washed with Et2O (100 mL) to give an off-white solid (29, 3.46 g, 99.1%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.05 (d, J=8.6 Hz, 1H), 7.75 (t, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.63 (s, 1H), 4.44 (q, J=7.3 Hz, 2H), 3.80 (s, 3H), 1.37 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].C(N(CC)CC)C.O>CS(C)=O>[CH:2]([C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4])=[O:1]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C=O)NC(=O)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (6.2 g, 27 mmol) and triethylamine (8.2 g, 81 mmol) in DMSO (60 ml) was added a solution of pyridine sulfur trioxide complex (12.9 g, 81 mmol) in DMSO (60 ml) dropwise with cooling in an ice-bath and stirred for 2 hours. The reaction mixture was poured over a mixture of ice and water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (5.05 g; 82%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1.[Na].[CH3:28][OH:29]>C(Cl)Cl>[CH3:28][O:29][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: CO
Reactant: CCOC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1Cl
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1OC

Procedure:
The ester from Step 3 (7.76 g) was added to a solution of sodium (920 mg) in anhydrous methanol (50 ml) and the resulting suspension was refluxed under an argon atmosphere for 75 minutes. The mixture was cooled, diluted with CH2Cl2 (200 ml), washed with water (3×50 ml) and reduced to dryness to provide the title compound, m.p. 133°-134.5°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[C:18]([N:17]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:16][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)NNC(=O)c1ccco1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccco1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.8 g), 1-furoyl-2-t-butyl hydrazine (2 g) and excess powdered potassium carbonate were stirred in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed several times with water. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The white solid product was chromatographed on silica gel (G:70°-230 mesh) using methylene chloride as eluent to afford the product in good yield: m.p. 152°-153.
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH2:12])=[N:5]2)[CH3:2].Br[CH2:14][CH2:15][O:16][CH3:17]>>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6](=[NH:12])[N:5]2[CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOC12COCC1SC(N)=N2
Reactant: COCCBr
Product: CCOC12COCC1SC(=N)N2CCOC

Procedure:
The product from Example 125B and 1-bromo-2-methoxyethane were processed using the method described in Example 12A to afford the title compound. MS (ESI+) m/z 247 (M+H)+.
Reaction SMILES: O.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]#[N:8])([O-])=O.Cl[Sn]Cl>COCCOCCOC.Cl>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: COCCOCCOC
Solvent: O
Product: N#Cc1c(N)cccc1Sc1ccccc1

Procedure:
To a water bath-cooled solution of 3.9 g (0.015 mol) of 2-nitro-6-(phenylthio)benzonitrile (Example 1) in 85 mL of diglyme was added dropwise, with stirring, 11.53 g (0.045 mol) of SnCl2.2H2 O in 35 mL of conc. HCl. The water bath was removed, and the reaction was stirred at room temperature for 0.5 h. This reaction mixture was poured into a vigorously stirring mixture of 100 mL of 50% NaOH and 300 g of crushed ice. Precipitate was collected by filtration and washed with 1N NaOH and water. Purification by flash column chromatography on silica gel with methylene chloride resulted in 2.3 g (68%) of 2-amino-6-(phenylthio)benzonitrile as a white solid: mp 73°-77° C.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH2:29])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[CH3:30][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH:29][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(N)c1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(NC(=O)C(C)C)c1

Procedure:
5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with isobutyryl chloride by method Q. This resulted in the product with the molecular weight of 474.26 (C28H34N4O3); MS (ESI): 475 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2n[nH]nc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)-c1sc(-c3n[nH]nc3-c3ccc(F)cc3F)cc1CCO2
Temperature: 200 °C
Yield: 84 %

Procedure:
To solution containing 4-(2-chloro-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-5-(2,4-difluorophenyl)-2H-1,2,3-triazole (0.085 g, 0.20 mmol), zinc cyanide (47.9 mg, 0.408 mmol;), and tetrakis(triphenylphosphine)palladium(0) (11.8 mg, 0.0102 mmol;) in N,N-dimethylformamide (2.83 mL, 36.6 mmol;) was evacuated then back-filled with nitrogen. The reaction mixture was heated in microwave to 200° C. for 10 min. The reaction mixture was quenched with sat.NH4Cl then extracted EtOAc (3×). The crude product was purified by column chromatography (EtOAc/Hex) to give 367 (84% yield). MS: (ESI+)=408.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24])[NH:8][C:7](=[O:25])[CH:6]=[CH:5]2.Br[CH2:27][C:28]#[CH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:25])[C:28]#[CH:27]
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)ccc3cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)ccc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 50.9 %

Procedure:
A stirred solution of 0.6 gram (0.002 mole) of 3-(6-fluoroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, 0.5 gram (0.003 mole) of 3-bromopropyne, and 0.5 gram (0.003 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was stirred at ambient temperature for about 16 hours. The reaction mixture was then subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate-heptane and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of 3-[1-(2-propyn-1-yl)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil, mp 236°-238° C. The NMR spectrum was consistent with the proposed structure. Other fractions were combined and concentrated under reduced pressure, yielding a small amount of the O-alkylated product, 3-[2-(2-propyn-1-yloxy)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil.
Reaction SMILES: [CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1>C(O)=O>[CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a mixture of methyl (+)-2-n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (395 mg) and tetrahydrofuran (4 ml) is added 90% formic acid (8 ml) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give methyl (+)-2 -n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (270 mg) as foam.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>CO>[CH2:7]1[CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH:1][CH2:9][CH2:8]1
Reactant: O=C(O)C1CCCCN1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Product: O=C(O)[C@@H]1CCCCN1

Procedure:
483 g (=3.75M) of enriched (-)-pipecolic acid are suspended in 3 liters of hot methanol. 565 g of D-(-)-tartaric acid are rapidly scattered in and an attempt made as quickly as possible to obtain a solution. Crystallization commences before a complete dissolution can be achieved. The mixture is cooled, filtered and well washed with methanol. The filtrate is concentrated and recrystallized. The obtained crystals are dissolved hot in ca 800 ml of water and 400 ml at acetone and treated with active charcoal. The clear almost colorless filtrate is diluted with ca 2 liters of acetone. The resulting crystals are filtered of and well washed with acetone/H2O 4:1 followed by 100% acetone. The filtrate is concentrated and diluted with acetone to obtain a second fraction. Both fractions are dried. [α]D20 =20.3° for the first fraction and -20.7° for the second fraction, (c=2, H2O) total weight 706 g. Separation is effected with 3 liters of Amberlite 7R 120 in the H+ form. After working the tartrate salt with 10% ammonia, the L-(-)-pipecolic acid is obtained by elution and concentration by evaporation and then once recrystalized out of a minimum of H2O and a maximum of alcohol, [α]D20 -27.5 (C=2, H2O).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][C:4]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[N:3]1.[Br:14]N1C(=O)CCC1=O>C(#N)C.[O-2].[O-2].[Mn+4]>[Br:14][C:5]1[C:4]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nc(-c2ccsc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: Cn1nc(-c2ccsc2)c(Br)c1C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A solution of [1-methyl-3-(thiophen-3-yl)-1H-pyrazol-5-yl]methanol (4b) (271 mg, 1.39 mmol) and N-bromosuccinimide (236 mg, 1.32 mmol) in acetonitrile (23 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×12 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was taken in dichloromethane (5 mL) and manganese dioxide (1.21 g, 13.95 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, filtered over Celite®, and the filtrate was concentrated in vacuo. to provide 4-bromo-1-methyl-3-(thiophen-3-yl)-1H-pyrazole-5-carbaldehyde (4c) (297 mg, 1.10 mmol, 78%), which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[C:22]([O:30][CH3:31])[CH:21]=1)([CH3:19])[CH3:18])=O)C.CS(O)(=O)=O.CCCCCC>CC#N>[OH:26][C:23]1[C:22]([O:30][CH3:31])=[CH:21][C:20]2[C:17]([CH3:19])([CH3:18])[C:7]3[NH:8][C:9]4[C:14]([C:6]=3[C:4](=[O:3])[C:25]=2[CH:24]=1)=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=4
Reactant: CCOC(=O)c1c(C(C)(C)c2ccc(OC(C)C)c(OC)c2)[nH]c2cc(C#N)ccc12
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CCCCCC
Product: COc1cc2c(cc1O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
6-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylic acid ethyl ester (Compound L7, 1.25 g, 2.97 mmol) was dissolved in MeCN (18 mL), added with methanesulfonic acid (3.75 mL), and then stirred at 50° C. for 8 hr. Hexane was added to the reaction solution, and the precipitated solid was filtered to obtain the title compound (yellow solid, 185 mg, 19%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1.I[CH:29]([CH3:31])[CH3:30]>>[CH3:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:16][O:15][C:12]1[CH:11]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:29]([CH3:31])[CH3:30])=[CH:27][C:6]=3[N:7]=2)[O:14][N:13]=1
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Reactant: CC(C)I
Product: CC(C)Oc1ccc2oc(-c3cc(OC[C@H](C)NC(=O)OC(C)(C)C)no3)nc2c1

Procedure:
Using tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate (200 mg) and 2-iodopropane (0.106 mL), and in the same manner as in Example 2, step E, the title compound was obtained (246 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][CH2:19]Br.O>CS(C)=O.C1COCC1>[F:15][C:4]([F:14])([F:3])[C:5]1[N:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(C(F)(F)F)nc2)CCC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (567 mg, 14.2 mmol, 60%) in DMSO (30 mL) was added dropwise a solution of Example 85D (1.2 g, 6.45 mmol) in THF (5 mL) at room temperature and then the mixture was stirred for 30 minutes, followed by the addition of a solution of 1,3-dibromopropane (1.4 g, 7.10 mmol) in THF (5 mL) at room temperature. The mixture was stirred for additional 2 hours. After addition of water (30 mL) carefully, the resulting mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound (1.45 g, 6.45 mmol, yield 100%) as a oil. The crude product was used in the next step without further purification. LC-MS: m/z 227.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: CN(C)C=O
Reactant: Cc1c(F)cccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(F)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-fluorophenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.47 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.5 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-fluorophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 2.19 g.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:8][C:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1
Reactant: Cc1c(CCl)oc2ccccc12
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: Cc1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Yield: 44 %

Procedure:
Alkylation of 2-chloromethyl-3-methyl-benzofuran with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to Example 136, Step 3, to give 3-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 44% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=21.6, 7.7 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).