Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH:5]=[C:4]([C:28]2[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[C:7]3[CH2:8][N:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:48](=[O:50])[NH:1][C:2]=3[N:3]=[C:4]([C:28]3[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH:37]3[CH2:38][CH2:39]3)[CH:5]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1Cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3c(O)cccc3OCC3CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 595.3 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(ethoxycarbonyl)amino]methyl}-4-pyridinyl)-1-piperidinecarboxylate (0.145 g, 0.268 mmol), which was obtained in the step (1) of Example 23-2, and triethylamine (0.226 mL, 1.609 mmol) in tetrahydrofuran(30 mL) was added triphosgene (0.079 g, 0.268 mmol) in tetrahydrofuran (10 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with water and brine successively, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate as a white solid (0.904 g, yield; 60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[CH:3][CH:2]=1.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+].[OH-].[Na+]>CC(O)=O.OS(O)(=O)=O.O>[N:14]([C:12]1[CH:11]=[N:10][N:9]([CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:13]=1)=[N+:19]=[N-:20]
Reactant: Nc1cnn(CCc2ccncc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1cnn(CCc2ccncc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 1-(2-Pyridin-4-yl-ethyl)-1H-pyrazol-4-ylamine (300 mg; 2.66 mmol; 1.0 eq.) in AcOH (2.0 mL) and H2SO4 (1.0 mL) was added dropwise a solution of sodium nitrite (220 mg; 3.19 mmol; 1.2 eq.) in water (1.50 mL) and the reaction mixture was stirred at 0° C. for 1 hour. A solution of sodium azide (207 mg; 3.2 mmol; 1.2 eq.) in water (1.5 mL) was then added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was then poured into ice water, basified to pH=10-11 with NaOH (5N) and extracted with EtOAc (twice). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a dark oil, which was used without further purification in the next step. MS (ESI+): 215.0 (purity 98.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.CS(C)=[O:16].[O-]Cl=O.[Na+]>O.CC(C)=O>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([C:12]([OH:16])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CS(C)=O
Reactant: CSc1ncnc2c(C=O)csc12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CSc1ncnc2c(C(=O)O)csc12
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (513 mg, 3.29 mmol) was dissolved in water (2 mL) and then 4-(methylthio)thieno[3,2-d]pyrimidine-7-carbaldehyde (300 mg, 1.68 mmol) dissolved in acetone (3 mL) and DMSO (3 mL) was added thereto at 0° C. NaClO2 (194 mg, 2.15 mmol) dissolved in water (2 mL) was added at the same temperature to the reaction mixture, which was stirred for 2 hours. After the reaction was completed water (10 mL) was further added to the reaction mixture, which was stirred for 2 hours and filtered to obtain a solid. The solid was washed with water several times and dried with N2 gas to obtain the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: COc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-7-methyl-2H-1,4-benzodiazepin-2-thione (IIz) was prepared by reacting 0.0064 moles of 5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-7-methyl-2H-1,4-benzodiazepin-2-one (Iz) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[O:10][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:9][C:4]=2[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccc(Cl)c(Cl)c1O
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(Cl)c(Cl)c2O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A mixture of 11.0 g of 3,4-dichloro-1,2-benzenediol, 15.38 g of potassium carbonate, 27 g of ethyl dibromoacetate and 100 ml of dimethylformamide is stirred at 100° C. under argon gas atmosphere for 4 hours. The reaction mixture is evaporated to remove solvent and ethyl acetate and water is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 10.75 g of ethyl 4,5-dichloro-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15].O.C(OCC)(=O)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[C:18]=2[C:19]#[N:20])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1-BOC-piperizine (piperazine-1-carboxylic acid tert-butyl ester, 20.0 g, 107.4 mmol) was added to a solution of 2,6-dinitrobenzonitrile (10.277 g, 53.2 mmol) in dry DMF (200 ml). After stirring at 50° C. overnight, the reaction mixture was cooled to room temperature and poured into a mixture of water/ethyl acetate. The organic fraction was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting brown residue was purified by flash chromatography to give 4-(2-cyano-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (12.172 g, 69%). MS: (M+H)+277.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Br[CH2:25][C:26]([NH2:28])=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:28][C:26](=[O:27])[CH2:25][N:19]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Benzyl 4-methoxy-3-(methylsulfonamido)benzoate (200 mg, 0.596 mmol) was dissolved in DMF (2 ml). 2-bromoacetamide (247 mg, 1.789 mmol) and K2CO3 (165 mg, 1.193 mmol) were added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with water and filtered. The precipitate was washed with water and dried in the vacuum oven to give benzyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (220 mg, 94% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[OH:43][CH:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:6]1[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=2[N:26]=[CH:27][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cnc2c(c1C(O)c1ccccc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 3, 150 mg, 0.4 mmol) in THF (6 mL) at −78° C. was added LDA (2M in THF, 1.0 mL, 2 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then benzaldehyde (84.8 mg, 0.8 mmol) in THF (1.5 mL) was added. The reaction was stirred at −78° C. for 1 h quenched with aq. NH4Cl (8 mL) then diluted with EA (30 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(hydroxy(phenyl)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 51.8% yield) as a solid. LCMS: [M+-THP-OH] 382 and TR=1.855 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH3:29])[CH3:28]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:3][C:2]=1[O:1][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 17 and 2-bromo propane, colorless oily N-[2-(4-methoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 19.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH3:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[C:35]([OH:37])=[O:36].CI.Cl>C1COCC1>[CH3:29][C:30]1[CH:34]=[C:33]([CH3:2])[S:32][C:31]=1[C:35]([OH:37])=[O:36]
Reactant: Cc1ccsc1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)O)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.2 equivalents of 2.0 M LDA solution in heptane/THF/ethylbenzene (0.97 mL, 1.019 mol) was added to a solution of 3-methylthiophene-2-carboxylic acid (1.42 g, 10 mmol) in anhydrous THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hr; and then methyl iodide (1.4 mL, 22 mmol) was added. The resulting mixture was stirred at 0° C. for an additional 2 hr, acidified with 2N HCl and extracted with methylene chloride (4×50 mL). The organic layers were then combined, concentrated and separated via HPLC to give 3,5-dimethylthiophene-2-carboxylic acid Compound 4A as a white powder. 1H NMR (300 MHz, CD3OD) δ 6.72 (s, 1H), 2.43 (s, 3H), 2.46 (s, 3H); MS (ESI) m/z: 155 (M−H+). Using the procedure of Example 1, Compound 1E was acylated with Compound 4A mediated by DIC/HOBt in anhydrous DMF to produce Compound 33 (73% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.88 (s, br, 1H), 7.85 (s, br, 2H), 7.78 (q, 4H), 7.18 (s, br, 2H), 6.92 (s, 1H), 2.58 (s, 3H), 2.55 (s, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]2[CH2:32][CH2:31]2)=[C:6]([C:8]2[C:12]([NH:13]C(=O)OC(C)(C)C)=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:7]=1.ClC1C=CC(OC2CC2)=C(C2N(COCC[Si](C)(C)C)N=CC=2NC(=O)OC(C)(C)C)C=1.Cl.CO>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]2[CH2:32][CH2:31]2)=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][NH:10][N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(COCC[Si](C)(C)C)nc1-c1cc(Cl)ccc1OC1CC1
Agent: CC(C)(C)OC(=O)Nc1cnn(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1OC1CC1
Agent: Cl
Solvent: CO
Product: Nc1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 3-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate and tert-butyl 5-(5-chloro-2-cyclopropoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate were dissolved in 50 mL of MeOH. 50 mL of 4 M HCl/MeOH was added dropwise. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and purified by silica gel chromatography, eluting with EtOAc to afford 0.25 g of 3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazol-4-amine. LCMS (ESI) m+H=249.8. 1H NMR (DMSO-d6, 400 MHz) δ: 12.32-12.10 (br, 1H), 7.41-7.34 (m, 3H), 7.09 (s, 1H), 4.12 (q, J=5.2 Hz, 2H), 2.94-3.88 (m, 3H), 0.79-0.74 (m, 4H)
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH:8]=C[CH:6]=[N:5][CH2:4]1.Cl[C:11]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[C:13]([Cl:30])[N:12]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:13]1[CH:14]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:16]=[C:11]([N:5]2[CH2:6][CH2:8][C:3]([F:2])([F:9])[CH2:4]2)[N:12]=1
Reactant: FC1(F)C=CC=NC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)CC1
Yield: 46.8 %

Procedure:
A solution of 3,3-difluoropyridine hydrochloride (533 mg, 3.72 mmol, 3.18 equiv), tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (1.00 g, 1.17 mmol, 1 equiv), and N,N-diisopropylethylamine (1.23 mL, 7.03 mmol, 6.00 equiv) in N-methylpyrrolidinone (2.3 mL) was heated at 130° C. in the microwave (CEM) for 1.5 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the resulting solution was washed with saturated aqueous ammonium chloride solution (2×20 mL). The aqueous washes were extracted with ethyl acetate (25 mL). The combined organic was washed with water (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (4:1 heptane/ethyl acetate) provided product as a clear oil (220 mg, 47% yield). 1H NMR (400 MHz, CDCl3): 6.51 (s, 1H), 6.03 (s, 1H), 4.25 (m, 2H), 3.83 (t, J=13.1 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 2.77 (m, 2H), 2.42-2.58 (m, 3H), 1.78 (m, 2H), 1.53-1.62 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[OH:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH:42]([OH:47])[CH2:41][C:40]1([CH3:49])[CH3:48].[CH2:50]([N:54]=[C:55]=[O:56])[CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)(Cl)Cl>[CH2:50]([NH:54][C:55](=[O:56])[O:47][CH:42]1[CH2:43][C:44]([CH3:45])([CH3:46])[N:39]([OH:38])[C:40]([CH3:49])([CH3:48])[CH2:41]1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCCN=C=O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCNC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.1 g of di-n-butyltin dilaurate is added to a solution of 1.0 g (5.8 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 0.58 g (5.8 mmol) of butyl isocyanate in 10 mL of carbon tetrachloride. After stirring for four hours at ambient temperature, the solution is concentrated and the title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
8.85 grams of 5-tert.-butyl-2,3-dimethyl-4-hydroxyphenylacetic acid, 9.45 grams of n-octadecanol and 0.665 grams of p-toluenesulfonic acid monohydrate were dispersed in 500 ml of toluene and heated at reflux for seven hours. A little ether was added to the cooled reaction mixture to prevent precipitation. The reaction solution was then successively washed with water, saturated sodium bicarbonate solution and water once again until neutral. After drying over anhydrous sodium sulfate and filtering, the clear filtrate was concentrated at reduced pressures. After washing with cold acetonitrile, the dried ground residue was crystallized from n-heptane yielding white crystals melting at 79° to 81° (Compound 15).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.[Li+].CC([N-]C(C)C)C.Br[CH2:30][C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[C:32]=1[Cl:40].Cl>CO.O.C1COCC1>[Cl:40][C:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[S:35][C:31]=1[CH2:30][CH:15]1[CH2:16][CH2:17][N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:12][CH2:11]2)[C:14]1=[O:18]
Reactant: Clc1c(CBr)sc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Cc2sc3ccccc3c2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: -78 °C

Procedure:
Charge a flask with cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (0.50 g, 1.68 mmol) (1.0 eq), dissolve with THF (0.2 M) and cool to −78° C. Add LDA (1.1 to 1.5 eq) and stir at −78° C. for 5 minutes. Add 2-bromomethyl-3-chloro-benzo[b]thiophene (U.S. Pat. No. 4,939,140) (0.53 g, 2.02 mmol) and warm to room temperature overnight. Dilute with methanol (0.2 M) and add concentrated HCl (10 eq.) and stir at room temperature. Pour into water after reaction complete by HPLC and extract with methylene chloride, dry over sodium sulfate, filter and concentrate in vacuo. Purification of the residue over silica gel (20% hexane in ethyl acetate) affords the title compound as a white powder (0.44 g, 71%): MS (APCI-pos mode) m/z (rel intensity) 364.1 (100), 366.1 (40).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5][C:6](=O)[CH:7]=1.O.C([O-])=O.[NH4+:18]>CO.[Pd]>[NH2:18][CH:6]1[CH2:5][CH2:4][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1CCC(N)CC1C
Temperature: 25 °C

Procedure:
Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (2.0 g, 10.98 mmol) is dissolved in MeOH (40 ml) and water (4.0 ml) to give a yellow solution. Ammonium formate (8.31 g, 132 mmol) is added and stirred at RT until the suspension dissolves to form a solution. Palladium on carbon (0.117 g, 1.098 mmol) is added and the reaction mixture is stirred at 70° C. for 1 hour. The mixture is filtered through Celite® (filter material) and washed with MeOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous portion is diluted with sat. sodium bicarbonate and washed with EtOAc. The pH is adjusted to pH14 using 1M NaOH and the aqueous is extracted with EtOAc. The combined organic extracts are dried MgSO4, filtered and concentrated in vacuo to afford the title compound; [MH]+186.24.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1>>[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:11]=1
Reactant: O=C(O)c1sccc1Br
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccsc2C(=O)O)c1

Procedure:
prepared by reaction of 3-bromo-thiophene-2-carboxylic acid with m-tolylboronic acid. LC-MS (basic): tR=0.49 min; [M−H]−=217.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Br:12]
Reactant: COc1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1cccc(CBr)c1
Reaction time: 3 h

Procedure:
A solution of 270 ul of 3-methoxybenzyl alcohol in 2.5 ml of dry tetrahydrofuran is cooled to 0° C. and 120 ul PBr3 added, followed by stirring for three hours. The reaction mixture is extracted with ether and the organic layer washed with saturated sodium bicarbonate and evaporated to give the desired product.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][CH:6]([Cl:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Cl:12])[F:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(F)Cl
Reactant: CC(C)N
Solvent: OCCO
Solvent: CCO
Product: CC(C)NC(=O)C(F)Cl
Reaction time: 2 h

Procedure:
A solution of 11.8 grams (0.2 mole) isopropyl amine in 20 milliliters ethyl alcohol were added dropwise at 10°-15° C. with stirring to a solution of ethyl fluorochloroacetate and 5 drops of ethylene glycol in 80 milliliters ethyl alcohol. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time, the solution was evaporated to leave a liquid, 25.2 grams, nD30 1.4395, identified as the title compound by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.COC(OC)N(C)C.[Cl:23]N1C(=O)CCC1=O>CC#N>[Cl:23][C:3]1[C:4]2[CH:8]=[C:7]([S:9](=[O:11])(=[O:12])[NH2:10])[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Agent: COC(OC)N(C)C
Solvent: CC#N
Product: NS(=O)(=O)c1cc2c(Cl)c(O)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (3.0 g, 0.013 mole) in CH3CN (60 ml) was treated with N,N-dimethylformamide dimethylacetal (1.75 ml, 0.013 mole). Within 5 minutes, the protected sulfonamide started to precipitate. After 10 minutes, this was redissolved by the addition of CH3CN (65 ml). N-Chlorosuccinimide, (1.91 g, 0.0143 mole) was added in one portion and the mixture was stirred at ambient temperature. After 2 days, another 175 mg of N-chlorosuccinimide was added and stirring was continued for another 3 days. The solvent was evaporated under reduced pressure and the residual solid was triturated with H2O (100 ml) and collected. This solid then was suspended in 6N HCl (70 ml) and heated on the steam bath for 61/2 hours. The resulting solid was extracted into ethyl acetate. Evaporation of the washed and dried extract under reduced pressure left 3.1 g (90%) of 4-chloro-5-hydroxy-2-sulfamoylbenzo[ b]thiophene, m.p. 198°-201° C. Recrystallization from H2O, decolorizing with charcoal, gave 2.6 g, m.p. 203°-205° C.