Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:48]=1.C(N(CC)CC)C>CN(C=O)C.CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:48]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.9 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (200 mg, 0.85 mmol), HATU (210 mg, 0.89 mmol) in DMF (5 mL) was added methyl 5-aminopicolinate hydrochloride (156 mg, 1.02 mmol) followed by triethylamine (226 mg, 2.24 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EA (10 mL) and washed with NaHCO3 (10 mL), NH4Cl (10 mL) and brine (10 mL) then dried over MgSO4 and concentrated to give 78 mg (25%) of methyl 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinate INT-14 which was used in the next step without purification. LCMS-ESI (m/z) calculated C17H15F3N2O4: 368; found 369 [M+H]+, tR=3.06 min (Method 1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.C1COCC1.O>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]=[C:10]2[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccc([N+](=O)[O-])cc23)o1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccc(N)cc23)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.9 g (2.4 mmol) of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-5-nitroindazole were dissolved in 100 ml of methanol/THF (1:1) by gentle warming, a solution of 2.5 g (14.4 mmol) of sodium dithionite in 50 ml of water was added and the mixture was stirred at RT for 16 h. For work-up, the mixture was concentrated and the residue was chromatographed over silica gel using dichloromethane/methanol (98.5:1.5). This gave 140 mg (17%) of the title compound. m.p.: 195-196° C.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][CH2:19][C@@H:20]1[N:24]([CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:23](=[O:35])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[CH:19]([C@H:20]1[CH2:21][CH2:22][C:23](=[O:35])[N:24]1[CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:18]
Reactant: COC(=O)CCCSCCN1C(=O)CC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)CCCSCCN1C(=O)CC[C@@H]1C=O
Reaction time: 0.25 h

Procedure:
A solution of anhydrous dimethylsulfoxide (0.21 mL, 2.7 mmol) in 5 mL of methylene chloride under argon atmosphere was cooled to −70° C. and trifluoroacetic anhydride (0.17 mL, 1.2 mmol) in 1 mL of methylene chloride was added dropwise. The reaction was stirred for 15 minutes maintaining the temperature and then methyl 4-({2-[(5R)-5-(hydroxymethyl)-2-oxo pyrrolidin-1-yl]ethyl}thio)butanoate (0.15 g, 0.55 mmol) in 2 mL of methylene chloride was added. The solution was stirred and kept at −70° C. for 20 minutes followed by the addition of triethylamine (0.27 mL, 1.9 mmol). The reaction was allowed to come to room temperature, stirred for 30 minutes and then quenched with the addition of aqueous phosphoric acid solution (2%, 50 mL) and methylene chloride (25 mL). The reaction phases were separated and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to yield methyl 4-({2-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]ethyl}thio)butanoate which was taken on to next step.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH:12]([OH:14])[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:35][N:2]([CH3:1])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C(C)O)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C(C)=O)[C@H]2OCc2ccc(OC)cc2)cc1
Yield: 88.8 %

Procedure:
A solution of 1-((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (450 mg, 0.90 mmol, mixture of diastereomers, faster eluting isomer: slower eluting isomer 1:5 by HPLC and 1HNMR) in dichloromethane (20 mL) was treated with Dess-Martin reagent (760 mg, 1.80 mmol) for 2 hours at room temperature. The reaction mixture was quenched by sat. aqueous Na2S2O3 solution (20 mL) and sat. aqueous NaHCO3 solution (20 mL), and extracted with dichloromethane (2×20 mL). The combined, organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue, which was purified by silica gel column, eluted with 2-3% methanol in dichloromethane to give compound 33 as a yellow syrup (400 mg, 88%). (ES, m/z): [M+H]+ 501.0; 1H NMR (300 MHz, CDCl3) δ 7.25-7.30 (m, 4H), 6.83-6.90 (m, 4H), 6.29-6.31 (d, J=6.0 Hz, 1H), 4.26-4.64 (m, 6H), 3.81-3.98 (m, 8H), 2.96-3.02 (m, 6H), 2.17 (s, 3H).
Reaction SMILES: [S:1]([C:5]1[S:14][C:8]2=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[S:14][C:8]2=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-sulfamoylthieno[2,3-b]pyridine-7-oxide (0.50 g, 2.2 mmol) and dimethylformamide dimethyl acetal (0.3 g, 2.2 mmol) in acetonitrile (3 ml) was stirred for 24 hours at 25° C. The solvent was evaporated and the residue was treated with water. After filtration and drying, there was obtained 0.57 g, (91%) m.p. 232°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[Br:21]Br.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[C:12]([Br:21])[C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c(=O)c(C(=O)O)nn1-c1ccc(F)cc1
Yield: 70.8 %

Procedure:
1-(4-Fluorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid (1.5 g) is suspended in 100 ml of dry methanol, and 0.242 g of sodium hydroxide is added. To the solution is added dropwise 1.038 g of bromine dissolved in 50 ml of methanol. The solvent is removed leaving a white solid, which is taken up in dilute base and the solution acidified with hydrochloric acid. The resulting precipitate is filtered and recrystallized from chloroform/ether to yield 1.4 g of 1-(4-fluorophenyl)-5-bromo-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (mp-219°-20°).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C:31]2[C:26](=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].N#N>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C:31]2[C:26](=[C:27]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([C:12]#[N:13])[CH:14]=4)=[N:4][N:3]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: N#Cc1cc(-c2nnc(Br)s2)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Prepared using General Procedure 4. A suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (1.5 g, 5.3 mmol), (S)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate IND INT-17 (1.9 g, 5.3 mmol) and potassium carbonate (2.2 g, 16 mmol) in DME:H2O (3:1, 70 mL) was degassed with N2 for 20 min before the addition of Pd(PPh3)4 (0.43 g, 0.3 mmol). The mixture was degassed with N2 for an additional 5 min and the suspension was heated under N2 at 85° C. for 12 h. Upon cooling, the reaction mixture was diluted with water (150 mL) and the mixture stirred for 30 min. The resulting solid was filtered, washed with water, and dried under high vacuum to afford 2.3 g (100%) of crude (S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as light brown solid which was used in the next experiment without purification. LCMS-ESI (m/z) calculated for C23H21FN4O2S: 436.1; found 459.1 [M+Na]+, tR=4.19 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:26][CH3:27])[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with diethylamine
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NC[C@H](N)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC[C@H](N)Cc1ccccc1
Yield: 103.3 %

Procedure:
A sample of the compound from step 164d (1.2 g, 6.8 mmol) was hydrogenated (4 atm) in ethanol over 1.2 g of 10% Pd/C for 21.5 hours at room temperature. The mixture was filtered to remove the catalyst, and the solvent was removed to afford the title compound (1.055 g). MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:35]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:36])[C:26]=2[N:25]=[C:24]1[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[NH2:36][C:27]1[C:26]2[N:25]=[C:24]([CH2:37][CH2:38][CH2:39][CH3:40])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][NH:17][C:15]([NH:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:16])[C:35]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCONC(=O)Nc1ccccc1
Temperature: 50 °C
Yield: 12.2 %

Procedure:
Triethylamine (495 μL, 3.55 mmol) and phenyl isocyanate (316 mg, 1.65 mmol) were added to a mixture of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (580 mg, 1.77 mmol) in chloroform (10 mL). The reaction was heated at 50° C. overnight and became homogeneous. The solution was diluted with 1 chloroform, washed with brine (2×), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide the crude product as an orange solid (700 mg). The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in ratios ranging from 100:0 to 95:5) to provide 90 mg of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-N′-phenylurea as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])[CH:3]=1.Br[CH2:32][C@@H:33]([CH3:53])[CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:36]([O:35][CH2:34][C@H:33]([CH3:53])[CH2:32][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:23])=[O:24])[C:4]1[CH:3]=[C:2]([C:1]2[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=2)[C:19]([C:20]2[CH:16]=[CH:17][CH:8]=[CH:9][CH:10]=2)=[CH:18][C:5]=1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccccn2)cc1
Reactant: C[C@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(-c3ccccc3)c(-c3ccccc3)cc2N(C[C@@H](C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S(=O)(=O)c2ccccn2)cc1
Reaction time: 4 h
Yield: 139.6 %

Procedure:
596 mg of methyl 4-({4,5-dimethyl-2-[(pyridin-2-ylsulfonyl)amino]phenoxy}methyl)benzoate was dissolved in 5.96 mL of DMF, and 820 mg of {[(2S)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane and 1.37 g of cesium carbonate were added thereto, followed by stiffing at 80° C. for 4 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 840 mg of methyl 4-[(2-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-diphenylphenoxy)methyl]benzoate.
Reaction SMILES: O1CCCC1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>C(OCC)(=O)C.CO.C(N(CC)CC)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:22][CH2:23][CH:24]([OH:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCCCCNCC(O)c1ccccc1)OCc1ccccc1

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from benzyl 6-bromohexanoate and 2-amino-1-phenylethanol. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 3:1:0.1). Melting point: 77°-78° C.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[S:18](Cl)(=[O:20])=[O:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:11][C:7]1[CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=[C:2]([NH:1][S:18]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)(=[O:20])=[O:19])[N:12]=[C:5]2[N:6]=1
Reactant: Cc1cc(C)n2nc(N)nc2n1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NS(=O)(=O)c3cccs3)nc2n1
Yield: 6.2 %

Procedure:
A mixture of 4.24 g (26.0 mmol) of 2-amino-5,7-dimethyl-1,2,4-triazolo(1,5-a)pyrimidine, 5.08 g (27.8 mmol) of 2-thiophene sulfonyl chloride and 0.16 g (1.3 mmol) of 4-dimethylaminopyridine in 30 ml of dry pyridine was heated at reflux for 47 hours. The majority of the pyridine was removed by evaporation at reduced pressure and the residue was taken up in 1N NaOH, treated with charcoal and filtered through celite. The filtrated was treated with charcoal and filtered through celite. The yellow filtrate was cooled in an ice bath and acidified with concentrated HCl to precipitate a yellow solid. Drying in vacuo gave 0.50 g (6 percent) of the desired sulfonamide as a yellow powder, m.p. 236°-237.5° C.: IR (KBr) 3390 (broad), 1493, 1375 and 1156 cm-1 ; 'H NMR (DMSO-d6) δ12.3 (1H, broad, --SO2NH--), 7.7-8.1 (2H, m, thiophene H's at 3- and 5-positions), 6.9-7.3 (2H, m including S at 7.03, thiophene H at 4-position and pyrimidine H), 2.62 (3H, s, --CH3) and 2.49 (3H, s, --CH3).
Reaction SMILES: [C:1]([O:36]C(C)(C)C)(=[O:35])[C:2]([O:4][C:5]([CH3:34])([CH3:33])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[C:18]3[S:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[CH:23][C:17]=3[N:16]=[CH:15]2)=[CH:10][C:9]=1[O:31][CH3:32])=[O:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([CH3:34])([O:4][C:2](=[O:3])[C:1]([OH:36])=[O:35])[CH3:33])=[C:9]([O:31][CH3:32])[CH:10]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)=[CH:25][CH:26]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)C(=O)O
Yield: 91 %

Procedure:
A solution of tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl oxalate (124 mg; 0.212 mmol) in 0.5 mL of TFA and 1 mL of CH2Cl2 was stirred at rt for 1.5 h. The solution was concentrated under reduced pressure to afford 102 mg (91%) of the title compound as a white foam. 1H NMR (CDCl3) δ 1.70 (s, 6H), 3.86 (s, 3H), 4.30 (s, 2H), 6.91-6.94 (m, 2H), 7.09 (d, J=8.80 Hz, 1H), 7.45 (d, J=8.79 Hz, 2H), 7.66-7.69 (m, 3H), 8.74 (s, 1H); 13C NMR (CDCl3) δ 22.76, 56.26, 74.60, 85.93, 111.25, 116.62, 119.30, 122.64, 127.93, 129.47, 129.70, 130.35, 136.86, 148.88, 151.00, 151.55, 155.17, 155.98, 157.04, 158.59, 159.55, 159.95; HPLC (Method #1) 4.13 min retention time, (99%); MS (ES): m/z 529 [M+H]+.
Reaction SMILES: [Br-:1].O[CH:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH2:6][CH2:7]2)[CH2:4]1.[H-].[Na+].IC.O.[CH3:21][O:22]CCOC>>[Br-:1].[CH3:21][O:22][CH:6]1[CH2:7][CH:8]2[CH2:9][CH2:10][N+:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:3]2
Reactant: CCCCC[N+]12CCC(CC1)C(O)C2
Reactant: COCCOC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCC[N+]12CCC(CC1)CC2OC
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of (±)-3-hydroxy-1-pentylquinuclidinium bromide (20 g, 72 mmol) in dry 1,2-dimethoxyethane (150 ml) at 0° C., under nitrogen, was added sodium hydride (3.48 g, 60% in mineral oil, 86.8 mmol) and then iodomethane (11.3 ml, 181 mmol). The temperature was allowed to rise to room temperature overnight. Water (200 ml) was added and the mixture was extracted with 6×100 ml dichloromethane. Drying and evaporation gave an oily residue which, after trituration with petrol ether, gave the title compound as a crystalline solid. Yield 23.9 g (That the yield was more than 100% is explained by the fact that there is a mixture of bromide and iodide as counter ions.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C>ClCCl>[CH2:14]([O:13][C:11]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 3-aminopropionate hydrochloride (2.00 g, 13.0 mmol) was dissolved in dichloromethane (40 ml), and benzyl chloroformate (2.00 ml, 14.1 mmol) was added. With cooling with ice, triethylamine (4.00 ml, 28.9 mmol) was added, followed by stirring at room temperature for 15 hours, then the reaction, liquid was concentrated. Ethyl acetate and water were added, the organic layer was collected, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a pale yellow oil (3.26 g, quant).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH:6]=[O:7])=[C:8]([OH:10])[CH:9]=1
Reactant: COc1cc(Cl)cc(OC)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(Cl)cc(O)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
A stirred solution of 4-chloro-2,6-dimethoxybenzaldehyde (Example 37A, 1.95 g, 9.72 mmol) in DCM (20 mL, 311 mmol) at −78° C. was slowly added boron tribromide (9.72 mL, 9.72 mmol). The reaction mixture was stirred at −78° C. for 10 minutes then warmed to r.t. and stirred for 1 hour while monitoring reaction progress by LCMS. Once all s.m. had been consumed, the reaction was quenched with water and extracted with DCM. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title material (1.79 g, 9.59 mmol, 99% yield) as a purple solid. LC (Method B): 2.199 min. LCMS (APCI) calcd for C8H8ClO3 [M+H]+ m/z 187.02. found 187.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 11.89 (s, 1H), 10.20 (s, 1H), 6.75 (t, J=2.0 Hz, 1H), 6.66 (m, 1H), 3.91 (s, 1H).
Reaction SMILES: CN(CCCN=C=NCC)C.[NH:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[NH:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:13]([C:21]([O:23][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylaminopropylethylcarbodiimide (EDC) (1.68 E, 8.78mmol) was added to a solution of the crude N-Boc-D-Phe (as described previously, assumed to be 7.32 mmol), benzyl alcohol (1.14 ml, 11.0 mmol) and 4-pyrrollidinopyridine (217 mg, 1.46 mmol) in dichloromethane (73.2 ml). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, and washed sequentially with a dilute solution of HCl (<5%, pH 3.0), a solution of saturated sodium bicarbonate, and brine. The combined organic layers were dried over MgSO4 and concentrated to obtain a yellow oil. This substance was subjected to silica gel chromatography, eluted with a solution that was 5:1 hexanes:ethyl acetate, and resulted in a yield of 2.31 g of N-Boc-D-Phe-OBn.