Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[N:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:37])=[O:36])[CH:34]=1.O>CS(C)=O.C(OCC)(=O)C>[Cl:28][C:29]1[C:30]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)=[CH:4][C:3]=2[C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:36])=[O:37])[CH:34]=1
Reactant: N#Cc1cccc(-c2ccc(O)c(-c3ccnnc3)c2)c1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
4′-Hydroxy-3′-(pyridazin-4-yl)biphenyl-3-carbonitrile (Preparation 119, 330 mg, 1.21 mmol) and potassium carbonate (334 mg, 2.42 mmol) were dissolved in dimethylsulfoxide (7 mL). Then 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 558 mg, 1.21 mmol) was added and the reaction was stirred at room temperature for 2 hours. Water (15 mL) and ethyl acetate (25 mL) were added and the two layers were separated. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% dichloromethane in ethyl acetate to give the title compound (561 mg, 65%).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[C:20]([BH3-])#[N:21].[Na+].Cl>CO.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C(O)C>[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH:21][CH2:20][C:15]2[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:14][CH:13]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: NCCCNCCCN
Reactant: [BH3-]C#N
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CSc1ccc(CNCCCNCCCNCc2ccc(SC)cc2)cc1

Procedure:
Dissolve 1,5,9-triazanonane (655 mg, 0.005 mol) in methanol (distilled from Mg) (50 mL) and add 4-(methylthio)benzaldehyde (1.52 g, 0.01 mol), sodium cyanoborohydride (0.62 g, 0.010 mol) and 1 drop of 1% bromocresol green in ethanol. Maintain the pH of the reaction with 1N hydrochloric acid in methanol until the indicator no longer changes. Evaporate the solvent in vacuo and partition the residue between 1N sodium hydroxide (50 mL) and ethyl acetate (100 mL). Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[CH:6]2
Reactant: CCOC(=O)C(NC(=O)CCc1cnc2ccc(OC)cc2c1)C(=O)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)CCc1cnc2ccc(O)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To a solution of 0.39 g (1 mmol) of diethyl (6-methoxy-3-quinolyl)methylacetamidomalonate in 10 mL of dry methylene chloride was added dropwise at -70° C. a 1M solution of boron tribromide in methylene chloride. The reaction temperature was gradually raised to room temperature while stirring overnight. Then, the reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using 1:1 ethyl acetate/methylene chloride and then ethyl acetate as eluents, to give 43 mg (11.5%) of the desired product as a solid. TLC Rf =0.46 (ethyl acetate); NMR (CDCl3) δ 8.4 (1H, bs), 7.95 (1H, d), 7.7 (1H, bs), 7.35 (1H, dd), 7.1 (1H, d), 6.8 (1H, bs), 4.25 (4H, m), 3.8 (2H, bs), 2.0 (3H, s), 1.3 (6H, m); IR (KBr) ν 3700-2800, 1740, 1660, 1645, 1620, 1500 cm-1. The product has the structural formula: ##STR108##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)=[CH:28][CH:27]=2)[N:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(Cl)nc21
Temperature: 78 °C
Yield: 86.4 %

Procedure:
To a reaction vial was added 2,6-dichloro-9-isopropyl-9H-purine (containing 6.3 mmol), 4-(4-methylpiperazin-1-yl)aniline (1.2 g, 6.3 mmol), isopropanol (32 mL, 0.2 M), and TFA (1 mL, 13 mmol). The reaction vial was capped, stirred and heated at 78° C. (block temperature) for 20 hr. The volatiles were removed to give a dark residue. Sat. aq. NaHCO3 (40 mL) was added. There was dark gummy solid precipitated out. Ethyl acetate (2×120 mL) and DCM (2×80 mL) were used to extract product. The combined organic layers were dried over Na2SO4 and evaporated to give a dark residue that was purified on silica with a gradient of 100% ethyl acetate to 10% ammonia (7 N in methanol)-90% ethyl acetate to give the title product as a light yellow solid (2.1 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1 H) 8.38 (s, 1 H) 7.61 (d, J=8.56 Hz, 2 H) 6.93 (d, J=8.93 Hz, 2 H) 4.71 (dt, J=13.39, 6.63 Hz, 1 H) 3.10 (br. s., 4 H) 2.45 (m, J=4.16 Hz, 4 H) 2.22 (s, 3 H) 1.52 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C19H24ClN7 386.2 (M+H)+ with Cl isotope pattern. The regiochemistry of the product was also confirmed by small molecule X-ray crystallography.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCOCC1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Reactant: CC(C)N
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)CNC(C)C)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In a reactor, 21 g (0.1 mol) of 4-acetylaminophenacyl chloride are introduced into a mixture comprising 100 ml of dioxane, 26 ml (0.3 mol) of isopropylamine and 20 ml of water. The reaction medium is stirred at 30°-40° C. for 2 hours. After the addition of 500 ml of iced water, a precipitate is collected, washed and dried. Recrystallization from ethyl acetate gives 21 g of N-(4-acetylaminophenacyl)isopropylamine, which is in the form of a white powder. Melting point (inst.)=156° C.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[Cl:5][C:6]1[C:11]([O:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9]([N:23]=[C:24]=[S:25])=[C:8]([F:26])[CH:7]=1>O1CCCC1>[Cl:5][C:6]1[C:11]([O:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9]([NH:23][C:24]([N:3]([CH:1]=[O:2])[NH2:4])=[S:25])=[C:8]([F:26])[CH:7]=1
Reactant: NNC=O
Reactant: Fc1cc(Cl)c(Oc2ncccc2C(F)(F)F)cc1N=C=S
Solvent: C1CCOC1
Product: NN(C=O)C(=S)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Formic hydrazide (0.6 g) was added to a mixture of 4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl isothiocyanate (3.4 g) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure and the residue processed. The resulting oil was dissolved in ethanol (30 ml), and hexane added to induce crystallization. The crystals were filtered and dried to give the product, (3.5 g, 69%).
Reaction SMILES: [F:1][C:2]([F:16])([C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][OH:9])[CH2:3][OH:4].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C.[F:37][C:38]1[C:43]([C:44]#[N:45])=[C:42]([F:46])[C:41]([F:47])=[C:40](F)[C:39]=1[F:49]>CC(C)=O>[N+:27]([C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:9][CH2:8][C:7]([F:10])([F:11])[C:6]([F:13])([F:12])[C:5]([F:14])([F:15])[C:2]([F:16])([F:1])[CH2:3][O:4][C:40]1[C:39]([F:49])=[C:38]([F:37])[C:43]([C:44]#[N:45])=[C:42]([F:46])[C:41]=1[F:47])([O-:29])=[O:28]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(F)c1F
Temperature: 80 °C

Procedure:
A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (78.63 g, 0.3 mol, Aldrich Chemical Co., Milwaukee, Wis.), 1-fluoro-2,4-dinitrobenzene (18.6 g, 0.10 mmol), triethyl amine (42 mL, 0.3 mol) and acetone (100 mL) was heated to 80° C. for 1.5 hr. After aqueous workup the excess hexanediol was removed by Kugelrohr distillation and the dimer by-product was removed by crystallization. The residual oil was treated with pentafluorobenzonitrile (19.3 g, 0.10 mol), triethyl amine (15.3 mL, 0.11 mol) and acetone (100 mL) and heated to reflux for 4 h. Aqueous workup followed by extraction gave 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluorobenzonitrile as an orange oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([C:12](=O)[C:13]([O-])=[O:14])C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:29][C:30]([NH2:32])=[O:31])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:12]1[C:13](=[O:14])[NH:32][C:30](=[O:31])[C:29]=1[C:21]1[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc(CC(N)=O)cc(OC)c1OC
Reactant: CCC(=O)C(=O)[O-]
Reactant: c1ccc2[nH]ccc2c1
Product: COc1cc(C2=C(c3cc4ccccc4[nH]3)C(=O)NC2=O)cc(OC)c1OC
Yield: 98.7 %

Procedure:
The general procedure was followed using indole-2-ethylglyoxylate (1.0 g, 4.61 mmol); 3,4,5-trimethoxyphenylacetamide (0.8 g, 3.0 mmol) and 1.0 M KOBut (10 ml, 10.0 mmol). Purification was achieved by column chromatography (ethyl acetate/hexanes 1/1) to yield the title compound (1.12 g, 65%) as red crystals. mp=252° C. 1H NMR (DMSO-d6), 300 MHz, δ [ppm]=3.68 (s, 6H, OCH3); 3.75 (s, 3H, OCH3); 6.87 (s, 2H); 6.98 (m, 2H); 7.14 (t, 1H); 7.53 (m, 2H); 11.04 (s, 1H, NH); 11.28 (s, 1H, NH). EI-MS (m/z): 378.7 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.B.O1CCCC1.CO.BrC1C=CC([C@H](O)CN[C@@H](C2C=CC=CC=2)C)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Agent: B
Agent: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a ice-cooled solution of (6S)-6-(4-bromophenyl)-4-((1R)-1-phenylethyl) morpholin-3-one (intermediate 12, 92 g) obtained in step 1-10 in tetrahydrofuran (400 ml) was added dropwise over 30 minutes a borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 600 ml, 600 mmol). After being warmed to room temperature and stirred for 2 hours, the mixture was ice-cooled again and added dropwise with methanol (70 ml). The solvent was evaporated under reduced pressure. The residue was added with methanol (750 ml) and 1 M aqueous sodium hydroxide (280 ml). The mixture was stirred at 80° C. for one hour, during which period 1 M aqueous sodium hydroxide (70 ml) was added 3 times in every 15 minutes. After the mixture was cooled to room temperature, methanol was evaporated under reduced pressure and the resulting solution was extracted with ethyl acetate. The organic layers was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (intermediate 13, 68 g, yield 88% from intermediate 11) as white crystals.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([C:25]([OH:27])=O)[CH:22]([CH3:24])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][CH:22]([CH3:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:25]([NH:45][O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: NOCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
CDI (2.45 g, 15.1 mmol) is added to a solution of N-(tert-butoxycarbonyl)-D-valine (3.28 g, 15.1 mmol) and CH2Cl2 (60 mL). The solution is stirred for 1 hour at room temperature. Diisopropylethylamine (2.90 mL, 16.6 mmol) and O-benzylhydroxylamine (2.64 g, 16.5 mmol) are added and the solution stirred for 16 hours at room temperature. The solution is concentrated, diluted with EtOAc, and washed with 5% HCl (2×50 mL), NaHCO3 (50 mL) and brine (50 mL). The organic solution is dried (MgSO4), filtered, and concentrated to give 4.42 g (91%) of the title compound as a white solid which is carried on crude.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:22])=[C:14]([N+:19]([O-])=O)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1>C(O)C.[C].[Pd]>[NH2:19][C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]2[O:3][C:2]([CH3:23])([CH3:1])[CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[C:13]=1[CH3:22]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Yield: 73.9 %

Procedure:
2,2,4,6,7-pentamethyl-5-nitro-3-phenyl-2,3-dihydrobenzofuran (2.0 g, 6.4 mmol) was dissolved in ethanol (15 ml) and the solution was subjected to catalytic reduction using 5% palladium carbon (2.0 g) as a catalyst. After the catalyst was filtered off, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether) and then crystallized from hexane to obtain the desired compound (1.33 g, yield: 73.6%), m.p. 131°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>CN(C=O)C.N1C=CC=CC=1.O>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:18])[CH:16]=[CH2:17]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a stirred solution of 2-Amino-6-naphthoic acid (0.3 g, 1.6 mmol) in DMF (2 mL) and pyridine (0.3 mL) was added at 0° C., acryloyl chloride (0.15 g, 1.6 mmol). The resulting mixture was allowed to come to rt and stirred further for 2 h. After that it was poured in water (5 mL) and the solid separated was filtered and dried under reduced pressure to get the desired product (160 mg, 41.5%) as a pale brown solid. This solid was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: COc1cc(N)ccc1OCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=10:80→20:80) and recrystallized from methanol-ethyl acetate to give the title compound (269 mg) as a pale-gray powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@@:10]([CH2:47][CH:48]=O)([CH2:34][CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@@:10]([CH2:47][CH2:48][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)([CH2:34][CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](CC=O)(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CCO[Si](C(C)C)(C(C)C)C(C)C)(CCN2CCOCC2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
N—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step F) and morpholine were combined according to a procedure similar to the one described in Example 91, Step F. Purification by chromatography on silica gel (eluent: 50 to 100% EtOAc/DCM, gradient elution over 15 min) provided the title compound as a clear, colorless glass.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 48.8 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 900 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-ethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 73, above] and 20.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 304 mg of the desired compound as white crystals, melting at between 108° and 110° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34][C@H:33]1[CH3:39])=[N+:30]=[N-:31]>>[N:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:34][C@@H:33]1[CH3:39])=[N+:30]=[N-:31]
Reactant: C[C@@H]1C[C@H](N)CC[C@H]1N=[N+]=[N-]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N=[N+]=[N-])[C@@H](C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,3R*,4R*)-4-azido-3-methylcyclohexanamine hydrochloride (example C12) the title compound is obtained as pale yellow foam.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:13].C([Li])CCC.[CH:19](N1CCCCC1)=[O:20].Cl>C(OCC)C>[Cl:13][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[CH:19]=[O:20]
Reactant: O=CN1CCCCC1
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Yield: 66.6 %

Procedure:
1-Bromo-2,6-dichloro-4- trifluoromethylbenzene (80 g, 0.27 mol) was dissolved in anhydrous diethyl ether (480 ml) and the solution was cooled to -78° C. Butyllithium (2.5M solution in hexane, 100 ml) was added dropwise with stirring in an atmosphere of nitrogen while maintaining the temperature below -70° C. After stirring for a further 1 hour at -78° C. N-formylpiperidine (30.8 g, 0.27 mol) was added dropwise. The mixture was stirred at -78° C. overnight and allowed to warm slowly to 0° C. Hydrochloric acid (2M, 200 ml) was added dropwise to the solution with ice-cooling. The two layers were separated and the organic phase was washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue was dissolved in a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:10) and the solution was filtered through a column of silica. Evaporation of the filtrate and distillation of the resultant oil gave 2,6-dichloro-4-trifluoromethylbenzaldehyde (43.7 g) as a colourless liquid, b.p. 115° C. at 14 mmHg.