Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:36]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][Br:36])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:20])([F:21])[F:22])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A mixture of (1-acetyl-5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (3.25 g, 9.94 mmol), AIBN (408 mg, 2.49 mmol) and N-bromosuccinimide (1.77 g, 9.94 mmol) in tetrachloromethane (50 mL) is heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, cyclohexane/EtOAc 9:1) to afford the title compound as a yellow solid (2.44 g, 6.02 mmol, 61%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.88 (s, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 4.62 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 2.76 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 4.23 (M(C16H1579BrF3NO3)+H2O)+.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Reaction time: 1152 h

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (1 g), dimethylamine (1 ml of a 33% solution in ethanol) and ethanol (2 ml) was kept at ambient temperature for 48 days. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute aqueous sodium hydroxide solution (5 ml) and the resulting mixture extracted with dichloromethane (2×50 ml). The extract was washed with brine, dried and the solvent removed by evaporation to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 143°-144° C.) which was recrystallised from hexane.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+].[N+]([O-])([O-])=O.[Ag+:31]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 70 °C

Procedure:
In a reaction vessel, deionized water, 10% solution of dodecyl thiopolyacrylamide (72 g) and 46.6 g of recrystallized behenic acid were placed. The content in the reaction vessel was heated at 70° C. with stirring at 150 rpm, while 10% potassium hydroxide solution (70.6 g) was added to the vessel. Thereafter, the content in the reaction vessel was heated at 80° C., and maintained at the same temperature for 30 minutes until the content became a turbid solution. Next, the reaction mixture was cooled to 70° C., and a silver nitrate solution (100% solution, 21.3 g) was added to the reaction vessel over 30 minutes by controlling the speed of adding. The content in the reaction vessel was maintained at the reaction temperature for 30 minutes, cooled to room temperature, and decanted, so that a nanoparticle silver behenate dispersion was obtained (solid content 3%) with median grain size of 150 nm.
Reaction SMILES: [CH2:1]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCCC.C([Li])CCC.[C:29](=[O:31])=[O:30]>CCOCC>[CH2:1]([C:13]1[O:14][C:15]([C:29]([OH:31])=[O:30])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccco1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCc1ccc(C(=O)O)o1
Reaction time: 1 h

Procedure:
A solution of 30.4 g (0.2 moles) of 2-dodecylfuran in 300 ml of anhydrous ether is stirred at -20° C. after which 0.22 moles (92 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring. The reaction mixture is stirred for 1 hour then poured over 200 g of crushed dry ice (solid CO2) after which the mixture is allowed to stand for 1 hour prior to dilution with a saturated ammonium chloride solution The organic layer is separated, washed with water and brine, dried over sodium sulfate and evaporated to give 5-dodecyl-2-furancarboxylic acid. The thus obtained acid in 500 ml of anhydrous ether is stirred at room temperature during which time 200 ml of a 2 molar solution of methyllithium in ether is added slowly. The reaction mixture is allowed to stand at room temperature for 2 hours after which it is poured into a saturated ammonium chloride solution The organic layer is separated and washed with water and brine, dried over sodium sulfate and evaporated to dryness to give white crystals of methyl 2-(5-dodecylfuryl) ketone. M.P. 35°-7° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:36]=[CH:35][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:37][CH2:38][CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:36]=[CH:35][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:37][CH2:38][CH3:39]
Reactant: C=CCc1c(O)ccc(C(=O)NC)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound of Example 6 (465 mg), the compound of Example 3 (1 g) and potassium carbonate (312 mg) were added to 5.0 ml of dimethylformamide (DMF), and the reaction mixture was stirred at room temperature for about 2 days. Water (20 ml) was added and the reaction mixture was extracted three times with ethyl acetate and the combined extracts washed twice with water, dried and filtered. Solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 20/80 ethyl acetate/hexane gave the product as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH3:22])[CH2:17]1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17]1
Reactant: CN1CCCC(CCl)C1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: CN1CCCC(Cn2cnc(-c3cc(C#N)ccn3)c2)C1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-chloromethyl-methyl piperidine according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C16H19N5, 282. Found, 282.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=O)[NH:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:16][C:17]=1[CH3:18]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1Br
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1[nH]c(C=NNC(=O)c2ccc(O)cc2)c(C)c1Br
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.06 g, 0.0004 mol) and 4-bromo-3,5-dimethyl-pyrrole-2-carboxaldehyde (0.08 g, 0.0004 mol) in abs. EtOH (5 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.1 g, in 77% yield, mp: 235.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 11.21 (s, 1H), 9.99 (s, 1H), 8.26 (s, 1H), 7.76 (d, 2H), 6.82 (d, 2H), 2.15 (s, 3H), 2.03 (s, 3H). 13C NMR (DMSO-d6) δ 163.9, 162.2, 140.2, 131.6, 131.3, 126.1, 124.0, 124.3, 116.8, 13.4, 11.8. Anal. Calcd for C14H14BrN3O2.¼H2O: C, 49.35; H, 4.14; N, 12.33; Br, 23.69. Found: C, 49.21; H, 3.95; N, 11.96; Br, 23.37.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:21])([F:20])[C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1>CO.[Pt](=O)=O>[ClH:1].[F:21][C:3]([F:2])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)nc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)nc2)C1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Methyl 6′-(trifluoromethyl)-2,3′-bipyridine-4-carboxylate hydrochloride (2.5 g, 7.86 mmol) was dissolved in MeOH (20 mL) and platinum(IV) oxide (0.036 g, 0.16 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 1 h. Additional catalyst was added and the hydrogenation was continued for 1 h. The catalyst was filtered off, washed with MeOH and the eluate evaporated yielding methyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate hydrochloride (2.2 g, 86%) as a brown solid. MS m/z 289 (M+H)+
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.[H-].[Na+].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1.O>C1COCC1>[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[CH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C(=Cc1ccc(-n2ccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.6 %

Procedure:
1.0 g of diethylbenzylphosphonate were dissolved in 50 ml of dry THF under nitrogen gas flow. To this solution, were added 0.21 g of 60% NaH while cooling the solution with ice, and the resultant solution was then stirred for 2 hours at room temperature. After cooling the whole solution with ice, 0.75 g of 4-(imidazole-1-yl)benzaldehyde were added thereto and stirred for 48 hours at room temperature. The solution reacted was condensed under reduced pressure, added with water, and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, for which chloroform is used for the developer, thereby affording 0.5 g of 4-(imidazole-1-yl)stilbene.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C=O)C>CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ccc(-c3ccccc3)nc2c1N
Temperature: 90 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol) and triethylamine (0.20 mL) were added to 3 mL of DMF containing [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (1:1 complex with CH2Cl2) under N2. The mixture was stirred at 90° C. for 4 h. The reaction was then cooled and diluted with Et2O. The organic layer was washed with H2O, brine, dried (MgSO4), concentrated and chromatographed (2:1 CH2Cl2 :hexane) to yield the title compound (140 mg, 50%): 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J=8 Hz, 1H), 8.07-8.13 (m, 3H); MS (DCI(NH3)) m/e 285 (M+H)+.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH:12]=[C:11](OC)[C:10](OC)=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4](C)[N:3]=1.[OH-].[K+].CC1(C)C(C)(C)OB(C2C=CC(N3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)O1.O>O1CCOCC1>[CH:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[NH:4][N:3]=1
Reactant: COc1cc2ncc3c(c(Br)nn3C)c2cc1OC
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)ncc1[nH]ncc12
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
1-Bromo-7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinoline (30 mg, 93 μmol) is dissolved in dioxane (1.0 ml) under argon. KOH (5.2 mg, 93 μmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (83 mg, 214 μmol), trans-bis(tricyclohexylphosphine)palladium(II) dichloride (10.4 mg, 14 μmol) and water (50 μl) are subsequently added. The reaction suspension is subsequently heated at 110° C. (microwave) for 90 min. The mixture is subsequently poured into water, stirred for 15 min, and the precipitate obtained is filtered off with suction. The filter residue is then treated in formic acid (2.5 ml) at room temperature for 18 h, subsequently diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 7,8-dimethoxy-3-methyl-1-(4-piperazin-1-yl)phenyl)-3H-pyrazolo[3,4-c]quinoline (22 mg, 55 μmol) as a solid. MS: 404.1 (M+H+). TLC (HPTLC): Rf=0.19 (methanol/Hünig's base 99:1, parts by volume).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].N.C>C1(C)C=CC=CC=1>[CH3:2][C:1]1[S:15][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)CNC(=O)c1cccnc1
Agent: N
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 8.0 g (0.045 mol) of 73 in 125 ml of toluene, 10 g (0.045 mol) of P4S10 was added. The suspension was refluxed for 4 h and left at room temperature overnight. The mixture was poured into ice water followed by basification with ammonia. The two-phase system was stirred with charcoal and filtered. The toluene phase was separated and the aqueous phase extracted with 2×100 ml of toluene. The combined organic phases were dried over MgSO4 and evaporated in vacuo leaving a heavy, yellow oil, 88. Yield: 2.3 g (0.013 mol, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1.N.C[N:44](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[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:44])=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(N)=O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 100.1 %

Procedure:
A mixture of rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid (0.33 g, 0.55 mmol), a solution of ammonia (0.5 M in dioxane, Aldrich, 2 mL, 1 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by chromatography (EtOAc) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzamide as a white solid (0.33 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=S(=O)(c1ccccc1)N1CCC(C(=NCc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 63.6 %

Procedure:
A solution of 22.26 g (0.064 mol) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 12.51 g (0.10 mol) of 4-fluorobenzylamine, and 0.76 g (0.0048 mol) of benzenesulfonic acid in 400 mL of xylene was heated at reflux for 25.5 h. Water was removed with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2 -hexane to give 18.49 g (63.68%) of white crystalline solid, mp 114°-116° C. A second crop of 3.27 g (11.28%) of product was isolated from the filtrate as a white solid, mp 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.CC(C)=O>C(O)C.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12]/[CH:13]=[CH:14]\[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(CC#Cc1cccnc1)CC2
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1nc2c(s1)CCN(C/C=C\c1cccnc1)CC2
Yield: 42 %

Procedure:
Prepared by catalytic hydrogenation of 2-amino-6 -(3-(3-pyridyl)-2-propyn-1-yl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine with palladium/barium sulphate (5%) in ethanol. Yield: 42% of theory, Melting point: 125°-126° C. (acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:24](=[O:25])[C:23]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)(C(OC)=O)[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([OH:25])=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(F)c(F)c2)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1c(-c2ccc(F)c(F)c2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 80 mg (0.14 mmol) of the product of Step B dissolved in 1 mL EtOH was added 9 mg (0.20 mmol) of sodium borohydride. The reaction mixture was stirred at RT for 5 min then partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was then redissolved in 10 mL MeOH and 2 mL of a 2.0 N solution of sodium hydroxide was added. The reaction mixture was stirred at 80° C. for 0.5 h, then cooled to room temperature and partitioned between EtOAc and 10% aq. NaHSO4. The organic layer was separated, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([OH:10])[CH3:9])[CH2:3]1.[Cl:12][CH2:13][C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:14](=[O:15])[CH2:13][Cl:12])[CH3:9])[CH2:3]1
Reactant: CC(O)C1CCCC(C)(C)C1
Reactant: O=C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)CCl)C1CCCC(C)(C)C1
Yield: 88.1 %

Procedure:
Following our general procedure, 15.6 g (100 mmol) of 1-(3′,3′-dimethylcyclohexyl)ethanol were esterified with 9.45 g (100 mmol) of chloroacetic acid in anhydrous dichloromethane in the presence of 1.22 g (10 mmol) of 4-(dimethylamino)pyridine and 22.7 g (110 mmol) of N,N′-dicyclohexylcarbodiimide. The usual work-up provided 28.4 g of crude product, which was purified by flash chromatography (600 g silica gel, pentane/ether, 19:1, Rf=0.77) to provide 20.5 g (88%) of chloroacetic acid 1-(3,3-dimethylcyclohexyl)ethyl ester, 4.80 g (20.6 mmol) of which were dissolved in 50 ml of diethyl ketone and 13 ml of 1,4-dioxane. To this solution, 1.77 g (20.6 mmol) of cyclopropanecarboxylic acid and 5.69 g (41.2 mmol) of potassium carbonate were added, and the resulting mixture was refluxed for 20 h. The reaction mixture was then poured onto 100 g of ice, and the product was extracted twice with 150 ml of ether. The combined ethereal extracts were washed with 100 ml of water and 50 ml of brine, dried with sodium sulphate, and concentrated under reduced pressure to furnish 26.0 g of crude material. This was purified by flash chromatography (175 g silica gel, pentane/ether, 9:1, Rf=0.52) to provide 3.56 g (61%) of the target compound cyclopropanecarboxylic acid 1-(3,3-dimethylcyclohexyl)ethoxycarbonylmethyl ester (12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCCC3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 8E (254 mg, 0.457 mmol) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (126 mg, 3 mmol). The mixture was stirred at room temperature overnight. The mixture was then neutralized with 5% HCl and diluted with ethyl acetate (200 mL). After washing with brine, it was dried over Na2SO4. Evaporation of solvent gave title compound.