Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:15]4[C:20]=2[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]4[C:20]([C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=2)=[CH:32][CH:33]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)cc1
Yield: 51.5 %

Procedure:
An amount of 3.74 g (10 mmol) of 9,10-diphenylanthracene-2-boronic acid synthesized in the same manner as in Exemplary Synthesis 1, 9.44 g (40 mmol) of p-dibromobenzene, and 300 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 2.32 g (5.15 mmol) of 2-(4-bromophenyl)-9,10-diphenylanthracene. The yield was 51.5%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]([CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:27][O:28][C:29]([CH:31]1[CH2:34][N:33]([CH2:2][C:3]2[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:32]1)=[O:30]
Reactant: COC(=O)C1CNC1
Reactant: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl (185 mg, 0.4230 mmol, 1 eq.) in anhydrous DCM (7 mL) is added azetidine-3-carboxylic acid methyl ester (HCl salt, 96 mg, 0.6345 mmol, 1.5 eq.) and DIEA (0.74 mL, 4.230 mmol, 10 eq.). The mixture is stirred at room temperature for 3 h. The reaction mixture is applied directly to silica gel chromatography (gradient from 5:1 hexanes/EtOAc to 1:2 hexanes/EtOAc) to give 1-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:14]=O)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:14][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNCc1ccccc1Cl
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1 eq) and 2-chloro-benzylamine (1.2 eq) in DCE (20 mL) was added acetic acid (0.8 eq) and allowed to stir for 20 minutes followed by the addition of sodium triacetoxyborohydride (2 eq). The reaction mixture was stirred for 12 h. After completion of reaction on TLC, the reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated using rotary evaporator to give sticky crude product, which was then purified with column chromatography (2-5% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—3.0 cm, Height of silica—approx. 4 inch) to afford the desired (rac)-2-[(2-chloro-benzylamino)-methyl]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (40-70%).
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:34]=[CH:35][CH:36]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30](=[O:33])[CH2:31][SH:32])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([Br:8])[N:4]=2)[S:32][C:31]=1[C:30]([NH:29][C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:34]=[CH:35][CH:36]=[C:16]([C:13]([C:11]#[N:12])([CH3:14])[CH3:15])[CH:17]=2)[CH:27]=[CH:26][C:25]=1[CH3:28])=[O:33]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Reactant: N#Cc1nc(Br)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(Br)nc2c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 3,6-dibromopyrazine-2-carbonitrile 15 (286 mg, 1.089 mmol) and 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (400 mg, 1.089 mmol) in ethanol (5 mL) was added potassium carbonate (211 mg, 1.524 mmol). The reaction was stirred 1 h at rt and 2 h at 50° C. Quenched in cooled 1N HCl solution (aq), the resulting precipitate was collected and dried to give crude compound 17 (588 mg). Purification by chromatography (0-10% EtOAc in CH2Cl2) gave pure 7-amino-2-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 17 (463 mg, 77%). 1H-NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.21 (s, 3H), 7.09 (br s, 2H), 7.27 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.81 (br s, 1H), 7.95 (d, J=7.0, 1H), 8.05 (s, 1H), 8.93 (br s, 1H), 9.58 (br s, 1H), 10.32 (br s, 1H). (m/z)=549 and 551 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][C@H:29]([CH3:35])[CH2:30][NH:31][C:32](=[O:34])[CH3:33])[N:21]=[CH:20][N:19]=2)=[CH:13][C:12]=1[CH3:36]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][C@H:29]([CH3:35])[CH2:30][NH:31][C:32](=[O:34])[CH3:33])[N:21]=[CH:20][N:19]=2)=[CH:13][C:12]=1[CH3:36]
Reactant: Fc1cccc(CCl)c1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(C)c3)c12
Yield: 46 %

Procedure:
The procedure described in Example 3 was repeated using 1-(chloromethyl)-3-fluorobenzene and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a white solid in 46% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.26 (s, 3H), 3.41 (dt, 1H), 3.58 (dt, 1H), 4.86 (m, 1H), 5.18 (s, 2H), 7.01 (d, 1H), 7.16 (td, 1H), 7.22 (d, 1H), 7.30 (m, 3H), 7.42 (m, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t, 1H), 8.22 (t, 1H), 8.43 (s, 1H), 9.95 (s, 1H); Mass spectrum MH+ 475.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl>O>[CH3:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Product: Cn1c(N2CCNCC2)nc2ccccc21
Temperature: 150 °C

Procedure:
A mixture of 1 g (6.02 mmol) of 2-chloro-1-methyl-benzimidazole and 2.58 g (30 mmol) of piperazine is heated to 150° C. without a solvent. The cooled melt is combined successively with water and dilute hydrochloric acid and extracted with dichloromethane. Then the aqueous phase is made alkaline with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated by evaporation. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=5:1:0.1).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[CH3:44][O:45][CH2:46][C:47]#[CH:48].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:48]=[C:47]([CH2:46][O:45][CH3:44])[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C#CCOC
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCc1cn([C@H]2[C@@H](C)CN(c3ccncc3NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)C[C@H]2NC(=O)OC(C)(C)C)nn1
Temperature: 70 °C
Yield: 95 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.2 equiv.), 3-methoxyprop-1-yne (1.5 equiv.) and triethylamine (1.5 equiv.), in dioxane (0.20 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 70° C. for 16 hrs. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-5-methylpiperidin-3-ylcarbamate in 95% yield. LC/MS (m/z)=653.2 (MH+), Rt=0.86 min.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15].Cl>>[CH3:20][O:19][C:17](=[O:18])[C@@H:13]([N:12]=[C:1]=[O:2])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](N=C=O)C(C)C
Temperature: 25 °C

Procedure:
A solution of 1.9M phosgene in toluene (9.41 mL, 17.89 mmol) was added to a suspension of H-Val-OCH3.HCl (1.0 g, 5.96 mmol). The reaction mixture was heated at reflux for 2 h under a dry ice condenser, cooled to room temperature, sparged vigorously with nitrogen for 1.5 h and then concentrated to dryness. Toluene (5 mL) was added to the residue and the resulting solution concentrated to dryness to give (S)-2-isocyanato-3-methylbutanoic acid methyl ester. This product was dried under high vacuum for 5 min and then used in the following step. 1H NMR(CDCl3) δ3.95-3.94 (d, J=3.82 Hz, 1H), 3.81 (s, 3H), 2.35-2.22 (m, 1H), 1.04-1.02 (d, J=6.8 Hz, 3H), 0.91-0.89 (d, J=6.74 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc([N+](=O)[O-])cc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.013 g, 69%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH:21]([C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[CH3:22])=[O:9])([CH3:6])[CH3:5].Cl>CO.[OH-].[Na+]>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH:21]([O:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:32])=[O:2])=[O:9])[CH3:22]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)c1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1c(C(=O)NC(C)(C)C(=O)O)ccc2ccccc12)c1nc2ccccc2s1
Yield: 33.6 %

Procedure:
135 mg 2-{[1-(1-Benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 1 ml methanol and 1.5 ml 1 M aqueous sodium hydroxide solution were heated to 100° C. for 2 min in a microwave reactor. The reaction mixture was then acidified using 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo. Precipitation with pentane yielded 44 mg of 2-{[1-(1-Benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:19])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.74 g of the desired product as an oil. M+ =227 as methyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:14])[CH2:12][O:11][NH:10][C:9]1=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23]Cl>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][N:10]1[C:9](=[O:13])[C:8]([CH3:14])([CH3:7])[CH2:12][O:11]1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CC1(C)CONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CON(Cc2c(F)cccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a stirred suspension of 3.6 grams (0.026 mole) of potassium carbonate and 0.14 gram (0.0005 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 50 ml of acetonitrile was added dropwise a solution of 3.0 grams (0.026 mole) of 4,4-dimethyl-3-isoxazolidinone (Example 30, Step B) and 4.7 grams (0.025 mole) of (2-chloro-6-fluorophenyl)methyl chloride in 25 ml of acetonitrile. The complete addition required 30 minutes. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours, and then filtered. The filtrate was diluted with 200 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil solidified and was recrystallized from petroleum ether to give 3.0 grams of 2-[(2-chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone; mp 49°-51°.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH:23](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCC/C=C/B(O)O
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCC/C=C/c1cnc2ccc(NCCCNC(=O)OC(C)(C)C)nn12

Procedure:
Prepared from the product from step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the crude Boc-protected olefin (122 mg, 96%) as a brown oil: Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.78 (d, J=9.7 Hz, 1H), 7.54 (s, 1H), 6.64-6.40 (m, 3H), 3.47 (q, J=6.3 Hz, 2H), 3.29-3.23 (m, 2H), 2.36-2.30 (m, 2H), 1.84-1.81 (m, 2H), 1.50-1.42 (m, 11H), 1.40-1.48 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>>[ClH:16].[N:2]1([CH2:8][CH2:9][CH2:10][C:11]([Cl:1])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)CCCN1CCCCC1

Procedure:
4-Piperidinobutyric acid hydrochloride (750 mg) and 4 ml of thionyl chloride were combined and stirred at reflux for 45 min., concentrated, triturated with ether and dried to give 700 mg of light brown solid which when dissolved in dry methanol gave Rf 0.1 in system D, distinctly different from the starting acid and presumably the methyl ester. The solid was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[C:37]([F:40])([F:39])[F:38].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:20][C@@:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][C:30]=1[C:37]([F:38])([F:39])[F:40]
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc([C@@](Cc2ccccc2)(NCc2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (21.5 mg, 0.057 mmol) in dichloroethane (0.5 mL) in a two drum vial was added 4-fluoro-3-(trifluoromethyl)benzaldehyde (21.9 mg, 0.114 mmol) followed by a drop of acetic acid. The reaction mixture was shaken for 20 minutes at room temperature before NaBH(OAc)3 (36.3 mg, 0.171 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were removed and the residue was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (with 0.1% TFA) to give (R)—N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine as a colorless oil (17.5 mg, 46% yield). LCMS: 4.32 min (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.78-3.91 (m, 4H), 6.60 (d, J=7.47 Hz, 2H), 7.14-7.27 (m, 7H), 7.35-7.48 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:30]1[CH2:33][O:32][CH2:31]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:30]4[CH2:33][O:32][CH2:31]4)[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Reactant: IC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C2COC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 27) (100 mg, 0.271 mmol) in DMF (3 mL) was added under Ar NaH (13.01 mg, 0.325 mmol) at 0° C. The reaction mixture was stirred for 30 min at rt. 3-Iodooxetane (0.030 mL, 0.352 mmol) was added. The reaction mixture was stirred for 30 min at rt, quenched with a saturated aqueous solution of sodium bicarbonate (75 mL), and extracted with EtOAc (2×75 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (75 mL), dried on Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%), followed by preparative achiral SFC (column: PPU, 250×30 mm, 5 μm, 100 A, Princeton; eluent: MeOH/scCO2; gradient: 1 min 20% MeOH, 20-25% MeOH in 6 min, 25-50% MeOH in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min) to afford 27 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 135) and ten fractions containing the impure title compound. These fractions were collected and evaporated to afford after a second SFC purification 16 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-2-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (title compound). tR: 0.81 min (LC-MS 2); ESI-MS: 425.1 [M+H]+ (LC-MS 2); Rf=0.25 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 2.02 (s, 3H) 3.36 (s, 3H) 4.84-5.03 (m, 4H) 5.56-5.69 (m, 1H) 6.12 (s, 1H) 7.14-7.29 (m, 2H) 7.31-7.38 (m, 2H) 7.39-7.42 (m, 1H) 7.73 (d, J=2.74 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[C:13]([CH3:22])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:21][S:20]([C:17]1[N:16]=[CH:15][C:14]2=[C:13]([CH3:22])[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:19]2[N:18]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(C)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n2nc(S(C)=O)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
Into a 30 mL vial, [A] 7-(4-Methanesulfonyl-phenyl)-5-methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.260 g, 0.000780 mol) and Methylene chloride (20 mL, 0.3 mol) were added. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.211 g, 0.000858 mol) was added and stirred at room temperature overnight. The reaction was partitioned with DCM and saturated NaHCO3. The organic was separated and washed with water then Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The organic was removed under vacuum to give a solid. The solid was triturated with Et2O and filtered to give 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.20 g, 73%) NMR 1H (CDCl3-d)-8.99 (s, 1H), 8.24 (d, 2H, J=8.45 Hz), 8.08 (d, 2H, J=8.40 Hz), 7.28 (s, 1H), 3.10 (s, 3H), 3.02 (bs, 4H), 2.54 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: Cc1ccnc(CN)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(4-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).