Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].CCN(CC)CC.C(O)(=O)[CH2:22][C:23]([CH2:28]C(O)=O)([C:25](O)=O)[OH:24].C1C[O:37][CH2:36]C1>C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>[C:23]([O:24][C:36]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])=[O:37])([CH3:22])([CH3:25])[CH3:28]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of 3-hydroxy-4-nitrobenzoic acid (1.83 g, 10 mmol) in THF (10 mL) was treated with Et3N (3.4 mL, 24 mmol) and di-tert-butyl dicarbonate (2.40 mL, 11 μmol) and stirred at room temperature for 16 h. The reaction mixture was poured into 10% citric acid solution (20 mL), extracted with EtOAc (2×10 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (2.36 g, 83%) as a cream solid; IR νmax (Nujol)/cm−1 2985, 1772, 1717 and 1592; NMR δH (400 MHz, DMSO) 13.85 (1H, s), 8.26 (1H, d, J 8.5 Hz), 8.04 (1H, dd, J 8.5, 2.0 Hz), 7.98 (1H, d, J 2.0 Hz) and 1.49 (9H, s).
Reaction SMILES: C[C:2]([CH2:9][C:10]#[CH:11])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C([N:24]([CH2:27][CH3:28])CC)C>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:6](=[O:7])[CH:2]([C:9]#[C:10][CH3:11])[C:3]([NH:24][CH2:27][C:28]1[CH:20]=[CH:19][CH:18]=[CH:15][C:14]=1[O:13][CH3:12])=[O:4]
Reactant: COc1ccccc1CN
Reactant: CCN(CC)CC
Reactant: C#CCC(C)(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Product: CC#CC(C(=O)NCc1ccccc1OC)C(=O)NCc1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.69 g [59] (24.3 mmol) in 100 ml dichloromethane was carefully added dropwise to a mixture of 6.67 g of 2-methoxybenzyl amine (48.6 mmol) and 5.06 g of triethylamine (50 mmol) in 100 ml diochloromethane, with exclusion of moisture. The mixture was agitated at room temperature for a further three hours, then repeatedly extracted with chloroform after adding water. The organic phase was successively washed with 1N HCl, saturated potassium carbonate solution and water and dried over sodium sulphate.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=[C:11]([CH2:14][CH3:15])[CH:12]=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCOCC>[CH2:14]([CH:11]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:3][N:2]=[CH:12]1)[CH3:15]
Reactant: CCC(C=O)=Cc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: CCC1C=NNC1c1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
62 ml (10 equiv.) hydrazine hydrate was added to 150 mL diethylether. The emulsion was cooled with an ice/NaCl bath to −10° C. A solution of 20.4 g 2-benzylidene-butyraldehyde in 100 mL ether was added dropwise at −10° C. and stirred at −10° C. for 3 hours. The mixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted 2 times with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 6.1 g of a clear fluid (102-106° C., 0.6 mbar) containing 94% of the desired product (mixture of diastereomeric pairs). Characteristic signals of the first diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J=6.5 Hz, 3H), 3.03-3.13 (m, 1H), 4.74-4.81 (m, 1H), 6.83 (br s, 1H). Characteristic signals of the second diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J=7.5 Hz, 3H), 2.84-2.93 (m, 1H), 4.28-4.34 (m, 1H), 6.76 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[NH:20][C:21](=[S:23])[S:22]/1.[CH3:25]CN(C(C)C)C(C)C.IC>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[N:20]=[C:21]([S:23][CH3:25])[S:22]/1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CI
Product: CSC1=NC(=O)/C(=C/c2ccccc2Nc2c(Cl)ccc(C)c2Cl)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To room temperature suspension of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone (3.177 g, 8.04 mmols) in 125 mL of ethanol is added Hunig's base (1.57 mL, 9.03 mmols) followed by iodomethane (600 μL, 9.63 mmols). After stirring at room temperature overnight the yellow solid is collected by filtration to give 2.861 g (87%) of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-(methylthio)-4(5 H)-thiazolone. An analytical sample is obtained by recrystallization from hexane-ethyl acetate; mp 233°-236° C. Calc'd for C18H14Cl2N2OS2:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH2:23][CH:3]12.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.O>CS(C)=O>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12
Reactant: O=C(O)c1ccc(N2N=C3c4ccccc4SCC3C2=O)cc1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 4-(3-Oxo-3a,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzoic acid (250 mg, 0.77 mmol) was dissolved in dimethyl sulphoxide (6 ml). O-Chloranil (189 mg, 0.77 mmol) was added and the mixture was stirred at room temperature overnight. Water (20 ml) was added and the solids were collected by filtration and washed with water. The filter cake was triturated with toluene, filtered and dried under vacuum. The title compound was isolated as a dark brown solid (230 mg, 0.71 mmol, 92%). LCMS: m/z 323 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>CCCCCC.C(OCC)(=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][NH:29][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
19.3 g(139 mmol) of potassium carbonate was added to 200 ml of dimethylformamide, and then the solution was heated to dissolve potassium carbonate. After cooling to room temperature, 8 ml(70 mmol) of ethyl bromoacetate and 10 g(70 mmol) of 1-naphthylamine were added to the solution, which was then stirred for 48 hours. DMF was removed under reduced pressure and ethyl acetate was added to the residue. The ethyl acetate layer was washed with water 4 times and saturated sodium chloride solution. Ethyl acetate was removed under reduced pressure, and then column chromatography was performed using a mixed solution(9:1) of hexane and ethyl acetate as an eluent to obtain 12 g of the title compound(Yield 75%, MW 229).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccc(F)cc2F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2,4-difluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.40-7.38 (m, 2H), 6.90-6.79 (m, 2H), 4.81-4.77 (m, 2H), 4.14-4.08 (m, 2H), 3.88 (m, 2H), 3.62-3.54 (m, 2H), 3.32 (t, J=8.7 Hz, 1H), 3.02 (d, J=9.5 Hz, 1H), 2.86-2.83 (m, 1H), 2.65 (m, 1H), 2.43-2.20 (m, 3H), 2.00-1.83 (m, 2H), 1.21 (d, J=6.6 Hz, 3H). MS: (M+H m/z 430.2).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NCC(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCC(F)(F)F)nc2c1
Yield: 66.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (500 mg, 1.58 mmol) in DMSO (23 ml) was added 2,2,2-trifluoroethan-1-amine (188 mg, 1.90 mmol) and DIEA (407 mg, 3.15 mmol,) with stirring, and the resulting mixture was allowed to react for 4 days at 110° C. in an oil bath. The reaction mixture was diluted with water (80 ml), extracted with dichloromethane (4×15 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-[(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylate as a yellow solid (400 mg, 67%).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5]Br.CN1CCCC1=[O:17]>O>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:17]
Reactant: CN1CCCC1=O
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Solvent: O
Product: OCCC(F)(Cl)C(F)(F)Br
Temperature: 130 °C
Yield: 49 %

Procedure:
A mixture of 1,4-dibromo-2-chloro-1,1,2-trifluorobutane (XVI) (7.5 g, 24.6 mmol), 1-methyl-2-pyrrolidinone (14 mL) and water (2.5 mL) was heated at 130° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (80 mL) and extracted with ether (2×75 mL). The ether extract was washed with water (3×40 mL), brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was chromatographed over silica gel to give 2.9 g (49%) of the desired alcohol as a clear oil.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3SC)[N:7]=[CH:6][C:5]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3][CH2:2]1.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>O>[CH:1]1([C:4]2[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:24]([CH3:28])(=[O:26])=[O:23])[N:7]=[CH:6][C:5]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: CO
Reactant: CCOC(=O)c1cnn(-c2ccccc2SC)c1C1CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccccc2S(C)(=O)=O)c1C1CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of ethyl 5-cyclopropyl-1-(2-methylthiophenyl)-1H-pyrazole-4-carboxylate (0.456 g, 1.51 mmol) in methanol (6 mL) at 0° C. was treated with a solution of oxone (1.40 g, 2.27 mmol) in water (6 mL). The resulting slurry was was stirred at 23° C. for 8 h. The mixture was treated with additional oxone (0.46 g, 0.76 mmol), stirred for 14 h and partitioned between CH2Cl2 and water. The organic layer was washed with water, dried over MgSO4 and concentrated in vacuo to afford 0.504 g (100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=CCCCC)=[CH:10][CH:9]=1)=[O:6].O.I([O-])(=O)(=O)=[O:35].[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([CH:18]=[O:35])=[CH:10][CH:9]=1)=[O:6]
Reactant: CCCCC=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
To a stirred room temperature solution of 3-fluoro-N-(4-hex-1-enyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide (2.7 g, 6.25 mmol) THF (15 ml) and water (5 ml) is added osmium tetroxide (2.5% in t-butanol) (1000 and sodium periodate (6 g) in portions over 30 minutes. After 1.5 hours, the mixture is diluted with ethyl acetate (200 ml) and washed with water (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes to give 3-fluoro-N-(4-formyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide as a tan powder (1.072 g). Mp: 204-5° C. 1H NMR 400 MHz (CDCl3) δ 10.3(s, 1H), 9.41(d, 1H, J=8.8 Hz), 8.47(d, 2H, J=7.6 Hz), 8.02(d, 1H, J=8 Hz), 7.92(d, 1H, J=8.4 Hz), 7.65-7.76(m, 2H), 7.31(s, 1H), 7.05(d, 1H, J=8 Hz), 6.79(d, 1H, J=11.6 Hz), 3.88(t, 4H, J=5.2 Hz), 3.27(t, 4H, J=5.2 Hz). MS: 379 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[C:18](Cl)=[CH:17][N:16]=3)=[C:10]([O:31][CH3:32])[CH:9]=2)[CH2:4][C@H:3]1F.COC1C=[C:41]([N:43]2[CH2:48]CC(N3CCN(C)CC3)[CH2:45][CH2:44]2)[CH:40]=CC=1N.[CH3:56]CN(C(C)C)C(C)C>C(O)CCCC.C(Cl)Cl.CO>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:19]2[C:18]([CH3:56])=[CH:17][N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:6][CH2:7][CH:2]([N:1]5[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]5)[CH2:3][CH2:4]4)=[CH:9][C:10]=3[O:31][CH3:32])[N:20]=2)=[CH:22]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: COc1cc(N2CC[C@@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Temperature: 25 °C
Yield: 54 %

Procedure:
As an alternate procedure to the compound described in Example 9, a solution of 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1, 3.39 g, 13.9 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27, 4.23 g, 13.89 mmol), and PTSA monohydrate (6.61 g, 34.74 mmol) in n-pentanol (56 mL) was heated in an oil bath at 140° C. overnight. The reaction mixture was allowed to cool to RT. Hunig's base (10 mL) was added. Solvent was removed in vacuo and to the residue was added methanol (500 mL). Silica gel (120 g) was added to the mixture. Concentration in vacuo removed the solvent, and the residue was loaded to silica gel column and eluted with 10% MeOH, 1% NH4OH in CH2Cl2. The collected fractions were concentrated and the residue was triturated with diethyl ether. Filtration afforded the solid and it was dissolved in a mixture of CH2Cl2 (100 mL) and MeOH (500 mL). Concentration in vacuo reduced the solvent volume to 70 mL and filtration yielded the solid as the title compound (3.8 g, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:42](=[O:44])[CH3:43])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CC(=O)Cl
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(NCCCCCCOC(C)=O)nc(Cl)n1
Yield: 65.4 %

Procedure:
In 10 ml of dichloromethane were dissolved 1.00 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.40 g of acetyl chloride, and under stirring, 0.50 g of triethylamine was added to the solution and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.70 g of the title compound as pale yellow oily product. nD19.6 1.5228.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH2:59]([O:66][C:67]([C@@H:69]1[CH2:73][C@H:72]([NH:74][C:75]([O:77][CH2:78][CH:79]2[C:91]3[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=3[C:85]3[C:80]2=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:76])[CH2:71][NH:70]1)=[O:68])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[CH2:59]([O:66][C:67]([C@@H:69]1[CH2:73][C@H:72]([NH:74][C:75]([O:77][CH2:78][CH:79]2[C:91]3[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=3[C:85]3[C:80]2=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:76])[CH2:71][N:70]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:68])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (435 mg, 1.69 mmol) in DMF at 0° C. was added DIPEA (1.18 mL, 6.76 mmol) and HATU (674 mg, 1.77 mmol). After 30 minutes (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94 g, 1.69 mmol) was added in one portion. The cooling bath was removed and the mixture stirred for 1 h, diluted with water, the resulting white precipitate collected, washed with water and air-dried to give (2S,4S)-1-((S)-2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.07 g, 93%).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH:7]1([NH2:10])[CH2:9][CH2:8]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]1([NH:10][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CC1
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51]C)[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].[CH2:56]1[O:59][CH:57]1[CH3:58].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH2:56][CH:57]([OH:59])[CH3:58])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC1CO1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCC(C)O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reaction time: 20 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (52 mg, Example 13) in dry methanol (1 ml) was added a large excess of propylene oxide (200 μl) followed by a catalytic amount of p-toluenesulfonic acid at room temperature. After stirring at this temperature for 20 h, the solution was concentrated and purified by preparative tlc on silica gel (1% NH4OH in 5% i-PrOH/CH2Cl2) to give 35 mg of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:11]2[CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15][C:10]=2[CH:9]=[CH:8]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:13]2[CH2:14][CH2:15][C:10]3[CH:9]=[CH:8][O:7][C:11]=3[CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1)(=[O:26])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2ccoc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.04 ml (0.5 mmol) of oxalyl chloride in 30 ml of dichloromethane, 0.07 ml (1.0 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To this solution, a solution of 0.122 g (0.330 mmol) of 4-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-ylsulfonyl)phenylphenylmethanol in 10 ml of dichloromethane and 1 ml of dimethyl sulfoxide was added at -78° C., followed by stirring for 15 minutes. To this mixture, 0.28 ml (2.0 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.