Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[I:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[C:54]([CH2:56][NH2:57])[N:53]=[C:52]2[S:58][CH3:59])=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:57][CH2:56][C:54]2[N:53]=[C:52]([S:58][CH3:59])[N:51]([C:48]3[CH:47]=[CH:46][C:45]([I:44])=[CH:50][CH:49]=3)[CH:55]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CSc1nc(CN)cn1-c1ccc(I)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1nc(CNC(=O)c2ccc(Cl)s2)cn1-c1ccc(I)cc1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (72 mg, 0.44 mmol) and triethylamine (0.150 mL, 1.10 mmol) in DMF (5 mL), BOP (235 mg, 0.53 mmol) was added. After 5 min of stirring, the solution was added to the sample of (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine (127 mg, 0.37 mmol) in a flask. After being stirred at room temperature overnight, H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in CH3CN (8 mL), H2O (10 mL) was added to induce precipitation, which was collected and dried on vacuum to give 5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (56 mg).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[CH:9]=[C:8]([F:15])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:13](=[S:14])[NH:12][C:10]1[CH:9]=[C:8]([F:15])[CH:7]=[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=S)Nc1cc(F)cc(OC(C)(C)C)c1
Temperature: 0 °C

Procedure:
1-tert-Butoxy-3-fluoro-5-isothiocyanato-benzene (24.0 g) and triethylamine (10.9 g) are dissolved in iso-propanol (150 ml). The reaction mixture is refluxed for 18 hours and the solvent is removed by vacuo. The crude product is dissolved in hexane:diethyl ether (19:1). The diethyl ether is removed by vacuo and the solution is cooled to 0° C. for 3 hours. The solution is filtered to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.10 (br s, 1H), 6.65 (br s, 2H), 6.45 (ddd, 1H) 5.60 (sept, 1H), 1.35 (d, 6H), 1.30 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C:35]1[CH:53]=[CH:52][C:38]([C:39]([NH:41][CH2:42][C:43]([CH3:51])([CH3:50])[CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:40])=[CH:37][C:36]=1[O:54][CH3:55].CC(C)CC(O)C>CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:34][C:35]4[CH:53]=[CH:52][C:38]([C:39]([NH:41][CH2:42][C:43]([CH3:50])([CH3:51])[CH2:44][N:45]5[CH2:49][CH2:48][CH2:47][CH2:46]5)=[O:40])=[CH:37][C:36]=4[O:54][CH3:55])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 120 °C
Yield: 17.9 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 101 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-1-yl-propyl)-3-methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (34 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]1[O:21][C:20](=[O:22])[CH:19]([C:23](OCC)=O)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].BrC[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[O:22]=[C:20]1[O:21][C@@H:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH:19]1[CH2:23][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:38][CH:39]=1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: CCOC(=O)C1C[C@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A solution of the product from Example 107A (13.3 g, 35.27 mmol) in ethanol (140 mL) at 0° C. was treated with a solution of NaOEt (14.9 mL, 21% in ethanol) and solid 2-[4-(bromomethyl)phenyl]pyridine (12.05 g, 48.59 mmol), stirred at 25° C. for 16 hours, treated with a solution of LiOH monohydrate (8.9 g, 212.11 mmol) in water (35 mL), stirred at 25° C. for 5 hours, cooled to 0° C., adjusted to pH 5 by addition of 10% citric acid and then partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (1 L) was heated at reflux for 16 hours, cooled and concentrated to give the title compound (10.55 g, 63% yield), which was used without further purification.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.I[CH2:15][C:16]#[N:17].OO>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[C:16]([CH2:15][C:3]1[N:4]2[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:1][C:2]=1[C:10]([O:12][CH3:13])=[O:11])#[N:17]
Reactant: COC(=O)c1cc2n(c1)CCCC2
Reactant: N#CCI
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc2n(c1CC#N)CCCC2
Yield: 78.4 %

Procedure:
A 500-mL three-neck round-bottomed flask equipped with an addition funnel, thermometer and charged with methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 101d (6.70 g, 37.4 mmol), iodoacetonitrile (12.5 g, 74.9 mmol), iron (II) sulfate heptahydrate (5.20 g, 18.7 mmol) and dimethyl sulfoxide (250 mL). Hydrogen peroxide (35%, 18.2 g, 187 mmol) was added dropwise to the mixture in 1 h through a syringe pump at room temperature using a water bath. Iron (II) sulfate heptahydrate (2 to 3 equivalent) was added to the reaction mixture in portions to keep the temperature between 25° C. to 35° C., until the color of the reaction mixture is deep red. If TLCs show the reaction not completed, then more hydrogen peroxide (2-3 equivalent) and more iron (II) sulfate heptahydrate (1-2 equivalent) were added in the same manner until the reaction is completed. After that time, the reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution (200 mL) and ethyl acetate (400 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated Sodium thiosulfate solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 78% yield (6.40 g) of 101e as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 4.23 (s, 2H), 3.94 (t, 2H, J=6.5 Hz), 3.81 (s, 3H), 2.74 (t, 2H, J=6.5 Hz), 2.00 (m, 2H), 1.83 (m, 2H); (APCI+) m/z 219.3 (M+H)
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1SC=CN=1)[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]1[CH:20]=[C:19]([Cl:21])[C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(OC)(=O)=[O:38].[BH4-].[Na+].O>CC#N.CCOC(C)=O.CCOCC.[Hg](Cl)Cl>[Si:1]([O:8][C@H:9]([CH:30]=[O:38])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:11][C:12]1[CH:20]=[C:19]([Cl:21])[C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@H](O[Si](C)(C)C(C)(C)C)c1nccs1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cl[Hg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution tert-butyl (1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate (1.85 g, 3.51 mmol) in MeCN(14 mL) was treated with 4 A mol. seives and was allowed to stir at RT for 10 minutes. Methyl trifluoromethanesulfonate (0.464 ml, 4.21 mmol) was added, and the reaction mixture was allowed to stir for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the crude residual material was dissolved in MeOH(14 mL), and cooled to 0° C. The mixture was then treated with sodium borohydride (0.398 g, 10.5 mmol) and allowed to warm to RT and stir for an additional 20 minutes. The reaction mixture was diluted with EtOAc, filtered through celite and concentrated under reduced pressure. The residue was dissolved in ACN(10 mL) and water (4 mL) and was treated with mercury(II) chloride (0.953 g, 3.51 mmol). After stirring for 30 minutes the reaction mixture was diluted with ether and filtered through a short plug of silica. The filtrate was then concentrated under reduced pressure and the crude residue was purified by column chromatography yielding tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[d][1,3]dioxol-5-yl)-4-oxobutan-2-ylcarbamate.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].ClS([N:39]=[C:40]=O)(=O)=O.CN(C=O)C.[OH-].[NH4+]>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[C:40]#[N:39])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
To an ice-cooled solution of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole (173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen is added a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35 eq.) in 1 ml of acetonitrile, after stirring for 20 min, a solution of DMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred for additional 1 h. The reaction mixture is poured into ice water and basified with diluted ammonium hydroxide solution; the mixture is extracted with dichloromethane, dried over sodium sulfate. The solvent is evaporated; the residue is purified through flash chromatography to give 11 mg of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.38 (1H, d, J=3 Hz), 7.15˜7.36 (4H, m), 7.07 (1H, dd, J=1.2, 8.4 Hz), 6.89˜6.93 (2H, m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d, J=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H,m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS (+VE) m/z 502 (M+1).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:20][CH2:19][NH:18][NH:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:40]([NH:39][CH2:37][CH3:38])=[O:41])[NH:18][CH2:19][CH2:20]2)=[CH:26][CH:25]=1
Reactant: CCN=C=O
Reactant: Fc1ccc(C(CCCN2CCNNCC2)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-[4,4-bis(4-fluorophenyl)butyl]hexahydro-1H-1,2,5-triazepine dihydrochloride (3.25 g, prepared as in example 13), N,N-diisopropylethylamine (3.38 ml) in dry dichloromethane (10 ml) at 5° under nitrogen was added ethyl isocyanate (0.62 ml) in dichloromethane (10 ml) and the solution was stirred at room temperature overnight. After extraction of the mixture with water, the dichloromethane solution was dried (Na2SO4) and evaporated to an oil. The crude product was chromatographed on a column of silica gel prepacked in dichloromethane. Successive elution with ethyl acetate-dichloromethane (4:1) and ethanol-ethyl acetate-dichloromethane (1:4:5) allowed a separation of a major component from impurities. The hydrobromide salt of the titled compound was formed from the material in 2-propanol and was recrystallized from 2-propanol-ethyl acetate; wt. 2.18 g (49%), mp=130°-134° dec.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2F)=[CH:21][C:20]=1[Cl:40]>CC#N>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2[N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[CH:21][C:20]=1[Cl:40]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: FC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(N2CCC(F)CC2)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
A mixture of 4-fluoropiperidine×HCl (67 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for 6 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water and concentrated.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH2:11][CH3:12])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]2[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:6]12)=[O:4].[CH2:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CCOCC>[CH2:11]([C:9]1[CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:36][CH2:37]2)[C:6]2[N:7]([N:23]=[CH:24][C:25]=2[C:26]#[N:27])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=1)[CH3:12]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1

Procedure:
A mixture of 3.3 g of 4-(chloroacetyl)4,5-dihydro-6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.6 ml of 1-benzylpiperazine and 1 g. of sodium carbonate in 110 ml of toluene was stirred and refluxed for 18 hours. The mixture was treated with 10 ml of 5N sodium hydroxide and the organic phase was separated, dried over sodium sulfate and evaporated to give a dark oil. This was dissolved in ether and combined with ethanolic hydrogen chloride to give a white solid and this solid was recrystallized from acetonitrile to give 3.4 g of the title compound, m.p. 184°-186° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:17](=[O:26])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([O:23][C:21]([C:18]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][CH2:20][N:15]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:16][C:17]1=[O:26])=[O:22])[CH3:25]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A mixture of 38.3 g (341.0 mmol) potassium tert.-butoxide and 625 ml absolute tetrahydrofuran was stirred at room temperature for 0.5 h. The resulting milky solution was cooled to 0° C. and then 50.0 g (168.0 mmol) ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride were added via a powder dropping funnel. The temperature was kept below 5° C. The mixture was warmed up to room temperature and further stirred for 1 h resulting in a yellow solution. After cooling to 0° C., a solution of 30.2 g (176.0 mmol) benzyl bromide in 20.0 ml of absolute tetrahydrofuran was dropwise added in 0.5 h. A maximum temperature of 2° C. was observed. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction solution was cooled to 0° C. and 200 ml saturated ammonium chloride solution was slowly added. After extraction and phase separation, the aqueous phase was extracted twice with 100 ml of ethyl acetate. The combined organic phase were washed twice with 100 ml of saturated sodium chloride solution, dried over Na2SO4, the solvent evaporated under reduced pressure and the residue dried to yield 58.3 g (99.3%) crude product. MS (ISP): 352 (100, [M+H]+), 174 (15).
Reaction SMILES: F[C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:16]C1C(I)=C(C=CC=1)C(O)=O.FC1C(I)=C(C=CC=1)C(O)=O>>[CH3:16][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: O=C(O)c1cccc(F)c1-n1cccn1
Agent: O=C(O)c1cccc(F)c1I
Product: Cc1cccc(C(=O)O)c1-n1cccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 33 substituting 3-methyl-2-iodobenzoic acid for 3-fluoro-2-iodobenzoic acid. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 6.53 (s, 1H), 2.07 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC.[I-].[Na+]>[CH2:15]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:13]
Reactant: CCc1cccc(O)c1[N+](=O)[O-]
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CCOc1cccc(CC)c1[N+](=O)[O-]
Yield: 97.6 %

Procedure:
A mixture consisted of 3.15 g (18.2 mmol) of 2-ethyl-6-hydroxy-1-nitrobenzene, 4.44 g (36.7 mmol) of allyl bromide, 2.70 g (19.5 mmol) of potassium carbonate, 262 mg (1.75 mmol) of sodium iodide and 30 ml of acetone was heated under refluxing for 2 hours. After cooling, the reaction mixture was diluted with ether and the diluted mixture was filtered to remove inorganic substances. The filtrate was concentrated and the concentrate was purified by column chromatography through 150 g of silica gel using a 1:9 mixture of ether and hexane as an eluent to give 3.68 g (98%) of the title compound as an oil.
Reaction SMILES: F[B-](F)(F)F.[F:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[SH:33][CH2:34][C@@:35]12[C@@H:52]3[C@H:43]([C@H:44]4[C@@:48]([CH2:50][CH2:51]3)([CH3:49])[C:47](=[O:53])[CH2:46][CH2:45]4)[CH2:42][CH2:41][C:40]1=[CH:39][C:38](=O)[CH2:37][CH2:36]2>O1CCCC1.Cl>[F:6][CH:7]=[C:38]1[CH2:37][CH2:36][C@@:35]2([CH2:34][SH:33])[C:40]([CH2:41][CH2:42][C@@H:43]3[C@@H:52]2[CH2:51][CH2:50][C@@:48]2([CH3:49])[C@H:44]3[CH2:45][CH2:46][C:47]2=[O:53])=[CH:39]1
Reactant: FC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CS)[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=CF)CC[C@@]43CS)[C@@H]1CCC2=O
Temperature: 0 °C
Yield: 47.7 %

Procedure:
17.2 g of fluoromethyl triphenylphosphonium tetrafluoroborate is suspended in 120 ml of tetrahydrofuran and mixed at 25° C. by portions with 7.8 g of potassium tert-butylate. Stirring is continued for one more hour, it is cooled to 0° C. and 1.5 g of 19-mercapto-4-androstene-3,17-dione (European patent 100,556) is instilled in 10 ml of tetrahydrofuran and stirring is continud for 30 more minutes. Then it is neutralized in 1N hydrochloric acid, the reaction mixture is added to waer, extracted 4 times with ethyl acetate, the organic phases washed neutral, dried on sodium sulfate and freed rom the solvent in a vacuum. After chromatography on silica gel with hexane/ethyl acetate, 752 mg of 3-fluoromethylene-19-mercapto-4-androsten-17-one with a melting point of 118°-120° C. is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:16]([C:25](OCC)=[O:26])=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH2:7]([N:14]1[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:16]([CH2:25][OH:26])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 0° C., LAH (1.8 mL, 3.7 mmol, 2M in THF) was added to ethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (560 mg, 1.8 mmol) in THF (18 mL). The reaction was stirred for 10 min and then warmed to room temperature for 1 h. Minimal water was slowly added to the reaction followed by 1 mL of 5 M sodium hydroxide. The reaction was stirred for 30 min, sodium sulfate was added, and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield crude (1-benzyl-5-phenyl-1H-pyrazol-3-yl)methanol, which was carried through without further purification. MS (ESI) m/z: Calculated for C17H16N2O: 264.13. found: 265.1 (M+H)+.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][OH:7])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cn1c(CO)c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.26 g) was added to a solution of the product from Example 27 step b) (0.5 g) in DMF (5 ml) and the solution stirred at room temperature for 20 mins. Water (5 ml) was added and the mixture stirred for a further 30 mins. The reaction was diluted with further water (50 ml), extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid Filtered off and dried to yield the title compound as a white solid (48 mg).