Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45]([O:47][CH3:48])=[O:46])#[CH:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:24]([O:23][C:22]([NH:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH3:20])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (A63) (487 mg, 1.17 mmol), Et3N (760 μL), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.40 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), CuI (22.0 mg, 0.117 mmol) and PPh3 (36.0 mg, 0.117 mmol) in DMF (4.6 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-25% EtOAc in cyclohexane) to give the title compound A64 as a yellow solid (400 mg, 62%); 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 7.70 (dd, J=7.83, 1.17 Hz, 1H), 7.61 (d, J=8.61 Hz, 2H), 7.43 (m, 3H), 7.34 (d, J=8.40 Hz, 2H), 4.78 (m, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 1.61 (s, 1H, peak obscured), 1.46 (m, 12H). LCMS-B: rt 8.90 min; m/z 555 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1.[ClH:34].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:34].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Br)cc1)CCC2

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.47 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]-amine (0.70 g) as starting materials were reacted and treated in the same manner as in Example 12. The obtained solid was dissolved in ethyl acetate (4 mL). Thereto was added 4 mol/L-HCl/ethyl acetate (0.35 mL), and the precipitated solid was collected by filtration to give N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.65 g). melting point: 104-113° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[C:6]2=[CH:10][CH:11]=[CH:12][N:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[C:6]2=[CH:10][CH:11]=[CH:12][N:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2cccc2c(=O)[nH]1
Product: CSc1nc(Cl)c2cccn2n1
Temperature: 75 °C

Procedure:
2-Methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (23.25 g, 0.1283 mol) was dissolved in Phosphoryl chloride (114 mL, 1.22 mol) and the reaction was then heated at 75° C. until HPLC showed consumption of starting material. The mixture was reduced and the solution was poured over ice. The solid was then filtered and washed with water to afford the desired product. The product was then allowed to dry under vacuum overnight to provide 25.47 grams of 4-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. 1H NMR (400 MHz, DMSO, d6) δ 8.16 (s, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[CH2:28][O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:42](Br)[CH:43]=[CH2:44]>CN(C=O)C>[CH2:44]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:43]=[CH2:42]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate (1 eq.) was dissolved in DMF (0.34M solution) and the solution was degassed. NaH (1.1 eq.) was added and the mixture was left stirring for 5 min. Allyl bromide (1.2 eq.) was added and stirring was continued for 5 h. All volatiles were evaporated in vacuo and the residual material was dissolved in Et2O. The solution was washed with 0.5N HCl, saturated aq. NaHCO3 solution and with brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo and the residual material was purified by flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as a colorless sticky solid (84%). The material was used without further characterization in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[C:19]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]2=[N:17][C:16]=3[NH2:27])=[CH:6][CH:5]=1)[CH3:2].C(O)C>[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[C:19]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]2=[N:17][C:16]=3[NH2:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 2-((4-ethoxyphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The contents were degassed under vacuum followed by hydrogen flush (three times). The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product as a yellow solid. Further recrystallization using toluene afforded product 2-(4-ethoxyphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a white fine crystal. 1H NMR (CDCl3): δ 8.52 (d, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.46 (s, 1H), 7.12 (dd, 1H), 7.06 (d, 2H), 6.75 (d, 2H), 5.95 (bs, 2H), 3.93 (q, 2H), 3.11-3.05 (dd, 2H), 2.95-2.90 (dd, 2H), 2.44 (s, 3H), 1.33 (t, 3H). LRMS [M+H]=358.2
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:32](=[O:33])[CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCc1cccnc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2cccnc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccn(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (20 mg, 0.04 mmol) in ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL) at room temperature. The mixture was heated to 40-45° C. and stirred for 3 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (10 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 17 mg (89% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C23H20Cl2N2O4 (M+Na) 481.0691, found 481.0699.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O>CC(C)=O.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[C:15]([OH:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
600 mg of alcohol 165 (2.64 mmol) was dissolved in 15 ml of acetone, cooled to 0° C. and added dropwise with 5 ml of Jones reagent (7.40 mmol, 2.8 eq.) (freshly prepared from 2 g of CrO3, 2.7 g of conc. H2SO4, 12 ml of H2O) and stirred for 2 h at RT, the course of the reaction being monitored using TLC (EE/CH 1:1). This was followed by addition of 4 ml of isopropanol, during which the orange color of the reaction mixture gradually turned green-brown. Filtration over Celite was followed by washing with 5 ml of an acetone/glacial acetic acid mixture (20:1) and concentrating to dryness. The remaining greenish residue was purified using silica gel column chromatography (CH2Cl2/MeOH 20:1), thereby obtaining 470 mg of vinylproline 166 (1.95 mmol, 74%) in the form of white crystals suitable for X-ray crystallographic analysis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4F)=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[O:47]1CCOC[CH2:48]1.[OH-].[K+].CO>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:34][CH2:35][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:38]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=4[O:47][CH3:48])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)CCN[C@H]1CC[C@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(-c2nn([C@H]3CC[C@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of trans-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (Example 526) (0.04 g, 0.06 mmol), p-dioxane (4 mL), potassium hydroxide (0.02 g, 0.31 mmol), a trace amount of methanol and water (0.4 mL) were heated at 80° C. for 1 hour. The mixture was stirred at ambient temperature overnight and at 80° C. for 4 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield trans-3-({4-[4-amino-3-(3-methoxy-4-{[2-methoxy-4-trifluoromethylbenzoyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.04 g, 0.06 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.72 (s, 1H), 8.61(d, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 7.61(s, 1H), 7.53 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 4.20 (s, 3H), 4.05 (s, 3H), 1.44-3.61 (m, 13H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].Cl.[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[C:12]([F:14])=[CH:13][C:2]=1[Cl:1])[CH3:9]
Reactant: CC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CCNC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-[2-Chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]propionic acid (20 g) and β-alanine methyl ester hydrochloride (8.2 g) were dissolved in dichloromethane (200 mL). After slowly adding 4-methylmorpholine (14.8 g) dropwise to the reaction mixture, stirring was performed for 1 hour. After adding (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (18.5 g) for 30 minutes, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (24 g) including a trace amount of impurities, which was recrystallized twice using a mixture solvent of ethyl acetate and hexane to give the target compound (18.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:10]2[C:14](=[CH:15][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Pyridin-3-yl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:12]=[CH:11][C:9]([NH2:10])=[N:8][C:6]2=[O:7])[CH2:3][CH2:2]1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21](Cl)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(#N)C>C(N(CC)CC)C>[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21]([NH:10][C:9]2[CH:11]=[CH:12][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:7])[N:8]=2)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccn(CC2CC2)c(=O)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(CC3CC3)c(=O)n2)cc1

Procedure:
A mixture of 495 mg. of 1-cyclopropylmethylcytosine, 702 mg. of N-acetylsulfanilyl chloride, 10 ml. of acetonitrile and 322 mg. of triethylamine was stirred and refluxed for 18 hours. The solvent was evaporated under reduced pressure, and the residue triturated with 10 ml. of water and 3 ml. of 10% aqueous sodium hydroxide. The alkaline solution was decanted from the dark insoluble portion and cleared by filtration. Addition of acetic acid to about pH 5 gave a gummy precipitate which solidified only very slowly. The aqueous solution was decanted and the gum triturated with 2 ml. of hot ethanol, and allowed to settle in an ice bath to obtain after filtration 280 mg. of product, melting at 222°-224°. A sample for analysis was recrystallized from aqueous ethanol; m.p. 225°-226°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH:21]1[CH:30]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:29]2[C:24](=[C:25]([F:42])[CH:26]=[CH:27][C:28]=2[F:41])[O:23][CH2:22]1)[CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:21]2[C:30]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])([C:29]3[C:24]([O:23][CH2:22]2)=[C:25]([F:42])[CH:26]=[CH:27][C:28]=3[F:41])[CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCN(CCCOCc1ccccc1)C1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCCN(CCCOCc3ccccc3)C1COc1c(F)ccc(F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The Methanesulfonic acid 3-{(3-benzyloxy-propyl)-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-amino}-propyl ester was dissolved in 60 mL of THF then potassium tertbutoxide (1M solution in tertbutanol, 3.27 ml, 3.27 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with 100 ml of brine and 100 ml of ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate then concentrated. The product was purified by column using EtOAc/Hex. as the eluent (gradient from 0/100 to 100/0 in 35 minutes). Yield: 438.8 mg, 80. 1H NMR (CDCl3 400 MHz) δ7.61 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.37-7.24 (m, 5H), 7.04 (td, 9.5, 5.1 Hz, 1H), 6.43-6.36 (m, 1H), 5.14 (d, J=12.4 Hz, 1H), 4.72 (d, J=13.9 Hz, 1H), 4.47 (dd, J=28.5, 11.7 Hz, 2H), 3.42 (t, J=6.2 Hz, 2H), 3.29 (s, 1H), 2.90-2.82 (m, 2H), 2.82-2.75 (m, 1H), 2.57 (d, 12.4 Hz, 1H), 2.45 (td, J=11.7, 2.2 Hz, 1H), 2.03-1.93 (m, 1H), 1.83-1.64 (m, 2H), 1.63-1.59 (m, 1H), 1.36-1.23 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[C:22]([Br:35])[CH:21]=1>>[Br:35][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1Br
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1ccsc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CC)CO)n2)cc1Br
Yield: 30 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-thiophen-3-yl-pyrimidine-4-ylamino)-butan-1-ol (426 mg, 1.5 mmol) with (RS)—S-(4-amino-2-bromphenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (404 mg, 1.3 mmol) according to procedure 5b, the desired product is obtained in 30% yield (214 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-15% ethanol)).
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]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[C:57]([O:60][CH2:61][C:62](Cl)=[O:63])(=[O:59])[CH3:58]>C(Cl)Cl>[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]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:62](=[O:63])[CH2:61][O:60][C:57](=[O:59])[CH3:58])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Solvent: ClCCl
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)COC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-ethoxycyclohexyl)-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 (40 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:6])[CH3:5].[O-]CC.[Na+].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O>CCO>[CH3:1][O:2][CH2:3][C:4](=[O:6])[CH2:5][C:12](=[O:14])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Methoxyacetone (5.22 mL, 56.8 mmol) was added dropwise to a cold (0° C.), stirred solution of sodium ethoxide (21% in EtOH, 20.2 g, 62.4 mmol) and EtOH (50 mL), under an argon atmosphere. The reaction mixture was stirred for 30 min at 0° C. Then, diethyl oxalate (7.71 mL, 56.8 mmol) was added. The reaction mixture was allowed to warm to rt, stirred for 16 h, quenched by addition of 1N HCl (75 mL), and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 5-10%) to afford the title compound (3.21 g) as a yellow oil. tR: 0.70 min (LC-MS 2); ESI-MS: 189.1 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1, CPS staining).