Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=O)[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:48]2)=CC=1>CCOC(C)=O>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)=[S:48])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cnc1C(=S)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 120 °C
Yield: 12.2 %

Procedure:
A sealable vial was charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide (Example 4, 0.068 g, 0.147 mmol) and toluene (1 mL). 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (0.059 g, 0.147 mmol) was added and the reaction mixture was heated to 120° C. overnight. Upon cooling to room temperature, the reaction mixture was taken up in EtOAc (75 mL). The organic layer was washed with aqueous saturated NaHCO3 and with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified through silica gel (gradient 30%-50% EtOAc-hexane) affording the title compound as a yellow solid (8.4 mg, 0.018 mmol, 12%). MS m/z=479 [M+H]+. Calculated for C19H16ClF5N4OS: 478.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OC)(OC)[O:11][CH3:12].ClC(Cl)C>ClCCCl>[OH:2][C:1]1[C:3]2[O:4][CH:10]([O:11][CH3:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Reactant: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COC1Oc2cccc(O)c2O1

Procedure:
A mixture of pyrogallol (25 parts), trimethyl orthoformate (32 parts) and 1,2-dichloroethane (250 parts) was heated with continuous distillation of the solvent for 4 hours. The volume of solvent was kept constant by simultaneous addition of dichloroethane. The mixture was then washed three times with water and dried over sodium sulphate. Removal of the solvent under reduced pressure and distillation of the residue gave 4-hydroxy-2-methoxy-1,3-benzodioxole, boiling point 104°-105° C/1 mmHg.
Reaction SMILES: C(C1[CH2:10][CH2:9][CH:8]([OH:11])CC1)(C)(C)C.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-:17].[Na+]>[Cl-].C[N+](C)(C)C>[CH2:12]([O:17][CH2:10][CH:9]1[O:11][CH2:8]1)[CH:14]1[O:16][CH2:15]1
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A 750 ml sulfonation flask equipped with thermometer, reflux condenser, N2 inlet and metering device is charged with 78.14 g (0.5 mol) of 4-tert-butylcyclohexanol and 0.83 g of catalyst A and the reaction mixture is heated to 100° C., whereupon the educt melts. With efficient stirring, 39.2 ml (0.5 mol) of epichlorohydrin are added, and the reaction mixture is thereafter allowed to react for 6 h. After cooling to 50° C., 2 g of tetramethylammonium chloride are added and to the solution are then added 4 g (0.05 mol) of a 50% aqueous solution of NaOH over 5 min, followed by the addition of 19 g (0.475 mol) of pulverised NaOH in increments over 45 min and the suspension is stirred for 2.5 h. The suspension is filtered, the residue is washed with 100 ml of toluene and the phases are separated. The organic phase is dried over MgSO4, filtered, and the filtrate is freed from solvent on a rotary evaporator at a bath temperature of 60° C., giving 103.0 g (97% of theory) of colourless glycidyl ether of 4-tert-butylcyclohexanol having the following properties: epoxy value: 4.09 eq/kg (87% of theory); total chlorine content: 1.8%; concentration of hydrolisable chlorine: 270 ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH2:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([N:13]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])[C:17]1=[O:16])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1cccc(F)c1CBr
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Temperature: 82 °C
Yield: 57.2 %

Procedure:
A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: NC1CCCCC1
Product: c1cc(N2CCC(CNC3CCCCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and cyclohexylamine.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([OH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=1[CH2:46][CH2:47][CH3:48]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[C:38]([OH:45])[C:37]=2[CH2:46][CH2:47][CH3:48])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 6 h

Procedure:
To a stirring mixture of ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide (0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was added a solution of 4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl -ethanone (1.9 g) in acetone (10 ml) dropwise with heating to reflux. After heating and refluxing with stirring for six hours, inorganic materials were separated by filtration and the filtrate was concentrated. The residue was separated and purified through silica-gel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound as crude crystals (2.1 g, 72.4%). This crystal was recrystallized from ethanol to colorless crystals, mp 65-66° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:11][N+:12]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:15][Si:16]([CH2:17][CH3:18])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:11][NH2:12]
Reactant: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC[Si](CC)(CC)OC(CN)c1c(Cl)ccc(F)c1Cl
Product: Cl
Temperature: 60 °C

Procedure:
To a 100 mL three-necked RBF were added (1-(2,6-dichloro-3-fluorophenyl)-2-nitroethoxy)triethylsilane (3.64 g, 9.88 mmol) in EtOH (16 ml) and water (4 ml) at room temperature followed by addition of iron (5.52 g, 99 mmol) and ammonium chloride (5.29 g, 99 mmol). The flask was purged with nitrogen and was heated to 60° C. under nitrogen for 3 h. The mixture was cooled to room temperature, diluted with 40 mL of MeOH, sonicated for 10 min. Then the solution was decanted through a pad of celite. This process was repeated for three times. The filtrate was concentrated to ˜30 mL and diluted with EtOAc (120 mL). The solid was filtered off and discarded. The filtrate was concentrated under reduced pressure. It was diluted with 50 mL of EtOAc, washed with water, brine, dried over anhydrous MgSO4, and concentrated to give 2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine hydrochloride as an off-white solid. The HCl salt was dissolved with 50 mL of DCM. The suspension was basicified w/satd aq NaHCO3 (pH=9). The organic layer was separated, washed with brine, dried over anhydrous MgSO4, and concentrated to give 2-(2,6-dichloro-3-fluorophenyl)-2-((triethylsilyl)oxy)ethanamine (2.73 g, 8.07 mmol, 82% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.23-7.29 (m, 1H), 6.99-7.06 (m, 1H), 5.35 (dd, J=8.6, 4.9 Hz, 1H), 3.29 (dd, J=13.1, 8.7 Hz, 1H), 2.92 (dd, J=13.2, 4.9 Hz, 1H), 0.83-0.93 (m, 9H), 0.46-0.61 (m, 6H); LCMS: 338.2 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>Cl.C(O)C>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][CH:26]([CH3:28])[CH3:25])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)ccc(NC(C)C)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) and acetone (116 mg) in 3M HCl solution in ethanol (2 ml) was added sodium cyanoborohydride (25 mg) in one portion. The mixture was stirred for 2 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried and concentrated in vacuo to give an oil, which was purified by preparative thin-layer chromatography on silica gel (ethyl acetate:n-hexane=1:2, V/V), to give 3-bromo-8-(2,6-dichloro-3-isopropylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine as a white solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].F[C:27]1[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=1O)C(OC[C@@H](C)CC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][C:27]3[CH:28]=[CH:29][CH:38]=[CH:39][CH:40]=3)=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1Cl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccccc3)cc2)cc1Cl

Procedure:
The reaction was performed as in Example 18 except using 3'-chloro-4'-octyloxybiphenyl-4-carboxylic acid instead of 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylic acid and (S)-2-methylbutyl 3-fluoro-4-hydroxybenzoate instead of (S)-2-methylbutyl 4-hydroxybenzoate. There was obtained 2-fluoro-4-(S)-2-methylbutyloxycarbonyl]phenyl 3'-chloro-4'-octyloxybiphenyl-4carboxylate.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C=O>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
(1-Carboxymethyl-3-hydroxy-2-methyl-pyrid-4-one)3 -AL+3 (4.5 g) in 200 ml of dimethylformamide (DMF) has added N-hydroxysuccinimide (2.9 g! followed by addition of dicyclohexylcarbodiimide (5.2 g) dissolved in 100 ml of DMF, is stirred and left to stand over night. The reaction produces a white precipitate, N,N'-dicyclohexylurea that is filtered off and discarded. Glucosamine [5.4 g] is added to the filtrate and allowed to react for 2 h, and then the pH is adjusted to 2.5 with sulphuric acid and rotary evaporated to dryness and is then extracted with several volumes of hot methanol. The combined extracts are concentrated until precipitation begins after which the solution is stored in refrigerator over night to complete precipitation of 2-deoxy-2-(N-carbamoylmethyl-[N'-2'-methyl-3'-hydroxypyrid-4'-one])-D-glucopyranose. Molecular mass, M+=382.8, by mass spectroscopy. The compound dissolved in ethanol/water mixture with added iron forms the purple coloured complex. HPLC analysis of mixture of 3-hydroxy-2-methyl-4-pyrone control and synthetic end product which showed a single sharp peaks well separated from the control.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].S(OC)(O[CH3:24])(=O)=O>O1CCCC1.O>[CH3:24][N:8]([C:13](=[O:15])[CH3:14])[C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COS(=O)(=O)OC
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
1.58 g of sodium hydride (60% content) was suspended in 19.8 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 19.8 g of a tetrahydrofuran solution containing 2.50 g of 2-nitroaniline was added dropwise over 1 hr, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.01 g of acetic acid anhydride was added over 1 hr at room temperature and stirred for 2 hours. To the reaction mixture, 2.49 g of dimethyl sulfate were added at room temperature and stirred for 1 hr. The reaction mixture was added to water and the separated organic layer was washed with saline then the organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 78%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.CC[N:23]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([NH2:23])=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccc(C=C(C(N)=O)c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a mixture 2-(4-fluorophenyl)-3-(4-methylthiophenyl)acrylic acid (prepared according to procedure given in Example 1) (3 g, 10.4 mmol), EDCI (4 g, 20.8 mmol), HOBt (1.4 g, 10.4 mmol) in DMF (35 mL) and triethylamine (3 mL, 20.8 mmol) was added slowly and stirred for 30 min. Reaction mixture was cooled to 5° C. and anhydrous ammonia gas purged for 10 min and stirred at 30° C. for 30 min. Reaction mixture was poured into water (250 mL) and extracted with ethyl acetate (2×200 mL). Combined organic layer was successively washed with water (3×200 mL) and brine solution (1×150 mL), dried over anhydrous sodium sulfate (2 g) and concentrated to afford the crude compound. The crude compound was triturated with hexane:ethyl acetate (9:1) (40 mL) for 3 times to afford a title compound as colorless solid (2 g, 67% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:6]([CH2:35][CH3:36])[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:7]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]#[N:22])=[CH:18][CH:17]=4)[CH2:14][CH2:15]3)=[O:9])=[C:6]([CH2:35][CH3:36])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(N)=O)cc4)CC3)c(CC)cc2C2CC2)[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CC2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide (compound 228.4, 80.0 mg, 0.160 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic anhydride (34.0 mg, 0.160 mmol, 1.00 equiv) and triethylamine (33.0 mg, 0.330 mmol, 2.00 equiv) were added dropwise to the stirred mixture. The resulting solution was stirred for 2 h at 25° C., then washed with 1×10 mL of brine. The aqueous layer was extracted with 2×20 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (42% CH3CN up to 57% in 8 min, up to 100% in 1.5 min, down to 42% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 15 mg (20%) of the title compound as a an off-white solid. m/z (ES+) 470 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.64 (d, 2H), 7.46-7.28 (m, 3H), 7.02-7.01 (m, 1H), 4.89-4.80 (m, 1H), 4.40-4.33 (m, 2H), 3.58-3.56 (m, 1H), 3.27-3.25 (m, 1H), 3.04-2.90 (m, 2H), 2.73-2.58 (m, 2H), 2.31-2.29 (m, 1H), 1.94-1.96 (m, 1H), 1.82-1.78 (m, 3H), 1.45 (t, 3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=1[F:25].C1(C)C=CC=CC=1.C(O)C>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>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:20][C:19]=1[F:25]
Reactant: OB(O)c1ccncc1
Reactant: Fc1cc(I)ccc1Br
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Fc1cc(-c2ccncc2)ccc1Br

Procedure:
Sodium carbonate (0.86 g, 0.0081 mol) in water (3.0 mL, 0.17 mol) was added to a mixture of 4-pyridinylboronic acid (0.5 g, 0.004 mol), 1-bromo-2-fluoro-4-iodobenzene (1.5 g, 0.0049 mol), and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) in toluene (6.0 mL, 0.056 mol) and ethanol (3.0 mL, 0.051 mol). The resulting mixture was irradiated by microwave at 120° C. for 30 min. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concented in-vacuo. The residue was purified by CombiFlash (EtOAc in hexanes: 40%) to afford the desired product.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]1([NH2:6])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>O1CCOCC1>[O:24]=[C:18]([NH:6][C:3]1([C:2]([F:8])([F:7])[F:1])[CH2:5][CH2:4]1)[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C1CCC(=O)O1
Reactant: NC1(C(F)(F)F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)NC1(C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
Slowly, 800.7 mg (4.96 mmol) of 1-(trifluoromethyl)cyclopropanamine and 0.85 ml (4.96 mmol) of diisopropylethylamine were added to a solution of 496 mg (4.96 mmol) of succinic anhydride in 10 ml of dioxane, with ice-cooling (10° C.). Stirring was continued for 20 min at room temperature, and the mixture was allowed to stand overnight at this temperature. Again, stirring was continued for 20 min at 80° C., the mixture was allowed to cool to room temperature, and the solution was concentrated. Repeatedly, the solution was washed alternately with ethyl acetate and with water. The combined organic phases were dried and concentrated. This gave 815.8 mg (73% of theory) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(Cc2ccccn2)CC1

Procedure:
Using General Procedure B, reaction of COMPOUND 249, pyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave COMPOUND 252 as an amber solid. 1H NMR (CDCl3) δ 1.84-1.87 (m, 4H), 1.92-2.00 (m, 2H), 2.09 (s, 6H), 2.45-2.50 (m, 1H), 2.95 (d, 2H, J=10.2 Hz), 3.60 (s, 2H), 3.84 (s, 4H), 7.04-7.09 (m, 2H), 7.12-7.17 (m, 1H), 7.33-7.39 (m, 2H), 7.61-7.67 (m, 1H), 8.34 (d, 2H, J=3.0 Hz), 8.55 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.39, 27.28, 54.32, 55.20, 57.77, 64.99, 122.26, 122.61, 123.50, 133.78, 136.69, 138.26, 146.19, 149.60, 157.92, 159.31. ES-MS m/z 402 (M+H). Anal. Calcd. for C25H31N5.1.0H2O: C, 71.57; H, 7.93; N, 16.69. Found: C, 71.73; H, 7.99; N, 16.54.