Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH2:10]([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:11]O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:30][C:13]([F:31])([C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([SH:1])[CH2:6][C:7]([O:9][CH2:11][CH2:10][C:13]([F:30])([F:31])[C:14]([F:28])([F:29])[C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[O:8]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CC(S)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 94.7 %

Procedure:
Mercaptosuccinic acid (Aldrich) (12.5 g, 0.083 mole) and 1H,1H,2H,2H-perfluorooctan-1-ol (Fluorochem Ltd.) (60.6 g, 0.166 mole) were suspended in toluene (400 ml). p-Toluene sulfonic acid hydrate (Aldrich) (0.36 g) was added and the mixture refluxed under argon atmosphere for 72 hours in a flask equipped with a Dean & Stark reflux condenser. The solution was allowed to cool and the toluene was removed by evaporation under reduced pressure. The resulting oil was redissolved in ethyl acetate (1000 ml) and washed with saturated aqueous sodium hydrogen carbonate (800 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-mercaptosuccinic acid bis-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) ester as a pale yellow oil (66.2 g, 100% yield).
Reaction SMILES: NC1C=CC(N[C:9]2[CH:10]=[CH:11][C:12]3[N:13]=[C:14]4[C:27]([O:28][C:29]=3[C:30]=2S(O)(=O)=O)=[C:26](Cl)[C:25]2[C:16]([O:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[C:20](NC2C=CC(N)=C(S(O)(=O)=O)C=2)[C:19]=3S(O)(=O)=O)=[C:15]4Cl)=CC=1S(O)(=O)=O>O.CC(C)=O>[CH:22]1[C:23]2[N:24]=[C:25]3[C:16](=[CH:15][C:14]4[C:27](=[CH:26]3)[O:28][C:29]3[C:12](=[CH:11][CH:10]=[CH:9][CH:30]=3)[N:13]=4)[O:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(Nc2ccc3c(c2S(=O)(=O)O)Oc2c(Cl)c4c(c(Cl)c2=N3)Oc2c(ccc(Nc3ccc(N)c(S(=O)(=O)O)c3)c2S(=O)(=O)O)N=4)cc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2c(c1)N=c1cc3c(cc1O2)=Nc1ccccc1O3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,10-bis(4-amino-3-sulphophenylamino)-6,13-dichlorotripheno dioxazine-4,11-disulphonic acid (M.I. 2585, 25.85 g, 0.01M) was dissolved in water (300 ml) at pH 7. A solution of N-(2,4-dichlorotriazin-6-yl) methanesulphonmethylamide (5.93 g, 0.02M) in acetone (80 ml) was added and the mixture stirred at 25° C. and pH 7 for 3 hours. Salt (5% w/v) was added with stirring and the precipitated solid was collected, washed and dried. Yield 1.7 g, M.I. 1472.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][N:18](CCC#N)[N:19]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2nnn(CCC#N)n2)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)cc(-c2nn[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Preparation H6, Step 4: To a solution of methyl 3-tert-butyl-5-(2-(2-cyanoethyl)-2H-tetrazol-5-yl)benzoate (500 mg) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (76 mg) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 3-tert-butyl-5-(2H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=247.
Reaction SMILES: [I-].[CH3:2][Li].[C:4]([C:6]1[C:10]([S:11][C:12]([F:15])([F:14])[F:13])=[C:9]([CH:16]=[O:17])[N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)#[N:5].Cl>C(OCC)C>[C:4]([C:6]1[C:10]([S:11][C:12]([F:14])([F:13])[F:15])=[C:9]([CH:16]([OH:17])[CH3:2])[N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:27])([F:28])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)#[N:5]
Reactant: [Li]C
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Agent: Cl
Agent: [I-]
Solvent: CCOCC
Product: CC(O)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Cooper (I) iodide (6.1 g, 0.032 mol) was suspended in anhydrous diethyl ether and cooled to 0° C. Methyllithium (1.6 M in diethyl ether, 40 ml, 0.064 mol) was added via cannula and stirred 10 minutes. A solution of the product of Example 3 (10 g, 0.023 mol) in diethyl ether was added via cannula creating a bright yellow suspension. After 15 minutes, 10% aqueous hydrochloric acid (40 ml) was added while venting the reaction vessel. The remaining suspension was filtered through Celite® and washed with diethyl ether several times. The organic phase was washed with saturated sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration from pentane provided crystals that were purified by silica gel chromatography using ethyl acetate:hexanes. The title compound was isolated as a white solid (7.56 g), m.p. about 123° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[CH:22]1[CH:21]=[CH:20][C:19]2[S:15][N:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:28][CH2:29]3)[C:18]=2[CH:23]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1

Procedure:
To a 125 mL round bottom flask equipped with an N2 inlet and condenser are added 0.73 g (3.2 mmol) 5-(2-chloroethyl)-6-chloro-oxindole, 0.70 g (3.2 mmol) N-(1,2-benzisothiazol-3-yl)piperazine, 0.68 g (6.4 mmol) sodium carbonate, 2 mg sodium iodide, and 30 mL methylisobutyl ketone. The reaction is refluxed for 40 hours, cooled, filtered, and evaporated. The residue is chromatographed on silica gel, eluting the by-products with ethyl acetate (1 L) and the product with 4% methanol in ethyl acetate (1.5 L). The product fractions (Rf=0.2 in 5% methanol in ethyl acetate) are evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid is filtered and washed with ether, dried, and washed with acetone. The latter is done by slurrying the solid with acetone and filtering. Ziprasidone is obtained as a high melting, non-hygroscopic solid product having an expected melting point of 288° C. to 288.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Yield: 191.6 %

Procedure:
A mixture of (R)-piperidine-3-carboxylic acid (3.0 g, 23 mmol), benzyl 2,5-dioxopyrrolidin-1-yl carbonate (5.79 g, 23.2 mmol) and Na2CO3 (6.15 g, 58.1 mmol) was stirred in water and 1,4-dioxane (1:1, 200 mL) at ambient temperature for about 96 h. The organic solvent was removed under reduced pressure. The aqueous layer was acidified with 1 N aqueous HCl and extracted with EtOAc (2×100 mL). The organic phase was washed with brine (150 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield crude (R)-1-(benzyloxycarbonyl)-piperidine-3-carboxylic acid (11.6 g, 191%) as a white solid: LC/MS (Table 1, Method a) Rt=1.80 min; MS m/z 264 (M+H)+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].[F:19][C:20]([F:26])([F:25])[C:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[F:19][C:20]([F:26])([F:25])[C:21]([C:17]1[S:13][C:14]([SH:18])=[N:15][CH:16]=1)([OH:24])[CH2:22][CH3:23]
Reactant: Sc1nccs1
Reactant: CCC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
iPr2NH (2.0 g, 19.9 mmol) was dissolved in THF (23 mL) and cooled to −78° C. n-Butyllithium (2.5M, 8.0 mL, 19.9 mmol) was added dropwise, followed by thiazole-2-thiol (0.9 g, 7.9 mmol) in THF (5 mL). After 10 minutes, trifluoro-2-butanone (0.5 g, 4.0 mmol) was added and the reaction was stirred at −78° C. for 6 hours. The reaction was warmed to room temperature and quenched with 5% aqueous NH4Cl (20 mL). The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 10b.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetate (275 mg) in THF (10 ml) and MeOH (5 ml) under N2 was added 2N NaOH (3.0 ml). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The aqueous residue was extracted with CH2Cl2. The aqueous layer was then acidified with 3.0 N HCl (ca. 2.1 ml) to pH 2, and extracted with CH2Cl2. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed, and the crude product recrystallized from CH2Cl2 /hexane to give the title compound. m.p. 180.5°-184° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of benzyl 2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.140 g, 0.25 mmol) in ethanol (1.4 ml) is hydrogenated with 10% palladium/charcoal (0.03 g) for 4.5 hours at 50° C. under 5 bar of hydrogen. The mixture is filtered, evaporated down in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=10/1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Cc1ncc2c(I)n[nH]c2n1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
7.100 g (approx. 10.92 mmol, purity 40%) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.626 g (14.20 mmol) of caesium carbonate were initially charged in 100 ml of DMF, and 2.939 g (14.20 mmol) of 2,3-difluorobenzyl bromide dissolved in 50 ml of DMF were added. The reaction mixture was stirred at RT for 3 h, added to 1.5 l of ice-water and extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.360 g of the target compound were obtained (31% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)=[O:37]
Reactant: Cc1ccccc1-n1ccnc1SCCCOc1ccc2c(c1)CCC(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 56.7 %

Procedure:
In 1 liter of dichloromethane was dissolved 67 g of 6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril. Thereto was added 32.6 g of m-chloroperbenzoic acid with ice-cooling. The mixture was stirred overnight. After the completion of the reaction, the reaction mixture was washed five times with an aqueous solution saturated with sodium hydrogencarbonate, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1). The crude crystals were recrystallized from ethanol-n-hexane to obtain 39.5 g of 6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:23]([Cl:24])=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=1[Cl:26].C(OCC)C>CN(C=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([S:9][CH2:17][C:18]2[C:19]([Cl:26])=[CH:20][CH:21]=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:4]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccnc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
4-methylpyrimidine-2-thiol hydrochloride (200 mg, 1.2 mmol) and potassium carbonate (357 mg, 2.6 mmol) was stirred for 30 minutes in anhydrous DMF (4 mL) at room temperature. Then, 2-(bromomethyl)-1,3,4-trichlorobenzene (345 mg, 1.3 mmol) in anhydrous DMF (1 mL) was added, and the mixture was stirred overnight at room temperature. The solid was removed by filtration and filtrate evaporation. The residue was dissolved in DCM and purified on silica gel using 5% DCM/MeOH to afford, after trituration with diethyl ether, 4-methyl-2-{[(2,3,6-trichlorophenyl)methyl]sulfanyl}pyrimidine as a white solid (88 mg, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H), 4.75 (s, 2H), 6.09 (s, 1H), 7.17 (d, J=5.1 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H); LRMS (ES+) m/z 319 (100%, M+1), 321 (100%, M+3), 323 (35%, M+5).
Reaction SMILES: [C:1]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>>[C:26]([O:25][CH2:24][CH2:23][S:22][CH2:21][CH2:20][C:1]([F:3])([F:2])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:14])([F:15])[C:16]([F:17])([F:18])[F:19])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
C6F13CH2CH2SCH2CH2OH (40.1 g, 0.094 mole, undistilled), acetic anhydride (16.2 g, 0.15 mole) and pyridine (0.98 g, 12.4 mmole) was heated at 65°-66° for 4 hours and 89° for 17 hours under total reflux. A sample after 4 hours showed incomplete reaction and after 17 hours, only a trace of C6F13CH2CH2SCH2CH2OH was present (GC analysis). The product was washed with saturated sodium bicarbonate (20 ml), extracted into ether, dried and the solvent removed by distillation; wt. 47.77 g. Total product was 49.3 g, 100% of theory. NMR was consistent for structure: proton resonances at 2.03 ppm, 3 protons, s, CH3 ; at 2.42 ppm, multiplet, 2 protons, CH2A ; at 2.78 ppm, multiplet, 4 protons, CH2A ; at 2.78 ppm, multiplet, 4 protons, CH2B and CH2C ; and at 4.24 ppm, t, 2 protons CH2D for C6F13CH2ACH2BSCH2CCH2DO2CCH3.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:22]([NH:21][C@@H:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[S:23])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(N=C=S)c1ccccc1
Agent: Cl
Product: C[C@@H](NC(=S)NS(=O)(=O)c1sc(Cl)cc1N)c1ccccc1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and D-α-methylbenzyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 96% impure product); 1H-NMR (DMSO-d6): δ1.46 (d, 3H, CH3), 5.36 (quint, 1H, CH), 6.45 (br s, 2H, NH2), 6.64 (s, 1H, H-4), 7.2-7.4 (m, 5H, ArH), 8.53 (br d, 1H, NH), 11.3 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:24][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:25]([CH3:24])[CH2:30]3)[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]=23)=[CH:13][CH:14]=1)[CH3:23]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)[C@H](C)C3)nc3c2CCC3)cc1
Yield: 27.4 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.094 g, 0.28 mmol) was reacted with (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.112 g, 0.56 mmol) to afford the title compound (0.038 g, 27%) as an orange foam. MW=494.63. 1H NMR (CDCl3, 500 MHz) δ 7.26 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.14 (s, 1H), 5.58 (s, 1H), 4.27 (br s, 1H), 4.17 (q, J=7.0 Hz, 2H), 4.04-3.97 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.73 (m, 1H), 3.60 (s, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.86-2.78 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H), 1.20 (d, J=6.6 Hz, 3H); APCI MS m/z 495 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]2)=[C:22]([O:33][CH3:34])[CH:21]=1.CC(O)=O.[OH-].[Na+]>O1CCOCC1>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(C#N)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (150 mg, 0.578 mmol) in Dioxane (Ratio: 1, Volume: 1013 μl) was added 1-(4-amino-2-methoxyphenyl)-1H-imidazole-4-carbonitrile (Preparation AA) (124 mg, 0.578 mmol), and AcOH (Ratio: 1.000, Volume: 1013 μl). The resulting mixture was brought to 100° C. in a sealed vial and stirred overnight. The mixture was brought to pH 8 by the addition of 1 N aqueous sodium Hydroxide. The resulting mixture was extracted with EtOAc (3×1 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (Waters Sunfire C18, 50×250 mm, acetonitrile/H2O/ammonium acetate) gave 1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile (57 mg, 0.130 mmol, 22.56% yield). LC-MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.02-8.08 (2H, m), 7.90-7.94 (1H, m), 7.31 (2H, t, J=7.63 Hz), 7.16-7.24 (4H, m), 6.99 (1H, dd, J=8.55, 2.14 Hz), 4.18 (1H, t, J=8.09 Hz), 3.56 (3H, s), 3.07 (3H, s), 2.76-2.84 (1H, m), 2.59-2.74 (2H, m), 1.98-2.05 (1H, m). The racemic mixture was separated by chiral chromatography to afford the enantiomers Example 204A and 204B.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][O:22][C:23]1[CH:34]=[CH:33][C:26]2[CH:27]=[C:28]([C:30](O)=[O:31])[O:29][C:25]=2[CH:24]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[O:29][C:25]2[CH:24]=[C:23]([O:22][CH3:21])[CH:34]=[CH:33][C:26]=2[CH:27]=1)=[O:31]
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: COc1ccc2cc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)oc2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-methoxy-benzofuran-2-carboxylic acid. MS: 448.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[N:30]1([C:36](=[O:44])[CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:44])[CH2:43][CH2:42]3)=[O:28])[NH:10][CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 51.9 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9%).