Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([CH2:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)([OH:7])[CH2:4][C:5]#[CH:6].[C:26]([C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31](OS(C(F)(F)F)(=O)=O)=[C:30]([CH3:45])[CH:29]=1)#[N:27].C(N(CC)CC)C>C1COCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:45][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]=1[C:6]#[C:5][CH2:4][C:3]([OH:7])([CH2:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)[C:2]([F:1])([F:24])[F:25])[C:26]#[N:27]
Reactant: C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
A mixture of 330 mg (0.88 mmol) of 1,1,1-trifluoro-2-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-4-yn-2-ol, 270 mg (0.88 mmol) of trifluoromethanesulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester, 310 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) dichloride, 17 mg (0.09 mmol) of copper (I) iodide, and 0.25 mL of anhydrous triethylamine in 2 mL of THF was warmed at 60° C. in a sealed tube in the microwave. After 20 minutes, the mixture was adsorbed onto CELITE® filter aid and chromatographed on silica gel eluting with ethyl acetate-hexanes (gradient: 0-30% EtOAc) to afford 205 mg (44%) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(C)(=O)=O)ccc4N3)c2)cc1
Yield: 19.9 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol), 4-dimethylaminopyridine (52.5 mg, 0.43 mmol), methane sulfonamide (83 mg, 0.87 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (28.5 mg, 20%) as a light yellow solid: MS (ESI) M+1=493.1.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:25]I>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sodium hydride (0.11 g, 4.65 mmol) was added to a solution of 6-[(3-{[tert-butyl(dimethyl)-I4-silyl]oxy}propyl)amino]-2-chloro-5-fluoronicotinonitrile (Example 309, 0.80 g, 2.33 mmol) in DMF (23.26 mL). The mixture was stirred at rt for 30 min, and then MeI (0.58 mL, 9.30 mmol) added. The reaction mixture was stirred at rt for 18 h, quenched with water, and the aqueous phase was extracted with ether. The combined ether extracts were washed with water, brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.88 g, 99%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, 1H), 3.70-3.60 (m, 4H), 3.17 (d, 3H), 1.84-1.76 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=3)[O:8][C:4]=2[CH:3]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:13]1[N:14]=[C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([F:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccnc1-c1nc2ccc(F)cc2o1
Product: Nc1ncc(Br)nc1-c1nc2ccc(F)cc2o1

Procedure:
3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (300 mg) was reacted with 1-bromopyrrolidine-2,5-dione using analogous procedures to those described in the starting material portion of Example 17 to give 5-bromo-3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (150 mg), which was reacted with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (183 mg) to give tert-butyl 4-[4-[5-amino-6-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (150 mg) according to the starting material portion of the procedure described in Example 17, except that 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) was used as the catalyst, 2M sodium carbonate as the base and dioxane:toluene (1:1) as the solvent. NMR Spectrum: (400 MHz, DMSOd6) 8.50 (s, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.80 (dd, 1H), 7.50 (dd, 1H), 7.20 (dd, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 3.00 (m, 2H), 2.10 (m, 1H), 1.90 (m, 3H), 1.50 (s, 9H) Mass spectrum: M+H+ 480.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH3:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:9][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCCBr
Product: CCCCCCCC/C=C\CCCCCCCCCCCCC
Temperature: -25 °C
Reaction time: 2 h

Procedure:
The reaction mixture was then cooled to -25° C. Next 25 mL tetrahydrofuran, 2.8 mL 1-bromopentane, and 1.14 grams cuprous bromide were added. The reaction mixture was held at -25° C. for 2 hours. Cooling coils were removed, and the reaction mixture allowed to slowly warm to 25° C. over the next 18 hours. Dilute HCl equal in volumetric amount to the reaction mixture was added, causing a phase separation. Hexane, equal in volumetric amount to the organic layer, was added. The organic layer was then separated. Next an aqueous sodium bicarbonate, equal in volumetric amount to the separated organic layer, was added to the separated organic layer. Once again the organic layer was separated and then fed to a distillation column. 2.6 grams of cis-9-tricosene were recovered.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[OH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Temperature: 50 °C
Yield: 66.1 %

Procedure:
To a solution of tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (38 g, 0.1376 mol) in dry THF (380 mL) was added 3-hydroxyphenyl boronic acid (22.77 g, 0.165 mol), potassium phosphate (88.2 g, 0.415 mol) and water (7.6 mL). The mixture was degassed with argon. 1,1′-Bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (11.23 g, 0.01376 mol) was added and the mixture was degassed again. The reaction was heated at 50° C. for 1.5 h and then allowed to cool to RT. Water was added and the mixture was extracted with ethyl acetate (3×). The total organic extract was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography using 100-200 mesh silica gel (8% ethyl acetate in hexane) to give the title compound (26.3 g, 66%). 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 6.68 (s, 1H), 6.30 (s, 1H), 5.37 (bs, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.46 (m, 2H), 2.31 (m, 2H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.09, 155.09, 138.87, 138.15, 129.31, 124.58, 120.98, 115.74, 113.54, 80.10, 45.45, 44.57, 36.08, 29.23, 28.50.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:32]([O:36][C:37]([NH:39][CH2:40][C@H:41]([N:45]1[CH2:50][CH2:49][N:48]([C:51](=[O:55])[CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]1)[C:42](O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33].Cl.[CH2:57]([O:60][NH2:61])[CH:58]=[CH2:59].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:57]([O:60][NH:61][C:42]([C@@H:41]([N:45]1[CH2:50][CH2:49][N:48]([C:51](=[O:55])[CH:52]([CH3:53])[CH3:54])[CH2:47][CH2:46]1)[CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:43])[CH:58]=[CH2:59]
Reactant: CC(C)C(=O)N1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)O)CC1
Reactant: C=CCON
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCONC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.4 g (4.4 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and then 2.3 ml (13.1 mmol) of diisopropylethylamine are added to a solution of 1.5 g (4.4 mmol) of (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic acid in 20 ml of dimethylformamide. After stirring at ambient temperature for 15 min, a solution of 500 mg (4.6 mmol) of O-allylhydroxylamine hydrochloride and of 0.8 ml (4.6 mmol) of diisopropylethylamine in 10 ml of dimethylformamide is added. The reaction medium is stirred at ambient temperature for 20 h, hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate, and then diluted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum, 1.45 g (83%) of tert-butyl [(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]1([C:7]2([C:35]#[N:36])[CH2:12][CH2:11][N:10]([C:13](=O)[CH2:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>O>[NH2:36][CH2:35][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][CH2:12]1
Reactant: N#CC1(c2ccccc2)CCN(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 3 parts of 4-phenyl-1-(3,3,3-triphenylpropionyl)isonipecotonitrile and 3 parts of lithium aluminum hydride in 150 parts by volume of tetrahydrofuran is refluxed overnight and then the excess of lithium aluminum hydride is decomposed by the successive addition of 1 part by volume of water, 1 part by volume of 15% sodium hydroxide and 3 parts by volume of water. The mixture is then filtered and the solvent evaporated to afford, as an oil, 4-aminomethyl-4-phenyl-1-(3,3,3-triphenylpropyl)piperidine. This compound is represented by the following structural formula ##STR13##
Reaction SMILES: [CH2:1]([N:10]([CH2:12][C:13]1[CH:14]=[C:15]([C:19](=O)[CH3:20])[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:20])=[CH2:22])[CH:14]=1)[CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cccc(CN(C)CC=Cc2ccccc2)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C)CC=Cc2ccccc2)c1
Yield: 50.5 %

Procedure:
The procedure described in Example 2 was repeated, except that Compound 46 (0.42 g; 1.50 mmol), methyl triphenylphosphonium bromide (1.5 eq), and n-butyl lithium in n-hexane (1.68 M: 1.5 eq) were used, to thereby yield 0.21 g of the target compound (yield: 50.5%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 29.8 %

Procedure:
According to the procedure described in Example 161C, to a suspension of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (1.0 g, 6.5 mmol) and K2CO3 (1.17 g, 8.5 mmol) in THF (15 mL) was added phenyl chloroformate (1.12 g, 7.2 mmol). The crude product was purified by silica gel chromatography with 0-50% EtOAc/hexane as eluants to afford phenyl 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate as solid (0.53 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.43 (m, 2H), 7.25 (m, 3H), 6.06 (s, 1H), 3.66 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.[C:17](O)([CH2:20][CH3:21])([CH3:19])[CH3:18]>C(OCC)(=O)C>[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[N:8]=1
Reactant: CCOC(=O)c1c[nH]nc1Br
Reactant: CCC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(C)(C)CC)nc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Concentrated sulfuric acid (0.45 mL, 4.8 mmol) was added to a mixture of ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.0 g, 4.6 mmol) and tert-amyl alcohol (3.0 mL, 27 mmol). The reaction was heated to 100° C. for 2.5 hours. The reaction was then cooled to room temperature and left stirring overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield ethyl 3-bromo-1-tert-pentyl-1H-pyrazole-4-carboxylate (1.3 g) as a crude brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cn1c(C=O)cc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaBH3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 65%) as a semi-solid: MS (ES) m/e-201 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[CH2:20](OC(C1C=NN(C2C=CC(Br)=CN=2)C=1C)=O)[CH3:21]>>[CH2:20]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)=[N:13][C:14]=1[CH3:19])[CH3:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Reactant: CCOC(=O)c1cnn(-c2ccc(I)c(C)n2)c1C
Product: CCc1ccc(-n2ncc(C(=O)O)c2C)nc1C

Procedure:
1-(5-Iodo-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester described n Reference Example 31 was used in place of 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester in Reference Example 28, and reacted and treated in a similar manner to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.16 (d, J=1.2, 1H), 7.96 (dd, J=8.0, 0.9, 1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.72-7.64 (m, 1H), 7.44 (s, 1H), 7.37 (dd, J=7.6, 0.9, 1H), 7.34 (s, 1H), 7.27 (dd, J=6.4, 1.3, 1H), 7.24 (s, 1H), 1.31 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH2:26][CH3:27])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH2:26][CH3:27])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:33]1[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[[2-Ethyl-1-(2-bromo-phenylmethyl)-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (1.3 g) was combined with 4-fluoro-phenylboronic acid in 20 mL of n-propanol at room temperature. After 30 minutes, the slurry was treated with palladium acetate, triphenylphosphine and 2 mL of 2 M sodium carbonate solution. The mixture was heated at reflux for one hour, cooled to room temperature and diluted with water. After stirring for 1 hour, the mixture was extracted with ethyl acetate, which was washed, dried, filtered, and concentrated to afford 1.1 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37](I)[CH3:38].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:37][CH3:38])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OCC)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To ethyl 3-{3-chloro-5-[5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}propanoate (D108) (180 mg, 0.40 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry DMF (3 ml) was added ethyl iodide (78 mg, 0.50 mmol) and the mixture heated at 80° C. with stirring for 30 minutes. Cooled mixture and added EtOAc (50 ml). Washed with water (3×40 ml) and dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 110 mg of white solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 1.42 (3H, t), 2.90 (2H, t), 4.02 (2H, q), 4.27 (2H, q), 4.49 (2H, t), 7.40 (1H, d), 7.74 (1H, s), 7.80 (1H, d), 7.95 (1H, dd), 8.16 (1H, dd), 8.21-8.22 (2H, m). MS (ES) C23H2135Cl2N3O4 requires 473; found 474 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O>>[F:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:16][CH2:15][NH:11][CH2:12][CH2:13][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-fluorophenylboronic acid and diethanolamin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: COc1cccc(C(=O)Nc2cccc(C(=O)C3CCN(C)CC3)c2)c1
Yield: 97.4 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-methoxybenzoyl chloride (97 μl, 0.687 mmol), 78.6 mg (97%) of the title compound were recovered.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][C:41]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-acetyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (300 MHz, MeOD) δ ppm 0.88 (dd, J=6.78, 2.26 Hz, 6H), 1.42-1.52 (m, 1H), 1.67 (ddd, J=13.75, 7.16, 6.97 Hz, 1H), 1.91-2.01 (m, 1H), 2.55 (s, 3H), 3.76 (t, J=7.72 Hz, 1H), 7.59 (t, J=5.84 Hz, 2H), 7.66-7.81 (m, 7H), 8.01 (d, J=8.29 Hz, 2H);