Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C1(C)C=CC=CC=1>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.C(O)C>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=[C:26]([C:21]3[CH:22]=[C:23]([C:12]4[C:11]5[C:6]([C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=6[CH:13]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:24]=[C:19]([Br:18])[CH:20]=3)[N:27]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a stream of argon, 0.71 g (3.21 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.0 mg (0.0321 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 60° C. and maintained at that temperature for 12 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (2:1) mixed solvent as an eluent to give 0.54 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3-bromophenyl]-1,3,5-triazine as a white solid (yield: 30%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[S:25][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:29](=[O:30])[CH:28]=[CH:27][C:24]4[S:25][CH:26]=[C:22]([Cl:21])[CH:23]=4)[C@@H:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)/C=C/c1cc(Cl)cs1
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1cc(Cl)cs1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, and 3-(4-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 26. 1H NMR (d6-DMSO, 300 MHz) δ9.74 (bs, 2H), 8.82 (s, 1H), 8.40 (d, 1H), 7.62 (m, 5H), 7.05 (d, 1H), 4.92 (m, 1H), 4.80 (m, 2H), 4.73 (m, 1H), 4.50 (m, 1H), 3.40 (m, 2H), 1.42 (m, 3H). ESI MS, [M+H]+=442, 444 (Cl pattern).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH3:33]>ClCCl>[O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28]([NH2:33])=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)Cl)C3)c2c1
Reactant: N
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(N)=O)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carbonyl chloride (100 mg, 0.21 mmol) in dichloromethane (20 mL) was added a saturated solution of ammonia in dichloromethane (10 mL) slowly at 0° C. After being stirred for 16 hours at room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 13 mg of the desired product (yield was 13.5%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.08-8.05 (m, 2 H), 7.33-7.31 (d, J=7.6 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.57-7.55 (m, 2 H), 5.85 (s, 1 H), 5.25 (s, 2 H), 4.5 (s, 2 H), 4.03-3.94 (m, 4 H), 3.71 (s, 2 H), 3.29-3.21 (m, 1 H), 2.45 (s, 3 H), 2.41-2.32 (m, 1 H), 2.31-2.21 (m, 1 H).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])/[N:7]([CH2:24][CH2:25][OH:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C.C(=O)(OC(Cl)(Cl)Cl)[O:36][C:37](Cl)(Cl)[Cl:38]>CCOCC>[C:37]([Cl:38])(=[O:36])[O:26][CH2:25][CH2:24][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cn(CCO)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reaction time: 2 h
Yield: 195.6 %

Procedure:
To a solution of Example 61A (300 mg, 0.768 mmol) and triethylamine (233 mg, 2.305 mmol) in Et2O (5 mL) was added activated charcoal (10 mg, 0.768 mmol), followed by addition of bis(trichloromethyl) carbonate (114 mg, 0.384 mmol) and the mixture was stirred for 2 hr. The reaction was filtered, and concentrated to give the title compound as an oil (340 mg, 0.751 mmol, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 3.80 (t, J=5.43 Hz, 2 H) 4.27 (t, J=5.43 Hz, 2 H) 7.32 (s, 1 H) 7.46-7.56 (m, 1 H) 7.88-7.97 (m, 1 H) 8.24-8.33 (m, 1 H); MS (DCI) m/z 453 (M+H)+.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[CH2:17]([OH:19])[CH3:18]>>[C:17]([NH:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])(=[O:19])[CH3:18]
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCO
Product: CCC(Cc1cccc(NC(C)=O)c1)C(=O)O

Procedure:
In a manner similar to Description 13, 2-ethyl-3-(3-nitrophenyl)propenoic acid was reduced and acetylated to give 2-(3-acetamidobenzyl)butanoic acid, m.p. 131°-132° C. (from aqueous ethanol) which was cyclised and the product hydrolysed to afford 5-amino-2-ethylindan-1-one, m.p. 105.5°-108° C. (from acetonitrile). Acetylation of the latter afforded 5-acetamido-2-ethylindan-1-one, m.p. 154°-155° C. (from acetonitrile).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15]>>[OH:11][CH2:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]#[N:22])=[O:15])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2
Reactant: NC12CCC(CO)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(CO)(CC1)CC2
Yield: 68.8 %

Procedure:
Using 4-amino-1-hydroxymethylbicyclo[2,2,2]octane (50.5 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (61.7 mg), the same procedure was followed as in Example 5 to obtain (2S)-1-[[N-(4-hydroxymethylbicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (57.0 mg).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[F:32][CH:3]([F:2])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:30][CH2:31]1)=[O:25]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and 2-propanesulfonyl chloride. Light-yellow solid. MS (m/z): 541.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][CH:20]=3)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=O)(C)(C)C.Cl>CO>[ClH:34].[Cl:35][C:30]1[CH:29]=[C:28]([C:22]2([C:24]([F:26])([F:25])[F:27])[O:21][CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:10]4([F:12])[CH2:9][NH:8][CH2:11]4)=[CH:14][CH:15]=3)[CH2:23]2)[CH:33]=[C:32]([Cl:34])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: Cl
Solvent: CO
Product: FC1(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1

Procedure:
To a stirred solution of 3-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Intermediate 2) (0.45 g, 0.845 mmol) in MeOH (10 mL) was purged HCl gas for 1 hour at room temperature. After consumption of starting material, reaction mixture concentrated in vacuo to get pale yellow semisolid (0.49 g, crude), which was triturated with n-pentane (2×5 mL) to get off product as white solid. Yield: 0.36 g, 98.53%. 1H NMR (400 MHz, DMSO-d6) δ: 3.20 (d, J=17.16 Hz, 1H), 3.64 (d, J=17.16 Hz, 1H), 4.30-4.54 (m, 4H), 7.29 (d, J=7.96 Hz, 2H), 7.48 (s, 1H), 7.52 (d, J=8 Hz, 2H), 7.69-7.71 (m, 3H), 9.36 (bs, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Br)[N:21]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Br:19])[N:21]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1cccc(Br)n1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
8.75 g (40.3 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester was dissolved/suspended in 100 mL DMF followed by the addition of 1.93 g (48.3 mmol) of 60% sodium hydride. After the bubbling has ceased 12.1 g (48.3 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the solution was stirred at r.t. overnight. The reaction was quenched using 900 mL of water, filtered and washed with 200 mL of water. The solid was further washed with 100 mL DCM. The DCM washes were evaporated and chromatographed on silica using 0-30% methanol in DCM. The purified compound was combined with the washed solid to give 14.9 g of the product as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>O1CCCC1.O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:25]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)=[O:12])[CH2:8]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ncccn2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 1.6 g (0.01 mole) of 1-(2-pyrimidyl)piperazine added dropwise. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly crystallized. Recrystallization from isopropyl ether yielded 2.7 g (66.3%) of fine white crystals, m.p. 127°-128° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:12](=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:15]([N:11]([CH3:10])[C:12](=[O:14])[CH3:13])[CH2:16]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Temperature: 120 °C

Procedure:
A solution of 4-fluorobenzaldehyde (2.01 g, 16.2 mmol) and N-methyl-N-(pyrrolidin-3-yl)acetamide (1.92 g, 13.5 mmol) in DMF (20 mL) was treated with K2CO3 (2.24 g, 16.2 mmol). The mixture was heated at 120° C. under nitrogen for 18 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, to afford N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:42])([F:43])[F:44])[CH:35]=1)[CH3:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 56 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d, 1H), 9.26 (s, 1H), 9.00 (d, 1H), 8.54 (s, 1H), 8.37 (d, 1H), 8.16 (d, 1H), 7.92 (dd, 1H), 7.82 (ddd, 1H), 7.44 (dd, 1H), 5.51 (m, 1H), 3.17 (dd, 1H), 2.99 (dd, 1H), 2.62-2.52 (q, 2H), 0.97 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].O>CN(C=O)C>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:16][C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: OCc1cc(C(F)(F)F)ccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methanol (340 mg, 1.9 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.8 mmol). After being stirred at room temperature for 5 min. 1,1-dimethylethyl bromoacetate (0.28 mL, 1.9 mmol) was added. Stirring was continued at room temperature for 1 h. Water (20 mL) was added and the resulting solution was extracted with EtOAc. The water layer was neutralized to pH=5 with HCl and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum to give the title compound which was used for the next reaction without purification. MS (M+H) 292.2.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:26])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]1[C:11](=[O:13])[O:12][C@H:9]1[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
In a four-necked round bottom flask, Et3N (1.5 mL, 10.9 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(octyloxy)carbonyl]amino}butanoic acid (1 g, 3.63 mmol) in dry CH2Cl2 (40 mL) under argon. After cooling at 0° C., HBTU (2.07 g, 5.45 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (ca. 0.19 g) was further triturated with cyclohexane, to afford a pure compound (0.165 g, 18%) as white solid. MS (ESI) m/z: 256.31 [M−H]−. FTIR (cm−1): 3326, 2958, 2924, 2856, 1857, 1692, 1547, 1333, 1270, 1087, 1025, 845. 1H NMR (CDCl3): δ 0.87-0.90 (t, 3H); 1.28-1.36 (m, 10H); 1.47 (t, 3H); 1.59-1.66 (m, 2H); 4.06-4.15 (m, 2H); 4.84-4.91 (m, 1H); 5.38-5.48 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH:24]1([Mg]Cl)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 30.2 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (78 mg, 0.253 mmol) obtained in Example 1 was dissolved in THF, and 18%-cyclohexylmagnesium chloride (0.7 mL, 0.506 mmol) was added thereto, followed by stirring for 5 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 30 mg of the titled compound (yield: 30%).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)-hydrazine (0.5 g) in 10 ml of toluene was treated with 50% sodium hydroxide (0.61 g). 3,4-dichlorobenzoyl chloride (0.6 g) was added and the mixture was stirred rapidly for 4 hours at 23° C. and then was allowed to stand for 48 hours. The solids were removed by filtration and washed with water to afford 0.75 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(3,4-dichlorobenzoyl)hydrazine as a white solid. m.p. 175-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1
Yield: 33.9 %

Procedure:
To a solution of aniline (27.9 g, 0.30 mol) and tert-butyl acrylate (38.4 g, 0.30 mol) in dry benzene (500 ml) was added tin tetrachloride (2 ml) and the resulting solution was heated under reflux for 18 8 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo giving a residue which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (22.53 g, 34%) as an oil. 1H NMR (300 MHz, CDCl3) δ7.12 (2H, t), 6.71 (1H, m), 6.62 (2H, d), 3.40 (2H, t), 2.54 (2H, t), 1.44 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH2:9])[CH:8]=1.N1C=CC=CC=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:8]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cc(OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To the solution of 5-methoxy-2-methyl-phenylamine (0.118 g, 0.86 mmol) and pyridine (0.1 mL) and CH2Cl2 (3 mL) at 0° C. was added dropwise propane-1-sulfonyl choride (0.135 g, 0.95 mmol) and the reaction mixture was stirred at RT overnight. The mixture was then concentrated and purified via silica gel chromatography to give the product as an oil (0.145 g, 69%): MS(ES) m/e 244.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccccc2)c1
Yield: 136.1 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (1.03 g, 3 mmol), phenylboronic acid (920 mg, 7.5 mmol), Pd(0) (100 mg) and Na2CO3 (4 mL of a 2 M solution) were mixed in 20 mL of toluene, and the mixture was stirred at reflux for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with CHCl3:MeOH 100:2, to afford 1.39 g of the title compound. MS (CI/NH3) m/z 341 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.38 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.21 (m, 1H), 4.41 (m, 1H), 4.54 (m, 1H), 7.40 (m, 3H), 7.50 (m, 2H), 8.10 (m, 1H), 8.54 (m, 1H), 8.20 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=3)[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:22][CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[N:3][CH:4]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)[CH3:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
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: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 21.5 %

Procedure:
5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (51 mg, 21%) was prepared from 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 0.52 mmol), [4-(methylsulfonyl)phenyl]boronic acid (105 mg, 0.52 mmol), 2M Na2CO3 (5 mL), Pd(PPh3)4 (50 mg, 0.04 mmol) and DME (5 mL) in a manner similar to Example 21, Step 3.