Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:7])[CH3:6])[CH2:3][CH2:2]1.Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC1CC1
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 15.9 g (0.162 mol) of N-cyclopropylacetamidine (which was prepared in the above-mentioned Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 11.8 g (yield: 67%) of 5-acetyl-1-cyclopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[C:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[N:33]([CH2:34]C(O)=O)[N:32]=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=1>>[CH3:28][C:29]1[N:33]([CH2:34][C:21]([N:18]2[CH2:17][CH2:16][CH:15]([C:12]3[S:13][CH:14]=[C:10]([C:9]#[C:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:20][CH2:19]2)=[O:23])[N:32]=[C:31]([C:38]([F:41])([F:39])[F:40])[CH:30]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C#CCc3ccccc3)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C#CCc3ccccc3)cs2)CC1

Procedure:
tert-Butyl 4-[4-(3-phenylprop-1-yn-1-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (IV-5, 320 mg) is then deprotected dann analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (174 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(3-phenylprop-1-yn-1-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (33 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:45]=[CH:46][CH:47]=2)[C:26]([C:28]2[CH:29]=[C:30]([CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])[N:31]3[C:36]=2[CH:35]=[CH:34][CH:33]=[CH:32]3)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:45]=[CH:46][CH:47]=2)[C:26]([C:28]2[CH:29]=[C:30]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[N:31]3[C:36]=2[CH:35]=[CH:34][CH:33]=[CH:32]3)=[O:27])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)=[CH:17][CH:16]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cc(CCCC(=O)O)n4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of ethyl 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]-butyrate (279 mg) in ethanol (10 ml) was added 4N sodium hydroxide (0.44 ml). Stirring was continued for 1 hour at 40° C. The reaction mixture was evaporated in vacuo, then added a solution of potassium dihydrogen phosphate (300 mg) in water and 1N hydrochloric acid (26 ml), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with ethyl acetate to give 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyric acid (229 mg).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([CH3:21])[CH2:6][CH2:7][CH2:8][S:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])C.[OH-].[Na+]>C(O)C.O>[CH3:21][C:5]([CH3:22])([CH2:6][CH2:7][CH2:8][S:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCSCSCCCC(C)(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCSCSCCCC(C)(C)C(=O)O)C(=O)O
Yield: 47.2 %

Procedure:
A solution of 2,2,12,12-tetramethyl-6,8-dithiatridecane-1,13-dioic acid ethyl ester (7.16 g, 18.25 mmol) and sodium hydroxide (3.13 g, 76 mmol) in ethanol (40 mL) and deionized water (4 mL) was heated to reflux for 2 h. The ethanol was evaporated and the residue dissolved in water (30 mL) and extracted with diethyl ether (20 mL). The aqueous layer was acidified with 2 N hydrochloric acid to pH 2 and extracted with diethyl ether (2×20 mL). The combined organic layers were washed with saturated sodium chloride solution (15 mL), dried over MgSO4, and concentrated to give the crude product (4.79 g) as an oil, which solidified on standing. Recrystallization (hexanes/ethyl acetate=2/1) yielded 2,2,12,12-tetramethyl-6,8-dithiatridecane-1,13-dioic acid (2.9 g, 47%) as nice white needles. Mp.: 72.0-72.5° C.). 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 11.55 (br, 2H), 3.65 (s, 2H), 2.62 (t, J=6.8 Hz, 4H), 1.70-1.51 (m, 8H), 1.21 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 184.76, 41.99, 39.54, 35.20, 31.07, 24.87, 24.54. HRMS (HR, LSIMS, gly): Calcd. for C15H29O4S2 (MH+): 337.1507, found 337.1508. Anal. (C15H28O4S2) calcd. (found): C, 53.54 (53.38); H, 8.39 (8.26); S, 19.06 (19.29).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[NH:21])[NH2:20])=[CH:15][CH:14]=1)(C)(C)C.C(Cl)[Cl:24].CO>CO>[ClH:24].[ClH:1].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH2:21])=[NH:20])=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(=N)N)cc1
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CCCCN)cc1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
12 N hydrochloric acid (0.71 mL, 8.6 mmol) was added dropwise into a stirring solution of [4-(4-carbamimidoylphenyl)butyl]carbamic acid tert-butyl ester (59) (124 mg, 0.43 mmol) in methanol (2 mL). After stirring for 2.5 h, TLC (methylene chloride/methanol/concentrated ammonium hydroxide, 6:3:1) indicated reaction completion. The reaction mixture was vacuum filtered. The solvent was removed from the filtrate by evaporation. Residual water was further removed as an azeotrope of toluene/methanol (1:1). Placement of the residue under vacuum for 2 h afforded the product 60 (106 mg, 94%) as a yellow foamy solid. 1H NMR (300 MHz, DMSO-d6) δ 1.62 (m, 4H), 2.70 (t, 2H), 2.78 (m, 2H), 3.49 (br s, 1H), 7.47 (d, 2H), 7.82 (d, 2H), 8.13 (br s, 3H), 9.25 (s, 2H), 9.42 (s, 2H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13].CN(C=O)C>CC(C)=O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: O=C(O)C1CCCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C1CCCCC1
Yield: 88.2 %

Procedure:
In 20 ml of acetone is dissolved 0.64 g of cyclohexanecarboxylic acid, and 2.5 ml of 2N-NaOH and then 1.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF are serially added to the above solution. The mixture is refluxed for 5 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is then chromatographed on a silica gel column. Following passage of 200 ml of n-hexane-diisopropyl ether (6:4), elution is carried out with 600 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.98 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:2]1.C(OC(=O)[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(C)(C)C>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:29]3[CH2:30][CH2:31][CH:26]([NH2:25])[CH2:27][CH2:28]3)=[CH:13][CH:12]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc([C@H]2COc3cccnc3O2)cc1
Product: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Intermediate M is prepared from Intermediate C and Piperidin-4-yl-carbamic acid tert-butyl ester according to Example 217.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[I:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:21])/[C:9](/[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:27]\[C:26]2[CH:29]=[CH:30][C:23]([I:22])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: O=C(CS(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)S(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-iodophenyl)-2-(4-iodobenzylsulfonyl)ethanone (10 mmol) and 4-iodobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH:16]=[N:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1.CN(C=O)C.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1
Reactant: O=C1CSc2cc(N=Cc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1CSc2cc(NCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Yield: 79.8 %

Procedure:
7-[3-(2-Quinolinylmethoxy)benzylidenamino]-3,4-dihydro-2H-1,4-benzothiazin-3-one (6.383 g, 15 mmol) obtained in Example 91 was dissolved in a mixed solvent consisting of 200 ml of DMF and 50 ml of MeOH, followed by the addition of 2.26 g (60 mmol) of NaBH4 in small portions. After the resultant mixture was stirred for 30 minutes at room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with CHCl3. The extract was washed with water, dried over MgsO4 and then concentrated. The concentrate was recrystallized from MeOH-AcOEt, whereby 5.117 g of the title compound were obtained as white powder (yield: 79.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]3[CH2:16][O:15]3)[CH:5]=[CH:4][C:3]1=2.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:16][CH:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[OH:15])=[CH:29][CH:28]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 30.9 %

Procedure:
26 g (110 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxirane, 15 g (90 millimoles) of ethyl 4-aminobenzoate, 135 g of basic alumina and 450 ml of toluene were refluxed for 2 hours. The solid was then filtered off and the filtrate was evaporated down. After recrystallization from n-heptane with a little ethyl acetate, the residue gave 11.0 g of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol. The structure was determined by H-NMR spectroscopy. 3-(4-Carbethoxyphenyl)-5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxazolidine:
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[C:19]#[CH:20]>>[CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:20][C:19]#[CH:18])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)Sc1ccc(CO)cc1
Reactant: C#CCBr
Product: C#CCOCc1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 26, by reacting p-[(1,5-dimethylhexyl)thio]benzyl alcohol with propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]-α-propargyloxy-toluene; nD29 = 1.5243.
Reaction SMILES: [BrH:1].N1C=CC=CC=1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([CH3:19])=[O:18]>CO>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17](=[O:18])[CH2:19][Br:1]
Reactant: Br
Reactant: CC(=O)c1cc2ccccc2o1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(CBr)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 120.5 %

Procedure:
A polymer of perbromide of pyridine hydrobromide (8.75 g; 17.5 mmol; 1.4 equivalent) is added to a solution of (benzofuran-2-yl)methylketone (2 g; 12.5 mmol) in methanol (40 ml). The resulting mixture is stirred at ambient temperature for 7 hours and the reaction is stopped by filtration. The methanol is eliminated under reduced pressure and an additional addition of diethyl ether allows crystallization of the expected product (3.6 g; yield=60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2ccccc2c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1Br

Procedure:
A stirred solution of 2-methoxynaphthalene (5 g.) in acetic acid (100 ml.) is treated dropwise with a solution of 1.1 molar equivalents of bromine in acetic acid (50 ml.). Upon disappearance of the bromine color, water is added. The solid which forms is collected by filtration, washed with water until neutral, recrystallized, rewashed, and dried to yield 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [C:1]([O:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([CH3:31])([CH3:30])Cl>O1CCCC1>[C:1]([O:4][C@H:5]1[N:8]([Si:28]([CH3:31])([CH3:30])[CH3:27])[C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To an ice-cooled solution of 50g (0.174 mole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-2 -azetidinone and 24.69 (0.244 mole) of triethylamine in 500 ml of tetrahydrofuran were added 26.5g (0.244 mole) of trimethylchlorosilane under a nitrogen stream. The reaction temperature was allowed to rise to room temperature and the reaction mixture was stirred for 2 hours. The precipitate was filtered off using a Celite (trade mark) filter aid. After the precipitate had been washed with ether twice, the filtrate and the washings were combined, and the solvent was evaporated. The residue was washed with ether to filter off the insoluble materials, Evaporation of the solvent from the filtrate gave 6.23 g (yield 100%) of the title compound as a semi-solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH2:14]1[CH:19]2[CH2:20][C:21]3([CH:24]=O)[CH2:23][CH:17]([CH2:18]2)[CH2:16][CH:15]1[CH2:22]3>>[C:21]12([CH:24]3[NH:1][C:2]4[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=4[S:10](=[O:12])(=[O:11])[NH:13]3)[CH2:20][CH:19]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:23]1)[CH2:22]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: O=S1(=O)NC(C23CC4CC(CC(C4)C2)C3)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using 1-adamantylcarboxaldehyde). M.p. 270-273° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:13](=O)[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2].Cl.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][O:25][NH2:26])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25]/[N:26]=[C:13](/[C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)\[CH3:14])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1OC(C)C
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1OC(C)C
Yield: 88.7 %

Procedure:
3′-Isopropoxy-4′-methoxyacetophenone (8) (150 mg, 0.720 mmol) was condensed with compound 19 (162 mg, 0.792 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing yellow oil was dissolved in CH2Cl2 (20 mL) and the resulting solution washed with H2O (2×15 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (15:85 v/v ethyl acetate/hexane elution) to afford the title compound CP30254 (229 mg, 89%) as a pale-yellow oil, which solidified upon extensive standing, m.p. 44.5-46.1° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[CH:14][C:13]([CH3:18])=[N:12][C:11]=3[S:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:17][C:15]2[CH:14]=[C:13]([CH3:18])[N:12]=[C:11]3[S:10][C:9]([CH3:19])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:16]=23)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(N)c2c(-c3cccc(Cl)c3)c(C)sc2n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(Cl)c3)c(C)sc2n1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 3-(3-chlorophenyl)-2,6-dimethylthieno[2,3-b]pyridin-4-amine (100 mg, 0.346 mmol) (Description 9) in THF (3 mL) was added potassium tert-butoxide (155 mg, 1.385 mmol) and the mixture stirred for 5 min before the addition of 3-chlorobenzenesulfonyl chloride (0.049 mL, 0.346 mmol). The mixture was then stirred for 1 h and the solvent then removed in vacuo. Ethyl acetate (10 mL) was then added and the mixture washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, was followed by trituration with MeOH, to afford the title compound (67.8 mg). LCMS (A) m/z: 463 [M+1]+, Rt 1.09 min (basic), Rt 1.44 min (acidic).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](=[NH:5])[NH2:4].Cl.[F:8][CH:9]([C:14](OC)=[O:15])[C:10](OC)=[O:11]>>[F:1][CH:2]([F:6])[C:3]1[NH:4][C:14]([OH:15])=[C:9]([F:8])[C:10](=[O:11])[N:5]=1
Reactant: COC(=O)C(F)C(=O)OC
Reactant: N=C(N)C(F)F
Agent: Cl
Product: O=c1nc(C(F)F)[nH]c(O)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Sodium metal (0.91 g, 40 mmol) was dissolved in MeOH (100 mL) to form sodium methoxide. 2,2-Difluoroethanimidamide.HCl (1.73 g, 13 mmol) was added followed by dimethyl fluoropropanedioate (2.0 g, 13 mmol). The resulting solution was stirred at 80° C. for 3 hours, then cooled to room temperature. Aqueous HCl (6 mL, 6M, 36 mmol) was added and the resulting mixture was concentrated in vacuo. The remaining solid was washed with cold water and filtered yielding 2-(difluoromethyl)-5-fluoro-6-hydroxy-4(1H)-pyrimidinone (1.43 g, 61%)
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:21]([NH:23][NH2:24])=[O:22])[C:13]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4].CCN(C(C)C)C(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C1COCC1>[CH:34]1([C:37]([NH:24][NH:23][C:21]([C:12]2[C:13]([NH:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[C:8]3[CH:7]=[N:6][N:5]([CH2:3][CH3:4])[C:9]3=[N:10][CH:11]=2)=[O:22])=[O:38])[CH2:36][CH2:35]1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)NN)cnc21
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)C3CC3)cnc21
Yield: 45 %

Procedure:
A solution of Intermediate 19 (0.045 g) in THF (2 ml) was treated with DIPEA (0.045 ml), then with cyclopropylcarbonyl chloride (0.013 g) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The layers were separated and the organic layer concentrated in vacuo, then applied to an SPE cartridge (aminopropyl, 1 g). The column was eluted with methanol to afford Intermediate 20 as a white solid (0.02 g). LCMS showed MH+=373; TRET=2.15 min.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]([CH2:36][CH2:37][CH3:38])([CH2:33][CH2:34][CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[OH:39])=O)(=[O:4])=[O:3].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]([CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH3:38])[C:29]4[C:24]([C:23]=3[OH:39])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:1][S:2](=[O:4])(=[O:3])[C:5]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1(CCC)C(=O)C(C(=O)Nc2ccc(OCc3ccccc3)cc2S(N)(=O)=O)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Temperature: 140 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
A solution of the compound of Example 2E (300 mg, 0.547 mmol) in anhydrous pyridine (5.2 mL) was treated with 1,8 diazabicyclo[5.4.0]undec-7-ene (82 μL, 0.55 mmol) and stirred at 140° C. for 18 hours, cooled to 25° C. and the pyridine removed by short path distillation under high vacuum (50° C./0.3 mm Hg). A solution of the residue in ethyl acetate was washed with water (2×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate in hexane to give the title compound (110 mg, 38%). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=7.72 Hz, 1 H), 7.64 (m, 1 H), 7.41 (m, 8 H), 5.21 (s, 2 H), 2.14 (m, 2 H), 1.83 (m, 2 H), 0.87 (m, 2 H), 0.64 (m, 8 H).