Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:33])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:32])[C:10]2[CH:34]=[CH:35][CH:36]=[CH:37][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:33])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[C:27]([O:31][CH3:38])[CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:32])[C:10]2[CH:34]=[CH:35][CH:36]=[CH:37][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(O)c2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)N(CC(=O)N1c3ccccc3N(Cc3ccccc3)C(=O)[C@H]3CCC[C@H]31)C2=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 96.7 %

Procedure:
To a suspension of (3aR*,10aS*)-9-benzyl-4-((3-hydroxyphthalimido)acetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (343 mg, 0.69 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (115 mg, 0.83 mmol) and methyl iodide (0.10 mL, 1.6 mmol). The mixture was stirred for 4.5 hours at room temperature, to which was added water. The resulting solid was separated by filtration, and the filtrate was subjected to extraction with chloroform. In this organic layer was dissolved the solid previously separated by filtration. The solution was dried over magnesium sulfate, which was subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-diethylether to give 340 mg (yield 96%) of the titled compound, m.p. 247°-248° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]CC3C=CC=CC=3)[C:19]=2[O:32]CC2C=CC=CC=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[Pd].CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:19]=2[OH:32])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1cc(OCCCCCCc2cccc(O)c2O)ccc1O
Yield: 69.1 %

Procedure:
A mixture of 0.22 g of 2-hydroxy-5-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid and 30 mg of 10% palladium on carbon in 10 ml of methanol was stirred in a hydrogen atmosphere for 5 hours. Workup as in example 36 and recrystallization from acetone-hexane gave 0.10 g, mp 159°-161° of 2-hydroxy-5-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([C:26](=[O:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])[CH3:27]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(=O)N(CCl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.8 mmol) and triethylamine (7.6 mmol) was stirred together in CH2Cl2 (30 ml) for 10 minutes before a solution of N-chloromethyl acetanilide (see Preparation 16) (3.8 mmol) in CH2Cl2 (5 ml) was added. The mixture was stirred at 40° C. for 2 hours before the solvent was distilled off and the residue washed with water and ether. Yield 0.3 g, (28%) M.p. 150°-155° C. (decomp) (CH2Cl2 /pet. ether) 1H NMR (CDCl3, δ): 1.90 (CH3), 5.60 (CH2), 6.9-7.4 (Ph), 8.18 and 8.42 (H-4, H-6, J3Hz). IR (KBr) 1670-1680 cm-1 (CO).
Reaction SMILES: [ClH:1].[OH:2][C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:8][CH2:7][N:6]([CH:9]([F:23])[CH2:10][CH:11]([N+:20]([O-])=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.CO>[Pd].[H][H]>[ClH:1].[OH:2][C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:8][CH2:7][N:6]([CH:9]([F:23])[CH2:10][CH:11]([NH2:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:5][CH2:4]1
Reactant: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)C(=O)c1ccccc1
Yield: 84.8 %

Procedure:
A mixture of 4.9 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone hydrochloride, 1.0 g of 5 % palladium on charcoal (50 % wet reagent) and 80 g of methanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and washed with hot methanol, and the filtrate was concentrated under reduced pressure. The residual solid was triturated with isopropanol, collected by filtration and washed with diisopropyl ether to afford 3.9 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-2-amino-4-fluorobutyrophenone monohydrochloride. M.P. 202°-204° C. The free base of this product was obtained by the conventional procedure. M.P. 106°-107° C (recrystallized from toluene).
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH:10]=[N+:11]=[N-:12])([CH3:9])[CH3:8].[CH:13](=[C:20](C#C)[C:21]#[N:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(OCC)(=O)C>[C:14]1([C:13]2[C:20]([C:21]#[N:22])=[N:12][NH:11][C:10]=2[Si:7]([CH3:9])([CH3:8])[CH3:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(C#N)=Cc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1[nH]nc(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
n-Butyl lithium (2.7 M solution in heptane) (3.3 ml, 9 mmol) was added drop wise to a stirred solution of trimethylsilyl diazomethane (2 M solution in diethyl ether) (4.5 ml, 9 mmol) in anhydrous THF (10 ml) at −78° C. under a nitrogen atmosphere, then stirred for a further 30 minutes. To this was added drop wise a solution of 2-benzylidene-but-3-yne nitrile (920 mg; 6 mmol) in anhydrous THF (5 ml), the mixture stirred for 30 minutes at −78° C. then gradually allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml) then washed with saturated ammonium chloride solution followed by brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1:8 then 1:4 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 1.0 g of 4-phenyl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[O:16].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([F:18])[C:4]=1[CH:15]=[O:16]
Reactant: F[B-](F)(F)F
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1c(F)c(C=O)c(OC)c2ccccc12

Procedure:
Aldehyde 27 (0.517 g, 2.39 mmol) was added to a flame-dried 50 mL round bottom flask under Argon, followed by Selectfluor (1.25 g, 3.37 mmol) and MeCN (20.0 mL). The reaction was then heated to reflux for 8 hours before being cooled and extracted with EtOAc. The organic layer was washed 3 times with brine, dried over MgSO4, filtered, and condensed to provide the crude aldehyde as a yellow solid. Following flash chromatography (3:1 CH2Cl2:hexanes) aldehyde 51 (0.254 g, 1.08 mmol, 45%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:18][CH2:17][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12](OC)=O)[C:7]2=[O:16])[CH2:5][CH2:4]1.[CH3:19][C:20]1(C)N[C:23](=O)[CH2:22][C:21]1=O>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]2=[O:16])[CH2:17][CH2:18]1
Reactant: COC(=O)C1C(=O)NC2(CCC(OC)CC2)C1=O
Reactant: CC1(C)NC(=O)CC1=O
Product: COC1CCC2(CC1)NC(=O)C(c1ccccc1)C2=O
Yield: 90 %

Procedure:
The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethyl-pyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)[CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.[NH:44]1[CH2:54][CH2:53][CH:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:45]1.C(N(C(C)C)CC)(C)C>C(O)(CC)C.ClCCl>[CH2:51]([O:50][C:48]([CH:47]1[CH2:53][CH2:54][N:44]([C:29]2[N:28]=[C:27]([N:22]3[CH2:21][C@@H:20]([N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:42])([F:43])[F:1])[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=4)[C:8]4[N:9]=[CH:10][C:11]([C:14]5[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=5)=[CH:12][N:13]=4)[CH2:24][C@H:23]3[CH2:25][CH3:26])[C:32]([Cl:33])=[CH:31][N:30]=2)[CH2:45][CH2:46]1)=[O:49])[CH3:52]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(Cl)ncc1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCC(C)O
Product: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cnn(C)c5)cn4)C[C@H]3CC)n2)CC1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzyl-[(3S,5R)-1-(2,5-dichloro-pyrimidin-4-yl)-5-ethyl-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (50.6 mg, 0.0784 mmol), ethyl isonipecotate (31 μL, 0.196 mmol) and diisopropyl-ethylamine (21 μL, 0.118 mmol) in sec-butanol (2 mL) is stirred at 120° C. for 10 hour. After addition of ethyl isonipecotate (12 μL, 0.0784 mmol) and diisopropyl-ethylamine (27 μL, 0.157 mmol), the mixture is stirred for additional 8 hours. The mixture is diluted with dichloromethane and washed with waterm 1N HCl aq, and the brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:2 to 5% MeOH in AcOEt) to give (1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester, 34.7 mg). The obtained solid is dissolved in MeOH (2.5 mL), 1N NaOH aq (225 μL, 0.225 mmol) and water (0.3 mL), and the resulting mixture was stirred at room temperature for 18 hour. 1N HCl (225 μL, 0.225 mmol) and then MeOH were added to the mixture and the solvent was removed by evaporation. The residue was dissolved in dichloromethane and then filtered. The filtrate was evaporated to give 1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid (29.2 mg, 51%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[CH:3][CH:4]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=CC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccco2)[nH]c1=O
Temperature: 130 °C
Reaction time: 21 h
Yield: 76.8 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (15.0 g, 90.9 mmol), 2-cyanoacetamide (8.5 g, 101 mmol) and potassium carbonate (38.0 g, 275 mmol) in dimethyl sulfoxide (80 ml) was stirred at 120 to 140° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with water. After adjusting to pH 3 with conc. hydrochloric acid, the resulting solid was collected by filtration and washed with water, to give the title compound (13.0 g, 77%) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:2]=1.[CH2:21]([Br:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C>[Br-:28].[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N+:1]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc[n+](Cc2ccccc2)c1
Product: [Br-]
Yield: 93.9 %

Procedure:
A mixture of 2.00 g (7.5 mmoles) of 2-[3-(3-pyridinyl)propyl]-1H-isoindole-1,3(2H)-dione, 8 mL of 2-propanol, and 1.71 g (10 mmoles) of benzyl bromide was heated under reflux for 1 hour. The solution was cooled to 0°, and the precipitated product was collected by suction filtration, washed with cold ethyl ether, and dried to afford 3.08 g of 3-[3-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)propyl]-1-(phenylmethyl)pyridinium bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:27]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[CH:18][C:19]=2SC)[C:3]=1[CH3:25].[CH2:26]1COCC1.O[O:32][S:33]([O-:35])=O.[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[CH:18][C:19]=2[S:33]([CH3:26])(=[O:35])=[O:32])[C:3]=1[CH3:25]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(C)=O)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: [K+]
Solvent: O
Product: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reaction time: 60 h

Procedure:
The 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylthio)phenyl)-ethanone (230 mg, 0.61 mmol) was added to a mixture of THF (4.6 mL) and water (1.5 mL). To the milky solution was added Oxone™ (940 mg, 1.5 mmol) and the reaction was stirred for 2.5 days. Another portion of Oxone™ (940 mg, 1.5 mmol) was added along with the same amount of THF and water amounts as initially. The slurry was stirred vigorously overnight. The reaction was then poured into water and stirred vigorously for 10 min. The mixture was filtered and washed with water. The precipitate was dissolved in EtOAc and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes) to give 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenyl)ethanone. Mass Spectrum (ESI) m/e=410.0 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC>[Br:12][C:10]1[CH:11]=[C:7]([CH:19]2[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]2=[O:22])[O:8][CH:9]=1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1coc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1NC(=O)C(c2cc(Br)co2)C(=O)N1

Procedure:
n-Butyl lithium is reacted with 2,4-dibromofuran in ether according to the procedure of Sornay et al. [Bull. soc. chim. Fr., p. 998 (1971)]. The resulting organolithium solution is reacted with alloxan at -60° to -65° C. according to Example 5, affording 5-(4-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>CS(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:2](=[O:1])[CH:7]=1
Reactant: Oc1cc(Br)ccn1
Reactant: ClCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(Br)ccn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.0 mL) was added KOH (0.13 g, 2.29 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(2-chloroethyl)morpholine (0.13 g, 0.69 mmol). The reaction mixture was then stirred at 45° C. for 30 min. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 5% MeOH-DCM) to obtain the desired product (0.085 g, 52%). MS: 287.10 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][S@](C(C)(C)C)=O)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reaction time: 0.5 h

Procedure:
(S)—N-((3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2-methylpropane-2-sulfinamide (855 mg, 2.67 mmol) from Step B and 2 N HCl (10 mL, 40.0 mmol) were combined in methanol (10 mL). After 30 minutes, the solvent was removed and the crude material was purified on a silica gel cartridge (Analogix®, Burlington, Wis., RS-25) loading with 10% methanol(2 N ammonia)/dichloromethane solution and eluting with 2-10% methanol (2 N ammonia)/dichloromethane to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.44 (d, J=7.4, 2H), 7.36 (t, J=7.5, 2H), 7.28 (t, J=7.3, 1H), 3.52 (q, J=13.0, 2H), 3.29 (q, J=7.3, 1H), 2.84 (dd, J=3.7, 9.3, 1H), 2.55-2.43 (m, 3H), 2.37-2.30 (m, 1H), 2.24 (d, J=5.3, 1H), 1.74-1.64 (m, 2H), 1.62-1.53 (m, 1H), 1.34 (dd, J=5.0, 10.1, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([SH:20])=[N:9]2)=[CH:4][CH:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([S:20][CH2:23][CH:22]=[CH2:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: SC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: C=CCBr
Product: C=CCSC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: Cl

Procedure:
By the procedure described in Example 1, 2.0 g of 4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-2-thiol was converted to 1.0 g of the title compound with allyl bromide. After recrystallization from nitromethane, the colorless crystals had m.p. 208° dec. The infrared and NMR spectra of the free base were consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:23])=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[C:32](F)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:39])=[O:38])[CH:36]=1>CS(C)=O>[Cl:30][C:31]1[C:32]([O:23][C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:38])=[O:39])[CH:36]=1
Reactant: Oc1ccc(-c2ccnc(C(F)(F)F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccnc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
2-(Pyridazin-4-yl)-4-(2-(trifluoromethyl)pyridine-4-yl)phenol (Preparation 79, 0.105 mg, 0.33 mmol) was dissolved in DMSO (3 mL) and potassium carbonate (91 mg, 0.66 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzensulfonamide (Preparation 16, 153 mg, 0.33 mmol). The mixture was stirred at room temperature for 3 hours and then partitioned between ethyl acetate (40 mL) and 1M aqueous sodium hydroxide solution (10 mL). The organic layer was separated and dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (207 mg, 81%) as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#N.C(O)=[O:20]>[Ni]>[O:13]=[C:12]1[CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]2[CH:18]=[C:3]([CH:1]=[O:20])[CH:4]=[CH:5][C:6]1=2
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Agent: [Ni]
Product: O=Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C

Procedure:
Heat a mixture of 5.0 gm. of 3-cyano-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 4.0 gm. of Raney nickel alloy in 60 ml. of 75% (v/v) aqueous formic acid at reflux for 1.5 hours. Cool to room temperature and filter. Concentrate to small volume and extract with methylene chloride. Wash the extract with water and with 1N sodium bicarbonate until neutral. Dry the neutral extract over sodium sulfate and concentrate to dryness to obtain the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[ClH:35].F[C:37]1[NH:38][CH:39]=[CH:40][N:41]=1>CN(C)C=O>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: Fc1ncc[nH]1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](Nc1ncc[nH]1)c1nc(C)no1
Reaction time: 6 h
Yield: 34.1 %

Procedure:
A solution of 985 mg of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl -methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl) -silanyloxy]-5-methoxy-6-methyl-benzoic acid methyl ester and 237 mg of 2-fluoroimidazole hydrochloride in 5 ml of N,N-dimethylformamide were stirred under argon at 50° C. for 3 h. A second portion of 117 mg of 2-fluoroimidazole hydrochloride was added and stirring was continued for 6 h. The reaction mixture was cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using methanol/dichloromethane (1:20, v/v) as eluent to yield 310 mg of (R)-3-hydroxy-2-[2-(imidazol-2-ylamino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester hydrochloride as yellow solid.