Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2O)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][SH:33]>>[CH3:3][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[S:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[CH:8]=[C:7]([C:19]([CH3:22])([CH3:20])[CH3:21])[C:6]=1[OH:23])([CH3:1])[CH3:4]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CS
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 15 (2.0 g, 0.0059) was added to trifluoroacetic acid (5 ml). After several minutes methyl thioglycolate (0.63 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. The trifluoroacetic acid was evaporated with a gentle flow of nitrogen gas. The residue was dissolved in diethyl ether (50 ml) and washed twice with 2 ml of 0.25 N NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The product was purified by silica gel chromatography to give a colorless oil. The structure was supported by NMR, infrared and elemental analysis.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O>CN(C=O)C>[CH2:1]([N:3]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
N-ethyl-methanesulfonamide (Mijs et al. J. Chem. Soc. Chem. Com. 1972 p 412) (5 g 40.6 mmol) was added to a suspension of sodium hydride (1.9 g, 55% in mineral oil) in anhydrous DMF (100 mL) under nitrogen. The mixture was warmed to 55° C. for one hour and 2,4-difluoronitrobenzene (4.4 mL) was added dropwise. The reaction was stirred at 60° C. overnight, poured into water (500 mL) and the product extracted into CH2Cl2 (5×100 mL). The organic extracts were washed with water, dried over MgSO4 and evaporated to give an oily product. The remaining DMF was removed by trituration with petrol. The crude product was purified by flash chromatography (ethyl acetate:petrol 1:1) to yield the desired product which was recrystallised from ethanol. Yield 3.5 g (33%). Calculated N % 10,68 C % 41,22 S % 12,23H % 4,23; Found N % 10,68 C % 41,39 S % 12,22H % 4,17.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:46]=[CH:45][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:44]=[CH:43][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[C:27]1[CH:43]=[CH:44][C:24]([NH:23][C:13]2[N:12]=[C:11]([NH:10][CH2:9][C:8]3[CH:45]=[CH:46][C:5]([O:4][CH2:3][CH2:2][Br:1])=[CH:6][CH:7]=3)[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
Tert-butyl (4-(4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butyl)carbamate (3.0 g, 4.21 mmol) was stirred in TFA/DCM (1:1) solution (20 mL) for 1 h. The solution was concentrated under vacuum to give N-(4-aminobutyl)-4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([S:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:25]=1>>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][S:32][C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: COc1ccc(N)cc1SCCN(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1SCCN(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 4-amino-2-(2-dimethylaminoethylthio)anisole (D48) using a similar procedure to Example 1 (50%) mp 138°-9° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[I-:12].[K+].Cl>[Cu](I)I.CN(C)P(N(C)C)(N(C)C)=O>[I:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: [I-]
Reactant: Brc1ccc2ccccc2c1
Agent: I[Cu]I
Agent: Cl
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Ic1ccc2ccccc2c1
Temperature: 160 °C
Yield: 100 %

Procedure:
2-Bromonapthalene (50.0 g, 242.0 mmol), copper iodide (230.0 g, 1210.0 mmol, 5 eq.), potassium iodide (200 g, 1210.0 mmol, 5 eq.) and hexamethylphosphoramide (500 mL) were stirred and heated to 160° C. for 8 h. This was cooled and added to 1N HCl (250 mL) then toluene (300 mL) and ether (300 mL) and the mixture filtered through celite. The organic layer was separated and washed with water (2×250 mL) dried over magnesium sulphate and concentrated to afford 2-iodonaphthalene (61.5 g, 59%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.46-7.52 (2H, m, ArH, 7.55-7.58 (1H, m, ArH), 7.68-7.74 (2H, m, ArH), 7.76-7.82 (1H, m, ArH), 8.22-8.26 (1H, m, ArH).
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])(=[O:4])=[O:3].[OH-].[Na+].Cl>CC#N>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([CH:16]([N:9]2[C:8](=[O:33])[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]2=[O:15])[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH3:32]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NS(C)(=O)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.8 g, 1.39 mmol) and 2N NaOH (1.59 mL, 3.18 mmol) in CH3CN (120 mL) was stirred at room temperature for 8 hours. The mixture was neutralized with 6N hydrogen chloride (0.6 mL) and then concentrated. The residue was dissolved in methylene chloride (90 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid was slurried in ethanol (50 mL) to give after isolation by filtration 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-[(methylsulfonyl)amino]isoindoline-1,3-dione (0.6 g, 86%) as a white solid: mp 191-193° C.; 1H NMR (DMSO-d6) δ 9.31 (s, 1H), 7.85-7.74 (m, 2H), 7.61 (d, J=6.6 Hz, 1H), 7.08 (s, 1H), 7.00-6.91 (m, 2H), 5.80-5.74 (m, 1H), 4.38-4.28 (dd, J=10.5, 14.3 Hz, 1H), 4.19-4.11 (dd, J=4.5, 14.3 Hz, 1H), 4.03 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.27 (s, 3H), 3.00 (s, 3H0, 1.32 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 167.43, 166.71, 148.92, 147.87, 136.26, 135.73, 131.91, 129.40, 125.01, 119.79, 118.39, 117.59, 112.41, 111.76, 63.83, 55.48, 53.00, 47.35, 41.06, 40.63, 14.64; Anal. Calcd. for C21H24N2O8S3+0.05 disulfonamide: C, 50.56; H, 4.86; N, 5.60; S, 13.12. Found: C, 50.25; H, 4.81; N, 5.60; S, 13.12.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:23]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2cc(C)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Yield: 71.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.5 g), 2,4-difluoronitrobenzene (3.1 g) and dimethyl sulfoxide, ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxyiate (5.1 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28])[CH3:17].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:23][C:22]=1[F:28])[CH3:17]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo Phenyl Acetic Acid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine (Intermediate 13, 3 mL), anhydrous tetrahydrofiran (7 mL), copper(I)iodide (0.04 g, 0.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 14-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.43 g, 77%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
The intermediate (0.56 g, 1.6 mmol) from step C was dissolved in CH2Cl2 (10 mL) and to it was added a 1 M solution of TBAF in CH2Cl2 (5 mL). After being stirred at room temperature for 2 hours, the solution was diluted with CH2Cl2. The resulting solution was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 2:1 EtOAc/hexanes provided the title compound (0.27 g, 71%) as an oil. MS calculated (M+H)+ 235. found 235.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](OC)=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCCOc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCCCCCCCCCCCO)cc1

Procedure:
The methyl 11-(p-tert-butylphenoxy)-undecanoate, 3.7 g, 10.6 mmoles, was dissolved in 100 ml dry diethyl ether and added, dropwise, to a stirred slurry of 0.5 g lithium aluminum hydride in 100 ml dry diethyl ether. After one hour the reaction mixture was filtered through Celite and the filtrate was treated with 100 ml 1 N hydrochloric acid. The organic layer was removed, dried (MgSO4), and concentrated to a yellow oil, 2.7 g. The oil was chromatographed on 200 g 90 to 200 mesh silica gel (2% MeOH/CH2Cl2 eluent) collecting the product as a white, waxy solid. The solid was recrystallized from warm pentane yielding pure 11-(p-tert-butylphenoxy)-undecanol, 1.1 g, m.p. 39° to 40° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2cc(O)ccc21
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CCC2=O
Reaction time: 25 h

Procedure:
To a solution of 5-hydroxy-indan-1-one (1600 mg, 10.8 mmol)in CH2Cl2 (20 mL) at 23° C. were added 4-N,N-dimethylaminopyridine (1830 mg, 15 mmol) and acetic anhydride (1500 mg, 1.4 mL, 15 mmol). The reaction mixture was stirred for 25 hours, quenched with 10% hydrochloric acid (HCl) (20 mL) and diluted with CHCl3 (500 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (20 mL), dried (MgSO4)and concentrated in vacuo. 1H NMR (250 MHz, CDCl3): d 7.78 (d, 2 H), 7.21 (s, 1 H), 7.10 (d, 1 H), 3.28 (t, 2 H), 2.75 (t, 2 H), 2.38 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2c(OC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 67.1 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-cyclopropoxyisoquinolin (0.24 g, 1.01 mmol) in DMSO (2 ml) was added cesium fluoride (0.38 g 2.52 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.15 g 67%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][C:16]([Br:21])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cnc2C(F)(F)F)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Yield: 57.1 %

Procedure:
In a 100 mL dried flask, the compound obtained from the previous step, 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27a (300 mg, 1.04 mmol) was dissolved in 50 mL of ethanol under stirring, and N-bromosuccinimide (369 mg, 2.08 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for an hour until the reaction was complete. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27b (220 mg, yield 57.8%) as a white solid.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:28][O:29]C(OC)(OC)OC>C(O)(=O)C>[CH2:1]([S:5]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:28]([OH:29])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:12]=2[CH:11]=1)=[O:27])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2nc(O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 0.220 mg of N-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide, 0.3 ml of tetramethoxymethane and 2.0 ml of acetic acid was stirred at 60° C. for 4 hours. Acetic acid was distilled off under reduced pressure, and the residue was extracted with chloroform and with water. The chloroform layer was concentrated, and 4.0 ml of methanol and 36% hydrochloric acid (4 drops) were added to the residue. The mixture was stirred at 60° C. for 2 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals precipitated were washed with water, and were dried to give 0.207 g of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole (379).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC(C)C)cc1O
Reaction time: 48 h

Procedure:
A 1.50 g portion of methyl 2,4-dihydroxybenzoate was dissolved in 30 ml of acetone, and 3.10 g of potassium carbonate and 1.7 ml of isopropyl iodide were added, followed by 48 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give 1.60 g of methyl 2-hydroxy-4-isopropoxybenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:5]=2[CH:4]=1.[H-].[Na+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[N:8]([CH2:18][C:19](=[O:21])[CH3:20])[S:9](=[O:11])(=[O:10])[C:5]=2[CH:4]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc2c(c1)S(=O)(=O)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CC(C)=O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
360 mg of 6-methoxy-1,1-dioxo-1,2-dihydro-benzo[d]isothiazol-3-one are added in small portions to a suspension of 72 mg of 60% NaH in mineral oil in 1.6 ml of anhydrous dimethylformamide. After stirring for 30 min. at ambient temperature, the reaction mixture becomes homogeneous and 162 μl of chloroacetone are added thereto. The reaction mixture is heated at 110° C. for 30 min. It is allowed to return to ambient temperature, and then the mixture is precipitated by addition of water. The precipitate is filtered off, rinsed several times with water, suction-filtered off and dried in vacuo.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[O:11][C@@H:12]2[CH2:28][C@@H:27]3[C@@:15]([CH3:38])([C@@H:16]4[C@@H:24]([CH2:25][CH2:26]3)[C@:23]3(O)[C@@:19]([CH3:37])([C@@H:20]([C:30]5[CH:31]=[CH:32][C:33](=[O:36])[O:34][CH:35]=5)[CH2:21][CH2:22]3)[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.O=S(Cl)Cl>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:39])[O:11][C@@H:12]2[CH2:28][C@@H:27]3[C@@:15]([CH3:38])([C@@H:16]4[C@@H:24]([CH2:25][CH2:26]3)[C:23]3[C@@:19]([CH3:37])([C@@H:20]([C:30]5[CH:31]=[CH:32][C:33](=[O:36])[O:34][CH:35]=5)[CH2:21][CH:22]=3)[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)[CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@H]1C3=CC[C@H](c4ccc(=O)oc4)[C@@]3(C)CC[C@@H]12
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-morpholinoethylcarbamate (43.7 mg, 0.08 mmol, 1 eq) in pyridine (3 mL) was added SOCl2 (57.1 mg, 0.48 mmol) at 0° C. The mixture was stirred at this temperature for about 2 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic layers were combined, dried with Na2SO4, concentrated and purified via Preparative TLC to afford (3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-morpholinoethylcarbamate (20 mg, 47.6%). LCMS (M+H+) m/z calculated 524.33. found 526.0. 1H NMR (CD3OD, 400 MHz) δ 7.64 (m, 2 H), 6.38 (m, 1 H), 5.37 (m, 1 H), 4.98 (m, 1 H), 3.78 (m, 4 H), 3.34 (m, 2H), 2.92 (m, 1 H), 2.90 (m, 7H), 2.50-1.30 (m, 18 H), 1.10(s, 3 H), 0.83 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[BH3-]C#N.[Na+]>C(Cl)Cl.C(OC)(C)(C)C.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: Nc1ccc(Br)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Brc1ccc(NC2CCCC2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 6-bromopyrid-3-ylamine (2.0 g, 11.6 mmol) in CH2Cl2 (30 mL) was added cyclopentanone (1.3 mL) 15.5 mmol), followed by TiCl4 (1.4 mL, 12.7 mmol) in CH2Cl2 (20 mL) and after stirring for 3.5 h at room temperature, NaBH3CN (2.17 g, 34.5 mmol) was added portion-wise. The reaction was left to stir overnight at ambient temperature, diluted with t-BuOMe (200 mL), washed with water, brine and dried (Na2SO4). Solvent removal and purification by chromatography afforded the sub-title compound (880 mg, 40%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(Cl)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-chloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.