Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([OH:27])=O)=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:60][NH:61][CH2:62][CH:63]([OH:66])[CH2:64][OH:65]>CN(C)C=O.O>[OH:66][CH:63]([CH2:64][OH:65])[CH2:62][N:61]([CH3:60])[C:25]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:7]3[CH:6]=[CH:5][C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])=[C:3]([O:2][CH3:1])[CH:8]=3)=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CNCC(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.300 g, 0.65 mmol)) in N,N-dimethylformamide (15 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.150 g, 0.78 mmol) and 1-hydroxybenzotriazole (0.110 g, 0.78 mmol). After the solution became homogeneous 3-methylamino-1,2-propanediol (0.082 g, 0.78 mmol) was added, and the solution was stirred at room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.118 g) as a white solid, m.p. 119-123° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]Br.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:13]([Br:25])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(OCc3ccccc3)nn2C(C)C)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(Br)c(OCc3ccccc3)nn2C(C)C)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-1-isopropyl-5-(4-methoxy-phenyl)-1H-pyrazole (3.7 g) in dichloromethane (50 mL) was added bromine (0.98 mL) at 0° C., and the mixture was stirred for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=2/1) to give the title compound (3.3 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](O)=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:19][C@@H:16]2[CH2:17][CH2:18][C@H:13]([C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:14][CH2:15]2)=[N:25][CH:26]=1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Reactant: Oc1ccc(Cl)cn1
Product: O=C([C@H]1CC[C@@H](Oc2ccc(Cl)cn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from trans-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 5-chloro-2-hydroxypyridine. MS (m/e): 378.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].Cl.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][NH:35][C:13]([C:4]3[CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:2]([CH3:1])[C:3]=3[CH3:16])=[O:15])[CH2:30][CH2:31]2)[CH:23]=[CH:24][CH:25]=1
Reactant: NCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: Cc1c(C(=O)O)cc(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)NCCCN2CCN(c3cccc(Cl)c3)CC2)cc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To the mixture of 1,2-Dimethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.46 mmol) and 3-(4-(3-chlorophenyl) piperazin-1-yl)propan-1-amine dihydrochloride (152 mg, 0.46 mmol) in methylene chloride (5 ml) was added EDCI (178 mg, 0.92 mmol), HOBT (130 mg, 0.9 mmol) and NMM (0.3 ml, 1.8 mmol) continuously. After stirring for 1 day at room temperature, MeOH was added to the resulting solution, and filter off. After evaporation under reduced pressure, the residue was purified by reverse phase preparative HPLC to provided title compound (149 mg, 71%) as white solid.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][C:7]1([CH3:23])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:17][CH3:18])[CH:14]=2)[N:9]([CH2:19][CH2:20]O)[C:8]1=[O:22].C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=2)[CH2:16][C:7]([CH3:23])([CH3:6])[C:8]1=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (1.05 ml, 1.56 g, 0.014 mol) was added to a solution of 3,4-dihydro-3,3-dimethyl-1-(2-hydroxyethyl)-6-methylthio-2(1H)-quinolinone (2.88 g, 0.011 mol) and triethylamine (2.27 ml, 1.64 g, 0.016 mol) in dichloromethane (50 ml) at 0° C. under nitrogen and the resultant mixture was stirred for 20 mins. Then the mixture was allowed to warm to room temperature and sirred for 20 hr. The reaction mixture was then washed with water (2×20 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was then dissolved in carbon tetrachloride (30 ml), filtered and the solvent was evaporated in vacuo to afford 1-(2-chloroethyl)-3,3-dimethyl-6-methylthio-2(1H)-quinolinone as an oil which solidified on standing.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([NH:5][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: C1COCCO1
Product: CCCCNCc1ccc(-c2ccccc2C#N)cc1

Procedure:
36 ml (367 mmol) of butylamine are added to a solution of 20.0 g (73.5 mmol) of 4-bromomethyl-2'-cyano-biphenyl (cf. EP 253,310, page 159) in 150 ml dioxane and the mixture is heated under reflux for 3 hours. The reaction mixture is then concentrated by evaporation in vacuo and the residue is partitioned between 300 ml of diethyl ether and 100 ml of water. The ethereal phase is washed twice with water, dried and concentrated by evaporation. The resulting oil is flash-chromatographed on 500 g of silica gel [toluene/methanol(19:1)]. The fractions containing the product are concentrated by evaporation to yield N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine in the form of a yellow oil that has an Rf value of 0.34 [toluene/methanol (4:1)].
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: BrC(Br)(Br)Br
Reactant: COc1nn(C)c(=O)n1-c1ccsc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1ccsc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a suspension of the title compound of Step E (2.6 g) in methylene chloride (20 mL) under N2 at room temperature was added sequentially triphenylphosphine (3.44 g) and carbon tetrabromide (5.58 g). The resulting orange solution was allowed to stir for 1 h at room temperature and was then concentrated under reduced pressure to give an orange oil. The residue was purified by flash chromatography (1:1 ethyl acetate:hexane as eluent) to afford 2.3 g of the title compound of Step F, a compound of the invention, as a white solid. 1H NMR (CDCl3): δ 7.34 (d,1H), 6.92 (d,1H), 4.65 (s,2H), 3.98 (s,3H), 3.45 (s,3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.CCN(CC)CC>CCO>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 150 °C
Yield: 90.1 %

Procedure:
A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (200 mg, 1.09 mmol), 4,6-dichloropyrimidine (240. mg, 1.61 mmol) and Et3N (0.380 mL, 2.73 mmol) in EtOH (3.00 mL) was heated to 150° C. for 15 min using MWI. The crude mixture was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (255 mg, 90%). LC/MS: Rt=1.13 min, ES+ 260. (AA standard).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:24][C:25]1([CH3:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.N1C=CC=CC=1>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([CH3:29])([OH:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(O)CNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(C)(O)C3)c(F)cc2c1=O
Yield: 86.6 %

Procedure:
A mixture of 0.9 g (2.9 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.54 g (4.3 mmoles) of 3-hydroxy-3-methylazetidine hydrochloride, 1 g (10.8 mmoles) of triethylamine and 10 ml of pyridine is heated under reflux for 10 hours. The product is cooled, and diluted with water. Filtering and washing yields 0.95 g (89%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-methyl-3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.38 g (1 mmole) of this ester with 1.5 ml of ethanol, and 8 ml of 0.5N sodium hydroxide under reflux for 3 hours. The mixture is cooled, filtered and acidified with acetic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1.[NH4+].[OH-].[H][H]>CO.C(Cl)Cl.[Ni]>[N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: [H][H]
Reactant: N#CCCn1cncn1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NCCCn1cncn1
Yield: 85.5 %

Procedure:
To a mixture of 3-(1H-1,2,4-triazol-1-yl)-propanenitrile (25 g, 0.204 mol) and Raney-Nickel (5 g, 0.2 w/w, wet) in methanol (300 mL) was added a solution of 25% aqueous NH4OH (75 mL). The above reaction mixture was hydrogenated under pressure (75 psi of hydrogen) for a period of 6 h. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was taken up in DCM (150 mL) then triturated 4 times and the combined organic layer was concentrated under reduced pressure to yield 22 g of the title compound as a liquid (85%). The above compound was converted to its hydrochloride using HCl gas in a mixture of ether/methanol (9.5/0.5) to yield 20 g of the product as its dihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1.[F-].[K+].Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36]>CN(C=O)C.[Cl-].[NH4+]>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)[N:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ncccn1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ncccn1)C2=O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole (314 mg; 1.37 mmol) and KF (132 mg; 2.3 mmol) in 8 ml of DMF was stirred under nitrogen at room temperature and then 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (400 mg, 1.14 mmol) was added. The reaction mixture was stirred at room temperature for 1.25 hours and diluted with cold saturated ammonium chloride solution. The mixture was extracted with ether (3×), the organic layer was dried over magnesium sulfate and then filtered and concentrated in vacuo. The yellow solid residue (495 mg) was dissolved in methylene chloride and was purified by column chromatography (silica gel; 20-40% ethyl acetate/hexane) and recrystallized from ether/hexane to afford 330 mg (60%) of 4-isopropyl-6-methoxy-2-[1-(2-pyrimidinyl)-3-(trifluoro methyl)pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2-pyrimidinyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 133°-134.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].[Br:16][CH2:17][CH2:18]Br.C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:18][CH2:17][Br:16])[C:6]2=[O:15]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: BrCCBr
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCBr)c(=O)c2cc1OC

Procedure:
1-(6,7-Dimethoxy-4(3H)-quinazolinone-3-yl)-2-bromo-ethane was prepared analogous to Example 1 (a) by reaction of 6,7-dimethoxy-4(3H)-quinazolinone with 1,2-dibromoethane in dimethylformamide. Viscous oil. Rf -value (chloroform/methanol = 9/1) : 0.85.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C(O[CH:12]=[C:13]([C:19]([CH3:21])=O)[C:14]([O:16]CC)=[O:15])C>>[CH3:21][C:19]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccccn1
Product: Cc1c(C(=O)O)cnn1-c1ccccn1
Yield: 63.1 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using 2-pyridylhydrazine (8.0 g) and ethyl 2-ethoxymethyleneacetoacetate (13.7 g), the title compound (9.4 g) was obtained, melting point: 165° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:7].Cl.[C:36]1([C:42]2([C:48]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:34])[F:1])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:45]2[CH2:46][CH2:47][C:42]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:48]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[O:49])[CH2:43][CH2:44]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CCNCC1
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccc(C(F)(F)F)cc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCC(C(=O)N3CCCC3)(c3ccccc3)CC2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
A solution of intermediate 15 (0.01 mol), 1-(4-phenyl-4-piperidinylcarbonyl)-pyrrolidine hydrochloride (0.01 mol) and triethylamine (0.015 mol) in THF (10 ml) and titanium(IV)isopropoxide (3.72 ml) was stirred at RT for 4 hours. Ethansol (10 ml) and sodium cyanoborohydride (0.01 mol) were added. The mixture was stirred for a few hours. Ice and ethanol (10 ml) were added and the mixture was stirred at RT for 30 minutes and then filtered over decalite. The solvent was evaporated and the residue extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 95/5). Two pure fractions were collected and their solvents were evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 4.07 g of (±)-cis-1-[3,5-bis(trifluoromethyl)-benzoyl]-4-[4-phenyl-4-(1-pyrrolidinylcarbonyl)-1-piperidinyl]-2-[[4-(trifluoromethyl)-phenyl]methyl]-piperdine (55% ) compound 111) and 1.3 g of (±)-trans-1-[3,5-bis(trifluoromethyl-benzoyl]-4-[4-phenyl-4-(1-pyrroldinylcarbonyl)-1-piperidinyl]-2-[[4-(trifluoromethyl)-phenyl]methyl]-piperidine (18%) (compound 112).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:20]=2[O:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:25]2[C:20]3[O:19][CH2:18][CH2:17][O:16][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cccc2c1OCCO2
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2OCCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (acidic): tR=0.97 min; [M+H]+=375.1. 1H-NMR (CDCl3): δ=0.61 (bs, 1H); 0.76-0.82 (m, 1H); 1.47-1.52 (m, 1H); 1.51 (s, 9H); 1.89 (bd, J=13.2 Hz, 1H); 2.42-2.47 (m, 1H); 3.34-3.74 (m, 3H); 4.30-4.35 (m, 1H); 4.32 (bs, 2H); 4.44 (bs, 2H); 6.91-7.05 (m, 2H); 7.67-7.73 (m, 1H); 8.43 (bs, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(C)=O>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:20]
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(OCc2ccc(F)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of compound 4a (0.56 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[CH2:22]([O:26][C:27]1[N:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)[C:23]#[C:24][CH3:25]>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:33]([C:30]3[CH:29]=[N:28][C:27]([O:26][CH2:22][C:23]#[C:24][CH3:25])=[CH:32][N:31]=3)=[O:34])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Product: CC#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)O[C@@H]4CCC(F)(F)[C@@H]43)c2)cn1

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-but-2-ynyloxy-pyrazine-2-carboxylic acid (CAS 1221447-98-814) following procedure Q yielded the title compound as an amorphous colorless material (34% yield). MS: m/z=474.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:22][C:18]1[CH:17]=[C:16](/[CH:15]=[CH:14]/[C:11]2[CH:10]=[CH:9][C:8]([N:6]3[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]3)=[CH:13][CH:12]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Cl
Reactant: NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A suspension of 61 mg (0.18 mmol) of (RS)-(E)-4-amino-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-pyrrolidin-2-one hydrochloride in 2.5 ml of dichloromethane is treated with 45 mg (0.44 mmol) of triethylamine. The mixture is cooled to 0° C. and, thereafter, 20 mg (0.26 mmol) of acetylchloride are added. After 1 hour at 0° C., the mixture is left to warm to RT and is diluted with dichloromethane. After washing with water, the organic layer is dried over magnesium sulfate and evaporated. The crude product is crystallised from ether to yield 49 mg (78% of theory) of (RS)-(E)-N-(1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidin-3-yl)-acetamide as a light brown solid; MS: m/e=339 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:8]([CH2:11][CH2:12][CH2:13]Cl)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+]>C1COCC1>[Br:1][C:2]1[C:3]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCCCl)c1ncccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ncccc1Br)C1CC1
Reaction time: 0.5 h
Yield: 152.6 %

Procedure:
To a solution of 3-bromo-2-((chloropropyl)sulfonyl)pyridine (0.05 g, 89% purity, 0.2 mmol) in THF (20 mL) was added t-BuOK (0.047 g, 0.42 mmol) at −38° C. and the mixture was stirred for an additional 30 minutes. The reaction was quenched by adding saturated NH4Cl aqueous solution (2.5 mL) and concentrated to dryness. The resultant residue was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were dried over MgSO4, and concentrated to dryness to give the title compound (0.08 g, crude), which was used in the next step without further purification. MS (ESI): mass calcd. for C8H8BrNO2S, 260.95; m/z found, 262.0 [M+H]+.