Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]2[CH2:16][C@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][O:38][CH2:39][C:40]2[CH:45]=[C:44]([F:46])[C:43]([F:47])=[CH:42][C:41]=2[F:48])[N:6]=1)=[O:4]>O1CCOCC1>[CH3:11][C:9]1[N:8]=[C:7]([N:12]2[CH2:16][C@H:15]([S:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:14][C@H:13]2[CH2:37][O:38][CH2:39][C:40]2[CH:45]=[C:44]([F:46])[C:43]([F:47])=[CH:42][C:41]=2[F:48])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(C)nc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)n1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)nc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)n1

Procedure:
(2S,4R)-6-Methyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine-4-carboxylic acid methyl ester was hydrolyzed following the general method for hydrolysis of an ester (ETOH/dioxane) to give (2S,4R)-6-Methyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine-4-carboxylic acid, MS: 656 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-chlorothiophenol (47.1 g, 0.326 mole) in sodium hydroxide solution (14.3 g, 0.358 mole in 750 ml water) was treated dropwise over 20 minutes with freshly distilled chloroacetone (28.5 ml, 0.358 mole) and the resulting mixture was stirred for a further 30 minutes at room temperature. The mixture was extracted with ether (3×200 ml) and the organic solution then washed with 2% sodium hydroxide solution (2×200 ml) and water (2×200 ml), dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a pale yellow solid. A small sample was recrystallized from pentane to yield a colourless crystalline solid m.p. 37°-38° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[C:14]1([CH:21]=CC=[C:17](O)[CH:16]=1)[OH:15]>>[OH:15][C:14]1[CH:21]=[C:4]2[C:5]([C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:1](=[O:2])[O:3]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCCC1=O
Reactant: Oc1cccc(O)c1
Product: O=c1oc2cc(O)ccc2c2c1CCCCC2

Procedure:
The Applicant has now found that this compound can be synthesized in two chemical stages. The first stage consists of condensing in a strong acid (such as sulphuric acid, trifluoroacetic acid or methanesuiphonic acid) 2-carbetoxycycloheptanone with resorcinol, intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one is isolated by precipitation using an alcohol/water mixture (for example by adding ethanol then water). In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride, by the action of formic acid, then condensed with the previous intermediate dissolved in a solvent such as DMA. The reaction medium is treated with water and extracted by an organic solvent (preferably 2-methyltetrahydrofurane: MeTHF), and crude compound 1 is then precipitated from the organic phase by adding an antisolvent (preferably methylcyclohexane). Finally pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone or ethyl acetate while hot and precipitation by adding an antisolvent (preferably methylcyclohexane).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH:27]([CH3:29])[CH3:28])[N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]1>CO>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]3)[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH:27]([CH3:29])[CH3:28])[N:23]=3)[C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)n1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Solvent: CO
Product: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](O)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1

Procedure:
The title compound was prepared from 48A and (trans)-4-aminocyclohexanol in a similar way as Example 44. HPLC Rt=2.850 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+1]=494.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH2:19][NH2:20])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=2)[C:33](O)=[O:34])[N:24]=1>>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:19][NH:20][C:33](=[O:34])[C:32]1[CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=[N:30][CH:31]=1
Reactant: CN(C)CCC(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CN(C)CCC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
This compound was synthesized from 3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (16 mg, yield 10%). 1H NMR (400 MHz, MeOD) δ 9.39-9.38 (d, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H), 8.85-8.84 (t, J=2.1 Hz, 1H), 8.08-8.05 (m, 2H), 7.84 (s, 1H), 7.26-7.22 (t, J=8.9 Hz, 2H), 3.79-3.66 (m, 2H), 3.18-3.11 (m, 1H), 2.63-2.46 (m, 2H), 2.37 (m, 6H), 2.06-2.00 (m, 2H). MS (ESI) m/z: Calculated for C24H22F4N6O3: 518.17. found: 519.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([NH:15][CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])[CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:16][C@H:17]([C:18]([O:20][CH3:21])=[O:19])[O:22][C:23]2=[O:24])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C(C)C
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C(C)C)C(=O)O1

Procedure:
Prepared from methyl (2R)-3-[(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 3, 0.908 g, 2.91 mmol) and 1,1′-carbonyldiimidazole (0.471 g, 2.91 mmol) according to the method of EXAMPLE 86, Step 9 (0.90 g, 92%); MS for C15H15FN2O6 m/z 339 (M+H)+.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH:6]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][N:19]=[C:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([F:32])=[CH:30][C:29]([CH2:33]O)=[CH:28][N:27]=3)[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])[CH3:7].C(N(CC)CC)C.[CH3:42][C:43]1[CH:44]=[N:45][NH:46][CH:47]=1.[H-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH:6]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][N:19]=[C:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([F:32])=[CH:30][C:29]([CH2:33][N:45]4[CH:44]=[C:43]([CH3:42])[CH:47]=[N:46]4)=[CH:28][N:27]=3)[CH2:22][CH2:21]2)[CH2:16][CH2:17]1)=[O:11])([CH3:7])[CH3:8]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(CO)cc3F)CC2)CC1
Reactant: Cc1cn[nH]c1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cnn(Cc2cnc(N3CCC(=NOC4CCN(C(=O)OC(C)C)CC4)CC3)c(F)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Mesyl chloride (96 μL, 1.2 mmol) was added to an ice cooled solution of 53-1 (0.25 g, 0.62 mmol) and triethylamine (0.26 mL, 1.9 mmol) in 5 mL of DCM. After 2 h, the mixture was diluted with DCM (30 mL), washed with brine (15 mL) and water (15 mL), dried and concentrated under vacuum. The residue was taken up in DMF and added to a mixture of 4-methyl-1H-pyrazole (0.8 mmol) and sodium hydride (30 mg, 60%, 0.8 mmol) in DMF which had been pre-stirred for 5 minutes. The mixture was heated to 100° C. for 2 h then allowed to cool down to room temperature, diluted with water (1.5 mL) and extracted with DCM (2 mL). The organic layer was concentrated under a stream of nitrogen, the residue was taken up in methanol and the mixture was purified by HPLC to afford 54-1: LC-MS 473.2 (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(#N)C>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([C:2]1[N:1]([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=1)=[O:37]
Reactant: Clc1ccc(C(CCOC2CCCCO2)Cn2ccnc2)cc1Cl
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C(=O)c1nccn1CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Imidazol-1-yl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (0.86 g) (see Preparation 30) and triethylamine (1.3 ml) were dissolved in acetonitrile (15 ml), under a nitrogen atmosphere, the solution cooled in an ice-bath and 2-methoxybenzoyl chloride (1.4 ml) added, dropwise. The mixture was allowed to warm to room temperature slowly and then stirred for 2 days. The acetonitrile was removed under reduced pressure and the residue dissolved in dichloromethane (20 ml) and washed sequentially with water and brine. The organic phase was then dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with 97:3, by volume, dichloromethane:methanol to give 1-[2-(2-methoxybenzoyl)imidazol- 1-yl]-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (1.1 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([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])[CH3:9])=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][C:25]([F:31])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH3:9])=[CH:4][CH:3]=2)=[CH:26][C:25]([F:31])=[CH:24][N:23]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Reactant: OB(O)c1cc(F)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](c1ccc(-c2cc(F)cnc2Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (1.19 g, 3.6 mmol) (Example 26) in 1,2-dimethoxyethane (3 ml) was added 2-chloro-5-fluoropyridine-3-boronic acid (0.95 g, 5.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.2 mmol) and 2M aqueous sodium carbonate (3.2 ml, 6.4 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 10 min and the solvent evaporated. The residue was partitioned between ethyl acetate and water. The organic phase washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified over silica gel eluting with heptane/ethyl acetate to give (R)-2-{1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.62 g, 1.6 mmol, 44%) as a clear glass. To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (0.16 g, 0:4 mmol) in methanol (4 ml) was added hydrazine hydrate (0.43 g, 8.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. Dichloromethane was added and the resultant white precipitate filtered off. The solvent was evaporated to give 1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (0.11 g, 0.4 mmol, 100%) as a yellow gum. To a solution of (R)-1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (26 mg, 0.1 mmol) in dichloromethane (1 ml) was added triethylamine (31.6 mg, 0.31 mmol) followed by 3,4-difluorobenzenesulfonyl chloride (28.7 mg, 0.14 mmol). The reaction mixture was agitated for 64 h at room temperature and the solvent evaporated. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6.7 mg, 0.04 mmol, 38%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (m, 2H), 7.78 (dd, 1H), 7.45-7.60 (m, 3H), 7.27-7.34 (m, 4H), 4.50 (q, 1H), 1.33 (d, 3H) ppm; MS (ESI) m/z: 427 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (100 g, 0.584 mol) and morpholine (60 g, 0.689 mol) in dimethyl sulfoxide (60 mL) was added potassium carbonate (120 g, 0.870 mol). The mixture was stirred at 70° C. for 6 hours, and then poured into ice-water. The precipitate was collected by filtration and washed by water, dried to afford the product 4-(3-methoxy-4-nitrophenyl)morpholine (100 g, yield 72%).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[C:22](#[N:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[C:22]([NH2:31])[N:12]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC=Cc1ccccc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Product: Nc1cc(-c2ccccc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, mp. 214-216° C., was prepared in accordance with the general method of example 22 from 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and cinnamonitrile.
Reaction SMILES: O[CH:2]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=1)[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH:2]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1 g, 4.49 mmol, 1 eq.) in 20 ml of DCM was cooled to 0° C. and PPh3 (1.65 g, 6.29 mmol, 1.4 eq.) was added followed by N-Bromosuccinimide (0.96 g, 5.39 mmol, 1.2 eq.). The reaction was stirred at 0° C. for 1 h and at r.t. for 1 h. The solvent was removed and residue purified by chromatography on silica gel to give N-[6-(1-bromoethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.025 g, 79% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:32][CH:31]=2)=[O:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH:20]([OH:44])[CH2:21][N:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([NH:34][C:35]3[N:40]=[C:39]([CH:41]([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH:28]=2)[CH:24]=[N:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[Si:11]([O:18][CH2:19][C:20](=[O:44])[CH2:21][N:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([NH:34][C:35]3[N:40]=[C:39]([CH:41]([F:42])[F:43])[CH:38]=[CH:37][N:36]=3)[CH:28]=2)[CH:24]=[N:23]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(=O)CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.21 mL, 2.39 mmol) was added to a solution of dimethyl sulfoxide (0.34 mL, 4.78 mmol) in methylene chloride (20 mL) at −78° C. The mixture was stirred for 10 minutes and 1-((tert-butyldimethylsilyl)oxy)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-ol (780 mg, 1.59 mmol) was added. After stirring for additional 15 minutes, triethylamine (1.11 mL, 7.97 mmol) was added. The mixture was allowed to warm to room temperature for 2 h. Water was added to the mixture, which was then extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40% EtOAc/Hexane) to afford 1-((tert-butyldimethylsilyl)oxy)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one. MS ESI calc'd. for C24H32F2N5O2Si [M+H]+ 488. found 488.
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>[Cl-].[Na+].O.O>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:26][N:25]=[N:24][N:22]=4)=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23]
Reactant: CC12CCC(C(=O)Nc3ccc(CC#N)cc3)(OC1=O)C2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC12CCC(C(=O)Nc3ccc(Cc4nnn[nH]4)cc3)(OC1=O)C2(C)C
Temperature: 135 °C
Yield: 60 %

Procedure:
4,7,7-Trimethyl-3-oxo-N-[4-(cyanomethyl)phenyl]-2-oxabicyclo[2.2.1]-heptane-1-carboxamide (6 g, prepared in the preceding paragraph), sodium azide (6.24 g), ammonium chloride (5.1 g) and dimethylformamide (100 mL) were heated in a 135° C. oil bath for 20 hours under a nitrogen atmosphere. Water was added to the hot mixture until homogeneity was achieved. The mixture was then cooled to room temperature, poured onto saturated brine solution in a separatory funnel, and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4 and concentrated in a rotary evaporator. The crude product was dissolved in hot acetone, then cooled in a 0° C. freezer to yield 4.1 g. (60% yield) of the title compound as a dark yellow solid; m.p. 224°-225° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:59])([CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]=O)=[C:50]([CH3:57])[CH:49]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:58])([CH3:59])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51](/[CH:55]=[CH:2]/[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][C:11]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:12][N:13]=3)=[CH:5][C:4]=2[N+:21]([O-:23])=[O:22])=[C:50]([CH3:57])[CH:49]=1
Reactant: O=[N+]([O-])c1cc(-c2nnc(-c3ccc(Cl)cc3)o2)ccc1CBr
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(/C=C/c2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C

Procedure:
Combine 2-(4-bromomethyl-3-nitro-phenyl)-5-(4-chloro-phenyl)-[1,3,4]oxadiazole (894 mg, 2.27 mmol) and PPh3 (656 mg, 2.50 mmol) in DMF (13 mL) and heat to 95° C. under N2 for 4.5 h. Add 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (intermediate A in Example 1-62, 675 mg, 2.72 mmol) and K2CO3 (627 mg, 4.54 mmol), continue heating at 95° C. for 6.5 h. Allow the reaction to cool to room temperature. Dilute the cooled reaction with EtOAc (150 mL) and extract with water (50 mL). Dry the organic layer over Na2SO4 and evaporate the solvent. Purify the resulting oil by silica gel chromatography (10-45% EtOAc/HEP) to afford a yellow solid: (M+H)+ 546.1.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>>[OH:16][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)[CH:17]=[CH2:18]
Reactant: O=CC1CCN(C(=O)c2ccccc2)CC1
Reactant: C=C[Mg]Br
Product: C=CC(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg of 1-benzoyl-piperidine-4-carboxaldehyde (step C) in 10 ml TBF at −78° C., was added 2.99 mmol of vinyl magnesium bromide. The solution was warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 15 mL of aq. NH4Cl and extracted with 3×20 ml Et2O and the combined organic layers were dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:EtOAc followed by 1:1 hexane:EtOAc followed by hexane:EtOAc:MeOH, 50:50:5 to give 411 mg of the title compound. 1H NMR (500 MHz) 1.31 (m, 2H), 1.74 (m, 5H), 2.69 (m, 1H), 2.92 (m, 1H), 4.80 (m, 1H), 3.68 (m, 1H), 5.22 (dd, 2H), 5.84 (m, 1H), 7.43 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C@H:10]1[N:18]2[C@@H:13]([CH:14]=[CH:15][CH2:16][C:17]2=[O:19])[CH2:12][CH2:11]1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C@H:10]1[N:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:19])[CH2:12][CH2:11]1
Reactant: O=C1CC=C[C@H]2CC[C@@H](c3c(F)cc(F)cc3F)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CC[C@@H](c3c(F)cc(F)cc3F)N12
Yield: 99.6 %

Procedure:
Platinum oxide (25 mg) was added to a solution of (3S,8aR)-3-(2,4,6-trifluorophenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one (548 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm at room temperature for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 550 mg of the title compound. The property value of the compound is as follows.