Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:19]([NH:8][C:7]1[C:2]([CH3:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1c(N)cccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 57.1 %

Procedure:
To a solution of 2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.32 g, 1.26 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added butyraldehyde (0.114 mL, 1.26 mmol), followed 10 min later by sodium triacetoxyborohydride (0.374 g, 1.76 mmol) and acetic acid (72 μL, 1.26 mmol). The resultant mixture was stirred for 22 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL), then extracted with CH2Cl2 (2×20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (221 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[NH2:13][C:10]1[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]([CH2:4][CH2:5][N:6]3[CH3:23])=[C:2]([F:1])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 71.2 %

Procedure:
20 mg of the compound (201) obtained in Example 72 was added to 0.4 ml of acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, the water was added to the reaction solution, and the deposited solids were filtered off and washed consecutively with water, ethanol and ether to obtain 13 mg of the subject compound (202) in a 72% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:9]([C:12]1[C:13]([NH:21][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)c1c(N)nn2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CC(C)(C)C)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 3,3-dimethylbutanoyl chloride (0.043 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (4 mL) and concentrated under vacuum to remove excess pyridine. The residue was crystallized from 60% ethanol-water (10 mL) to provide the title compound (40 mg). 1H NMR (300 MHz, CD3OD) δ ppm 1.13 (s, 9H) 1.31-1.53 (m, 6H) 2.33 (s, 2H) 2.95-3.24 (m, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 275 (M+H)+; Anal. Calculated for C15H22N4O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.74; H, 8.10; N, 20.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.[NH2:15][C:16]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:20][N:19]=[C:18]2[O:29][CH:30]=[CH:31][C:17]=12>>[NH2:15][C:16]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:12]([C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:11][CH2:10]3)=[O:13])=[CH:26][CH:27]=2)[CH2:20][N:19]=[C:18]2[O:29][CH:30]=[CH:31][C:17]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2cc(F)ccc2F)CC1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3cc(F)ccc3F)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 407 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gives N-[1-(3-benzyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidin-2-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-7).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[Si:27]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2.42 g (10 mmol) thymidine in 15 ml DMF was added 1.7 g (25 mmol) imidazole and 1.6 g (10.6 mmol) tert-butyldimethyl silyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After removing the solvent, the solid was recrystallized with ethyl acetate/pentane to obtain 2.5 g pure 5'--O--(tert-butyldimethylsilyl) thymidine 1 (70% yield).: m.p. 193-194° C.; 1H NMR (500 MHz, CDCl3) δ9.0 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.36 (dd, J=5.8, 8.1 Hz, 1H, H-1'), 4.44 (m, 1, H-3'), 4.03 (m, 1H, H-4'), 3.85 (m, 2H, H-5'), 2.66 (d, J=3.8 Hz, 1H, OH), 2.35 (m, 1H, H-2'), 2.07 (m, 1H, H-2'), 1.89 (s, 3H, C=CMe), 0.89 (s, 9H, CMe3), 0.09 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ163.8 (C-4), 150.4 (C-2), 135.4 (C-6), 110.9 (C-5), 87.2 (C-4'), 85.0 (C-1'), 72.6 (C-3'), 63.6 (C-5'), 41.1 (C-2'), 25.9 (SiCMe3), 18.3 (SiCMe3), 12.5 (C=CMe), -5.4 (SiMe2), -5.5 (SiMe2).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[CH2:18]([O:17][C:13]([CH2:14][CH2:15][N:12]([CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[O:16])[CH3:19]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN(CCC(=O)OCC)CCc1ccc2c(c1)OCO2
Yield: 43.8 %

Procedure:
A mixture of 16.5 g of 3,4-methylenedioxyphenylethylamine and 40.5 g of ethyl acrylate is refluxed for 24 hours over an oil bath. After cooling, the mixture is concentrated under reduced pressure to distill away excess ethyl acrylate. 16 g of N,N-bis (β-ethoxycarbonylethyl)-3,4-methylenedioxyphenylethylamine is obtained as the residue.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[F:20][C:21]([F:32])([F:31])[CH2:22][S:23][CH2:24][C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27]>>[CH3:19][S:16]([N:15]1[C:3]2[C:2](=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[CH:27]=[C:26]1[C:25]([OH:30])([CH2:28][CH3:29])[CH2:24][S:23][CH2:22][C:21]([F:20])([F:32])[F:31])(=[O:18])=[O:17]
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Procedures Example C, reacting N-(2-iodo-4-nitro-5- trifluoromethyl-phenyl) -methanesulfonamide (0.62 g, 1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl) -pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([CH3:42])[CH3:41])=[N:11]2
Reactant: CC(C)I
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(OC(C)C)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 4 hour. The mixture was diluted with water (20 mL), extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a cream solid, 0.023 g.
Reaction SMILES: BrC1C=C(C([N:16]2C[CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1.C(N(CC)C(C)C)(C)C>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:17][C:18](=[O:22])[NH:19][CH2:20]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 22A and the compound from Example 35A. 3.5 equivalents of N,N-diisopropylethylamine are used. During the reaction, the product precipitates. The precipitate is collected by suction filtration, washed with tetrahydrofuran and dried under high vacuum. 1.17 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([OH:23])[C:15]=1[CH:24]=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:15]=1[CH:24]=[O:25]
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 10.0 g of tert-butyl-dimethyl-chlorosilane and 10.0 g of sodium iodide in 50 ml of acetonitrile was stirred at room temperature for 1 h. The mixture was cooled to 0° C. and 14.0 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester were added at once followed by dropwise addition of 6.7 g of triethylamine over 15 min. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to-give 13.0 g of 3-(tert-butyl-dimethylsilanyloxy)-2-formyl-5-methoxy-6-methyl-benzoic acid methyl ester as white crystals, m.p; 125°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:19])[NH2:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:35]=1[N+:44]([O-:46])=[O:45]>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:18])[NH:19][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([N+:44]([O-:46])=[O:45])[CH:36]=3)(=[O:41])=[O:42])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)NS(=O)(=O)c3ccc(F)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1H (0.200 g, 0.587 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.245 mL, 1.76 mmol) and 4-fluoro-3-nitrobenzenesulfonyl chloride (prepared according to the procedure described in U.S. patent applicaiton Ser. No. 09/957,256, 0.169 g, 0.704 mmol), stirred overnight, and concentrated. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to provide the desired product. MS (ESI) m/e 543 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:29][CH:30]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
5-Cyano-2-benzofurancarboxylic acid (300 mg, 1.60 mmol) and t-butyl 4-aminophenoxyacetate (395 mg, 1.76 mmol) were dissolved in N,N-dimethylformamide (40 ml), and 1-hydroxy-1H-benzotriazole (238 mg, 1.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (342 mg, 1.76 mmol) were added. The mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give 512 mg of t-butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate as a pale-yellow solid (82%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5]1.C[CH2:27][O:28]CC.C(OCC)=O>CO>[OH:28][CH:27]=[C:5]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[O:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:3]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1C(=O)C2=CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
NaH (1.89 g, 47.3 mmol) was added in small portions to a mixture of tert-butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (3.0 g, 9.5 mmol), Et2O (75 mL), and MeOH (120 μL) at rt. The mixture was allowed to stir for 1 h before ethyl formate (9.2 mL, 110 mmol) was added dropwise. The mixture was allowed to stir at 25° C. overnight before it was quenched with 1M aqueous HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (0-100% ethyl acetate in hexanes) provided tert-butyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.2 g, 36%) as a light yellow solid. ESI-MS m/z calc. 345.2, found 246.2 (M+1-Boc)+; Retention time: 2.62 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 15.13 (d, J=8.3 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.88 (dd, J=7.8, 1.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.10-3.95 (m, 2H), 3.25-3.15 (m 2H), 2.15 (d, J=12.7 Hz, 2H), 1.80-1.66 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:41])=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)=[N:24]3)[CH2:19][CH2:18]2)=[O:16])[CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd].CC(=O)OCC>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:25]2[C:26]([CH3:30])([CH3:29])[C:27](=[O:28])[N:23]([CH:20]3[CH2:21][CH2:22][N:17]([C:15]([C:13]4[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[CH3:41])=[O:16])[CH2:18][CH2:19]3)[N:24]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Under a blanket of nitrogen 4.0 g of 2-(1-{[5-(benzyloxy)-2-methylphenyl]carbonyl}piperidin-4-yl)-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 84) are dissolved in 80 ml of methanol and 0.4 g palladium on charcoal (10%) and 2.25 g ammonium formiate are added. The reaction mixture is heated to reflux or 20 min until the starting material is consumed according to TLC analysis. The mixture is filtered over a plug of celite, and the solvent is removed under reduced pressure resulting in the crude product, which is taken up in EA and washed twice with water and with brine. Crystallization from EA and PE results in the title compound.
Reaction SMILES: C(=O)CC.C(=O)CCC.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][OH:14])[CH3:11]>>[CH2:10]([C:12](=[CH:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11]
Reactant: CCCCC(CC)CO
Solvent: CCCC=O
Solvent: CCC=O
Product: CCCC=C(C=O)CC

Procedure:
The aldol condensation of propanal or butanal is an important step in the production of oxo alcohols such as 2-ethyl hexanol. For example, as described in GB 1462328, butanal is typically condensed using an aqueous caustic catalyst at a temperature of the order of 80 to 140° C. to give 2-ethyl hexenal which is then hydrogenated to 2-ethyl hexanol.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([O:19]CC)=O)=[N:3]1.C[N:23](C)C=O.O.[NH4+]>CO>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([NH2:23])=[O:19])=[N:3]1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(SC)nc1-2
Reactant: CN(C)C=O
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CSc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
13.00 g (0.043 mol) of ethyl 1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were suspended in a mixture of 200 mL of methanol, 200 mL of dimethylformamide and 200 mL of ammonium hydrate 30%. The mixture was stirred at 65° C. in a closed bottle for about 8 hours. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was purified by chromatography on a silica gel column eluted by a mixture cyclohexane/ethyl acetate, giving 6.16 g (52% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][C:25]3[CH:34]=[CH:35][C:22]([C:21]([F:20])([F:36])[F:37])=[CH:23][CH:24]=3)=[CH:28][CH:29]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5 Step A and 4-(4-trifluoromethylPhenoxy)-phenol in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H21F3O5 [M−H]−: 469.2
Reaction SMILES: C(O[C:6]([N:8]1[C:12]2=[N:13][C:14]([Cl:18])=[C:15]([Br:17])[N:16]=[C:11]2[CH:10]=[CH:9]1)=[O:7])(C)(C)C.[CH2:19]=[O:20].[OH-].[Na+].Cl>O1CCOCC1.O>[Br:17][C:15]1[N:16]=[C:11]2[C:10]([CH2:19][OH:20])=[CH:9][N:8]([CH2:6][OH:7])[C:12]2=[N:13][C:14]=1[Cl:18]
Reactant: CC(C)(C)OC(=O)n1ccc2nc(Br)c(Cl)nc21
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn(CO)c2nc(Cl)c(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromo-3-chloro-pyrrolo[2,3-b]pyrazine-5-carboxylic acid tert-butyl ester (6.0 g, 18.0 mmol) in 1,4-dioxane (100 mL) was added methanal (5.4 g, 180.4 mmol) and 1 M NaOH solution (54 mL) and the reaction mixture was stirred at room temperature for 16 h. 1.2 N HCl was added into the reaction mixture until the mixture reached pH 7. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with water (50 mL) and extracted with ethyl acetate (150 mL×3). The organic layers were combined and concentrated in vacuo to give (2-bromo-3-chloro-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (4.4 g, 83%) as yellow solid. LC-MS: 292.2 (M−H). This was used directly without further purification.