Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10]([OH:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: CC(O)c1cc2cc(Br)sc2nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cc(Br)sc2nc1Cl
Temperature: 90 °C

Procedure:
A 2.2 g (7.5 mmol) portion of 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)-ethanol was dissolved in toluene and treated with manganese dioxide (6.5 g, 75 mmol, 10 eq). The mixture was heated to 90° C. overnight, then cooled rt and filtered through Celite™. The filter cake was rinsed with toluene and concentrated to afford crude material. The residue was purifed by column chromatography using ethyl acetate in hexanes to afford 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanone. LC/MS (M+1, found=291.9). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.36 (s, 1H), 2.75 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 1.90 g (10.0 mmol) of 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione in 25 mL of H2SO4 (97%) kept in an ice bath was added dropwise 1.2 mL of HNO3 (69-70%) and the solution was stirred ;at room temperature for 48 h. It was poured into 300 mL of ice-water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid 1.40 g (60%). The solid was purified by DMSO/H2O precipitation followed by NaOH/HCl precipitation to leave 0.85 g of a yellow solid; mp>250° C.; 1H NMR (DMSO-d6), 2.079 (s,3), 2.246 (s,3), 7.048 (s,1), 11.770 (s,1), 12.030 (s,1). HRMS calcd. for C10H9N3O4 235.0588; found 235.0584.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)[CH3:3].[C:30]([OH:33])(=[O:32])[CH3:31]>CO>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3].[C:30]([O-:33])(=[O:32])[CH3:31].[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CC(=O)O
Agent: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC(=O)[O-]

Procedure:
To a solution of toremifene base (1.00 g, 0.0025 moles) and methanol (20 ml) was slowly added acetic acid (160 μl, 0.0028 moles). The mixture was stirred for a while and evaporated to dryness. The acetate of toremifene was obtained as sticky white solid. 1H-NMR (d4-MeOH) d 7.37 (tt, 2H), 7.33-7.25 (m, 3H), 7.25-7.10 (m, 5H), 6.82 (dt, 2H), 6.63 (dt, 2H), 4.08 (t, 2H), 3.39 (t, 2H), 3.09 (t, 2H), 2.89 (t, 2H), 2.60 (s, 6H), 1.92 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[ClH:25].Br[C:27]1[CH:45]=[CH:44][C:30]([O:31][C:32]([CH3:43])([CH3:42])[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1>>[ClH:25].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:27]2[CH:45]=[CH:44][C:30]([O:31][C:32]([CH3:43])([CH3:42])[C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])=[CH:29][CH:28]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CN1CCN(C(=O)C(C)(C)Oc2ccc(Br)cc2)CC1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Agent: Cl
Product: CN1CCN(C(=O)C(C)(C)Oc2ccc(-n3c(C(=O)O)cc4cc(-c5ccc(C(C)(C)C)cc5)ccc43)cc2)CC1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 1-(2-(4-bromophenoxy)-2-methylpropanoyl)-4-methylpiperazine hydrochloride (see (a)), followed by precipitation of the hydrochloride salt using HCl (4 M in dioxane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([N:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:28]3[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:29]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(3,4-dichlorophenyl)piperazine-1-carboxamide (0.548 g, 2 mmols) and 1-N-BOC-3-pyrrolidinone (370 mg, 2 mmols) were stirred at room temperature in dichloromethane (20 ml) for approximately 15 minutes. Added to this mixture was sodium triacetoxyborohydride (1.06 g, 5 mmols) and the reaction stirred overnight at room temperature. Saturated sodium bicarbonate solution (5 ml) was added and the mixture stirred for 1 hour then poured onto a hydromatrix column and the product eluted with dichloromethane (100 ml). The crude product was subjected to chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 10% methanolic ammonia in dichloromethane to give the title compound as a white solid (780 mg).
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])C1C=CC=CC=1>CCO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
Ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (1.03 g, 1.94 mmol) was dissolved in EtOH and then treated with 10% Pd/C (37 mg). The reaction mixture was purged with N2 for 5 min then Hydrogen gas was bubbled through the mixture with stirring at RT for 1.5 h. The mixture was filtered through Celite and concentrated in vacuo. The residual yellow solid was triturated with Et2O to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (602 mg, 89%) as a white solid: m/z 349 (M+H)+ (ES+), 347 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.46 (s, 1H), 7.08-7.01 (m, 2H), 6.90-6.82 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.83 (br s, 6H), 0.99 (t, J=7.1 Hz, 6H).
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:21]([CH3:22])=[CH:20][C:10]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[O:23][CH3:24].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[OH-].[NH4+]>CN(C=O)C.O>[Si:25]([O:6][C:7]1[C:21]([CH3:22])=[CH:20][C:10]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[O:23][CH3:24])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCOP(=O)(Cc1cc(C)c(O)c(OC)c1)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(C)c(O[Si](C)(C)C(C)(C)C)c(OC)c1)OCC
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Imidazole (7.08 g, 104 mmol) was added portionwise to a well stirred mixture of diethyl (4-hydroxy-3-methoxy-5-methylbenzyl)phosphonate (10 g, 35 mmol) and t-butyldimethylsilyl chloride (7.84 g, 52 mmol) in 25 ml DMF and stirring was continued for 16 h at room temperature. The mixture was poured into water kept at 0° C. to which was added a 25% ammonium hydroxide solution until pH 7 was reached. The aqueous phase was extracted with chloroform, the organic phase was dried over MgSO4. Evaporation of the solvent gave 14 g (100%) of diethyl (4-t-butyldimethylsilyloxy-3-methoxy-5-methylbenzyl)phosphonate as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][C:4]=1[CH3:17]>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]2=[O:14])=[CH:5][C:4]=1[CH3:17]
Reactant: COc1ccc(C(C)(C)CCC(=O)O)cc1C
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1C)C(C)(C)CCC2=O
Yield: 54.1 %

Procedure:
A solution of 4-(4-methoxy-3-methylphenyl)-4-methyl-pentanoic acid (Compound 5, 7.8 g, 33 mmol) and 150 mL of methanesulfonic acid was stirred at room temperature under an argon atmosphere for 24 h, then poured into ice, extracted three times with ethyl acetate, washed with NaHCO3 1N, brine, and dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by flash chromatography (Hexane:Ethyl Acetate=4:1) to afford 3.9 g (54%) of the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:19][C:16]([F:17])([F:18])[C:14]1[N:15]=[C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)[NH:12][CH:13]=1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: CC(C)(C)OC(=O)NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (32 mg, 0.11 mmol) in DCM (1 mL) was added TFA (500 uL). The clear solution was stirred at room temperature for overnight. Solvents were removed and the resulting materials were re-suspended in Toluene (15 mL) and concentrated down to dryness to provide the title compound 1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropylamine as a TFA salt, m/z 192.41 [M+1]+
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:48])[C@H:11]([C@H:44]([CH2:46][CH3:47])[CH3:45])[NH:12][CH2:13][C@@H:14]([NH:36]C(OC(C)(C)C)=O)[CH2:15][S:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([NH:9][C:10](=[O:48])[C@H:11]([C@H:44]([CH2:46][CH3:47])[CH3:45])[NH:12][CH2:13][C@@H:14]([NH2:36])[CH2:15][SH:16])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC[C@@H](N)CS)C(=O)NCCc1ccccc1
Reaction time: 3 h
Yield: 44.2 %

Procedure:
The product of Step D (0.09 g, 0.14 mmol) was dissolved in 4 mL of 25% trifluoroacetic acid (TFA) in CH2Cl2 at ambient temperature, triethylsilane (0.089 mL, 0.56 mmol) was added and the solution was stirred for 3 h. The reaction mixture was concentrated and partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer was washed with brine and dried (Na2SO4). Filtration, concentration and trituration with hexane provided 0.02 g (44%) of the title compound, mp 69°-73° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]#[N:19].Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][N:8]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Temperature: 0 °C
Yield: 68 %

Procedure:
6-Bromo-1H-indole-3-carboxylic acid (0.24 g, 1 mmole) was dissolved in anhydrous dimethylformamide (2 ml) and cooled to 0° C. in a nitrogen atmosphere. With stirring, sodium hydride (60% in oil, 0.088 g, 2.2 mmole) was added all at once and the mixture was stirred at this temperature until no more bubbles evolved (ca. 20-30 minutes). Bromoacetonitrile (0.132 g, 1.1 mmole) was added to the reaction mixture which was then allowed to warm to room temperature over the next hour. The reaction mixture was poured into water, acidified with HCl and a precipitate formed. When dried the product weighed 0.190 g (68% yield) and was sufficiently pure to be used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH:6]1[CH2:7][C:8]2[NH:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[N:30][C:29]=3[C:9]=2[CH2:10][CH2:11]1)[CH3:5]
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: NNc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)nc23)C1)S(=O)(=O)c1ccccc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
In a sealed tube, 50 mg (0.15 mmol) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester in 4 mL of glacial acetic acid were treated with 27 mg (0.18 mmol, 1.2 eq) of (6-chloro-pyridin-3-yl)-hydrazine hydrochloride and stirred at 115° C. for 3 hours. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 1:1 followed by trituration with Et2O yielded 52 mg (76%) of (RS,SR)-2-benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-propionic acid methyl ester as a white solid, MS: 433 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Oc3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 26 mg (0.17 mmol, 1.1 eq.) of phenyl chloroformate were reacted according to General Method 5. Yield: 25 mg (39% of theory)
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[C:8]=1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[N+:2]=[N-:3].C([N-]C(C)C)(C)C.[Li+].[C:33]1([CH2:39][CH2:40][CH:41]=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:33]1([CH2:39][CH2:40][CH:41]([CH:11]2[C:10](=[O:14])[N:9]3[CH:12]2[CH2:13][C:7]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[C:8]3[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[OH:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [N-]=[N+]=NCCOC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Reactant: O=CCCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCOC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)CCc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzyl 3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (66 mg) in anhydrous THF (0.5 ml) is added dropwise over 5 mins to a stirring solution of lithium diisopropylamide (from 31 μl diisopropylamine and 140 μl 1.6N BuLi) in anhydrous THF (3.5 ml) at -78°. After stirring an additional 15 mins at -78° under N2, the solution is treated with 3-phenylpropionaldehyde (134 mg, 5 equivalents) in THF (0.5 ml). After 5 more mins at -78°, the solution is treated with saturated aqueous NH4Cl (3 ml) and allowed to warm to room temperature. The mixture is diluted with EtOAc (50 ml), washed with water (3×10 ml) and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residue is chromatographed on silica gel to yield benzyl 6-(3-phenyl-1-hydroxypropyl)-3 -(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][C:4]1[C:3]([CH2:2][N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 4-chloromethyl-3,5-dimethylisoxazole (100 mg, 0.69 mmol) in CH2Cl2 (4 mL) was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.71 mmol, 320 mg) and iPr2NEt (3.0 eq, 2.06 mmol, 0.36 mL) and stirred at 35° C. for 8 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the desired product (111 mg, 55%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.17 (s, 3H, CH3), 2.28 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 2.31 (s, 3H, CH3), 3.23 (s, 2H, NCH2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2);
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[O:20]1[CH2:19][CH:18]=[C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8]([C:6]([OH:7])=[O:5])=[N:9][NH:10]3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1n[nH]c2cc(C3=CCOCC3)ccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissloved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%). The acids were coupled with the bicyclobase according to procedure A.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[N:3]([C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1)[CH2:22][CH2:21][CH2:20][S:1]3
Reactant: BrCCCBr
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(=O)n3c(nc21)SCCC3
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
In 80 ml of dimethylformamide was dissolved 4.0 g (22.0 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 9.1 g (66 mmol) of potassium carbonate and 3.34 ml (32.9 mmol) of 1,3-dibromopropane were added to the solution, followed by stirring at 80° C. for 8 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1) to give 1.87 g (38%) of Compound 44. The compound was recrystallized from ethanol for purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=1[C:21]([O:23]CC)=[O:22]>ClC(Cl)C>[C:1]([C:19]1[C:15]([CH3:14])=[C:16]([C:21]([OH:23])=[O:22])[NH:17][C:18]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1[nH]c(C(=O)O)c(C)c1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
To a mixture of benzoyl chloride (1 equiv.) and aluminum chloride (1 equiv.) in dichloroethane at 0° C. was added ethyl 3,5-dimethyl-2-pyrrolecarboxylate (1 equiv.). The mixture was stirred at 80° C. for 4 hr. The mixture was then extracted with ethyl acetate (EtOAc) and H2O. The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried and concentrated to give (51%) of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([CH:7]([C:11]([OH:13])=[O:12])C(O)=O)=[O:6].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1.C(=O)([O-])O.[Na+]>O>[F:15][C:2]([F:1])([F:14])[CH2:3][CH2:4][C:5]([CH2:7][C:11]([O:13][CH2:16][CH3:17])=[O:12])=[O:6]
Reactant: O=C(O)C(C(=O)O)C(=O)CCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)CCC(F)(F)F
Reaction time: 6 h
Yield: 24903.6 %

Procedure:
A mixture of 179 g of the 4,4,4-trifluorobutyrylmalonic acid ditheyl ester thus obtained, 260 ml of water and 322 mg of p-toluenesulfonic acid was refluxed with vigorous stirring for 6 hours. The reaction solution was then poured into saturated aqueous sodium hydrogencarbonate solution and extracted three times with diethyl ether. The ether layers were combined and the combined layer was washed with brine, dried over anhydrous magnesium sulfate. After the drying agent was removed, the solvent was removed under reduced pressure. The obtained residue was distilled inder reduced pressure to yield 98.8 g of the desired ethyl 4,4,4-trifluorobutyrylacetate in a yield of 74%.