Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:37]([C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:36][CH:35]=2)(=[O:39])=[O:38])[CH:6]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methylsulfonylbenzenesulfonyl chloride.
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C1N2CCN(CC2)C1>C(#N)C>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:29][C:21]1[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=1[F:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 50 °C

Procedure:
To a homogeneous solution of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (1.00 g, 3.74 mmol, Compound D of Example 1) and 2-fluoro-4-nitrophenol (588 mg, 3.74 mmol) in anhydrous acetonitrile (25 mL), at room temperature under a nitrogen atmosphere, was added DABCO (462 mg, 4.12 mmol). The mixture was then heated at 50° C. for 3 h. The mixture was cooled to room temperature then partitioned between chloroform and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with chloroform. The combined organic layers were washed once each with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a pale yellow solid that was used in the next step without further purification. MS(ESI+) m/z 389.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:24]([CH3:26])[CH3:25])[C:11]([C@@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][C@@H:14]1[O:20]C(=O)C)=[O:12])=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH:24]([N:10]([C:11]([C@@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][C@@H:14]1[OH:20])=[O:12])[C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:26])[CH3:25]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1OC(C)=O)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Yield: 13.2 %

Procedure:
(1R,2S,4R)-3-[Isopropyl-(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (36 mg, 0.17 mmol) was dissolved in a mixture of dioxane:H2O (4:1) (700 μl) and then 470 μl of LiOH 1N was added to it. After 3 h at 50° C. the reaction mixture was cooled to room temperature and the solvents were removed. The residue was then partitioned between 10 ml of H2O acidified to pH 4 and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2×10 ml). The combined ethyl acetate layers were dried (Na2SO4), concentrated and the residue was purified by preparative chromatography to obtain 9 mg (29%) of (1R,2S,4R)-3-[Isopropyl-(2-hydroxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (CDCl2, 400 MHz): 3:2 mixture of rotamers 7.76-7.73 ppm (m, 2H, Haro); 7.50-7.38 ppm (m, 3H, Haro); 7.36 ppm (s, 1H, Haro); 4.93-4.87 ppm (m, 1H); 4.25 ppm (s, 0.70H, major rotamer); 3.97 ppm (s, 0.3H, minor rotamer); 2.35-2.28 ppm (m, 1H); 1.99-1.53 ppm (m, 5H); 1.28 ppm (d, 0.6H, minor rotamer); 1.25 ppm (d, 1.4H, major rotamer); 1.06-1.03 ppm (m, 3H), 0.96-0.72 ppm (m, 1H); 0.79 ppm (d, 3H); 0.67-0.56 ppm (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25](Cl)=[O:26])[CH2:13]2)[CH3:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[CH2:37][CH2:36]1>C(Cl)Cl>[C:41]([CH:38]1[CH2:39][CH2:40][N:35]([C:25]([N:14]2[CH2:15][CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH:12]([CH:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH3:11])[CH2:13]2)=[O:26])[CH2:36][CH2:37]1)#[N:42]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)N2CCC(C#N)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of (3RS,4SR)-3-[(SR)-1-(5-Cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (30 mg, 0.070 mmol) in CH2Cl2 (4 mL) were added Et3N (0.015 mL, 0.11 mmol) and piperidine-4-carbonitrile (commercially available) (9 mg, 0.084 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 24 mg (69%) the title compound as light yellow oil. ES-MS m/e: 498.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[NH2:34]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:14]([C:15]([NH:34][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[O:17])=[C:5]2[N:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Reactant: Cc1ccncc1N
Solvent: CN1CCCC1=O
Product: Cc1ccncc1NC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a solution of benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (150 mg, 0.4129 mmol) in NMP (1.666 mL) was added 4-methylpyridin-3-amine (44.65 mg, 0.4129 mmol) and the reaction mixture was stirred at 100° C. for 17 hours in a sealed tube. The solid precipitate was filtered and dried under vacuum to afford the desired Compound I-C-1 as a yellow powder (60.4 mg, 42%). LC-MS (M+H)+ 337.2; 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.40 (s, 1H), 9.30 (dd, J=6.9, 0.6 Hz, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.33 (d, J=4.8 Hz, 1H), 7.01 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:16]([NH:20][C:21]([NH:15][S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:2]([Cl:1])=[CH:3][Cl:4])(=[O:13])=[O:14])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Temperature: 25 °C
Yield: 74.4 %

Procedure:
2-(1,2-Dichloroethen-1-yloxy)benzenesulfonamide (13.4 g), 12.4 g of n-butyl isocyanate and 15.2 g of anhydrous potassium carbonate were combined in 200 ml of dry tetrahydrofuran and heated to reflux for three hours. The mixture was then cooled to room temperature, filtered and the solvent removed by evaporation. The residue and precipitate were recombined and dissolved in 600 ml of water and the mixture acidified with 10% hydrochloric acid. The resultant precipitate was removed by filtration, washed with water, air dried and then washed with hexane. After drying in vacuo at 80° overnight, 13.65 g of solid product melting at 122°-125° was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (4 g, 26.5 mmol) and NaOH 1M (52.9 ml, 52.9 mmol) in THF (60 ml), methanesulfonyl chloride (2.474 ml, 31.8 mmol) was slowly added and the reaction was stirred at RT overnight. The mixture was acidified and extracted twice with EtOAc; the combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The resulting solid was suspended in MeOH (120 ml) and stirred overnight. The precipitate was collected by filtration to give 4-(methylsulfonamidomethyl)-benzoic acid (1.99 g, 8.68 mmol, 32.8% yield, MS/ESI+ 229.9 [MH]+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[NH3:21].CO>>[OH:19][C:6]1([CH2:5][C:4]([NH2:21])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: N
Reactant: CCOC(=O)CC1(O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: NC(=O)CC1(O)CCN(Cc2ccccc2)CC1

Procedure:
A solution of ethyl[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetate (15 g, 54.15 mmol) [prepared according to Caroon, J. M.; et al. J. Med. Chem. 1981, 24, 1320.] in 7N NH3-MeOH (16 mL) was heated to 100° C. in a sealed tube for 3d. The solution was cooled and concentrated and the residue washed with DCM providing the title compound (4 g, 30%) as a white solid which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cc(Br)ccc1Br
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(Br)ccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,5-dibromoaniline to yield 2-[(2,5-dibromophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(C(F)(F)F)nc1
Reaction time: 1.5 h
Yield: 44.8 %

Procedure:
A solution of [6-(trifluoromethyl)pyridine-3-yl]methanol (0.886 g, 5.0 mmol) in DCM (20 ml) was added to a mixture of Dess-Martin periodinane (2.334 g, 5.5 mmol) in DCM (20 ml) at rt. The reaction was stirred for 1.5 hrs then diluted with Et2O (100 ml) and 4N NaOH (15 ml). The mixture was stirred for 10 mins then separated. The organic layer was washed with 4N NaOH (15 ml) then brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 15% EtOAc/hexanes) to give the aldehyde (0.392 g, 45%). 1HNMR (400 MHz, CDCl3): δ 7.89 (1H, d, J 8.1), 8.37 (1H, d, J 8.1), 9.20 (1H, s), 10.22 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH3:10].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.ClCCl>[CH3:10][C:4]1[CH:5]=[C:6]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: Cc1cc(O)ccc1CO
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 4-(hydroxymethyl)-3-methylphenol (4.25 g, 30.8 mmol) in ethanol (90 ml) was added 2M aqueous sodium hydroxide (17 ml, 34 mmol) and then benzyl bromide (3.65 ml, 30.8 mmol, Aldrich). The pale yellow mixture was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an orange oil. The residue was loaded in dichloromethane and purified on silica (100 g×3) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give {2-methyl-4-[(phenylmethyl)oxy]phenyl}methanol (2.59 g).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:12][C:11]1([CH3:19])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, methacryloyl chloride and triethylamine in methylene chloride to afford the title compound as a colorless oil. Analyses by nmr, ir and ms give data consistent with the desired structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CC(C)=O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:11]2[C:10](=[O:12])[CH2:9][CH2:8][C:7]2=[O:13])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCC(=O)N1Cc1ccc(F)cc1
Yield: 85.1 %

Procedure:
Freshly ground potassium carbonate, K2CO3 (31 g, 225 mmol) was added to dry acetone (200 ml) in a 3-necked flask equipped with drying tube, condenser, and mechanical stirrer. Succinimide (7.43 g, 75 mmol) and 4-fluorobenzylbromide (11.21 mL, 90 mmol) were added. The mixture was refluxed for 19 hours and filtered through Celite. Acetone was removed under vacuum, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and also with brine, dried (MgSO4), filtered and concentrated to give crude. Crude product was chromatographed (EtOAc/Hexane) on silica gel to give N-4-fluorobenzyl-succinimide 1 as white solid (13.22 g, 85%). 1H NMR (CDCl3) δ 7.4 (dd, 2H), 7.0 (t, 2H), 4.6 (s, 1H), 2.7 (s, 4 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[OH:19])[CH:3]=1.O1CCCC1.C([Mg]Cl)(C)C.C(O[B:41]1[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]1)(C)C>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]([C:4]2[CH:3]=[C:2]([B:41]3[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]3)[S:6][C:5]=2[C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[OH:19])=[CH:21][CH:22]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(C(O)c3ccc(Cl)cc3)c(-c3ncn(C4CCCCO4)n3)s2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a mixture of {5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol (5.19 g, 11.4 mmol) in tetrahydrofuran (146.9 mL, 1811 mmol) was added isopropylmagnesium chloride (1M in THF, 34.2 mL, 34.2 mmol) at −40° C. under argon. After addition, the reaction temperature was raised to rt for 15 min. The mixture was then cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.149 mL, 39.94 mmol) was added. After the addition, the mixture was brought to rt. After 1 h, the mixture was heated at 75° C. overnight. The mixture was cooled to rt and quenched with saturated ammonium chloride solution. The mixture was stirred for 10 min then extracted with EtOAc. The organic layer was dried and evaporated in vacuum. The mixture was purified by chromatography to afford (4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methanol as a thick oil (5.32 g, 65.0%). LCMS: (FA) ES+ 502.2, 504.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19](O)=[O:20])=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:30]1C=CN=C1)=O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19]([NH2:30])=[O:20])=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:23][C:24]([F:27])([F:26])[CH2:25]2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)C1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To an ice-cold solution of 1-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinoyl)pyrrolidine-2-carboxylic acid (8.6 mg, 22.6 μmol) in DMF (2 mL) was added carbonyldiimidazole (10.2 mg, 63.1 μmol). After 5 minutes the reaction mixture was warmed to ambient temperature and stirred for 2 h. NH3 gas was bubbled through the solution for 10 minutes and stirring was continued for 12 h. The reaction mixture was poured onto ice-water (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (9 mg, quant.) as colorless wax; MS (EI): m/e=381.5 [MH+].
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[N:46]7C(OC(C)(C)C)=O)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[NH:46]7)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3nc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)cnc3c2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2cc1-c1cnc2cc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 156.6 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (30 mg, 0.044 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed under vacuum and the residue was triturated with Et2O to yield a TFA salt of 2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline (32.7 mg) as yellow solid. LC-MS retention time 1.33 min; m/z 475 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.47 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.31 (dd, J=8.8, 1.8 Hz, 1H), 8.26 (dd, J=8.5, 1.3 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 4.85-4.97 (m, 1H), 4.67 (dd, J=10.8, 7.5 Hz, 1H), 3.45-3.57 (m, 2H), 2.77-2.86 (m, 1H), 2.65-2.74 (m, 1H), 2.52-2.65 (m, 2H), 2.02-2.15 (m, 2H), 1.18-1.30 (m, 2H), 0.95-1.09 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([N:10]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[C:14]([O:20][CH3:21])[CH:13]=1)([CH3:9])[CH3:8].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O.O>[CH:23]1([N:10]([CH:7]([CH3:9])[CH3:8])[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OCc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2OC)c1

Procedure:
A slurry of K2CO3 (0.75 g, 5.43 mmol) in a solution of 4-bromomethyl-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.0 g, 2.7 mmol) and 3-methoxy phenol (0.35 g, 2.74 mmol) in dimethylformamide (DMF) (15 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water (50 ml), extracted twice with ethyl acetate and dried (Na2SO4) The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product as a dark oil. This material was purified by chromatography on silica gel using mixtures of ethyl acetate, CH2Cl2 and hexane as eluents to give the title compound as a glass.
Reaction SMILES: CO[C:3]1[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:22][O:23]C1C=CC2OC(C3C=CC(F)=CC=3)=CC=2C=1>>[CH3:22][O:23][C:9]1[CH:10]=[CH:3][C:4]2[O:11][C:12]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[CH:6][C:5]=2[CH:8]=1
Reactant: COc1ccc2oc(-c3ccc(F)cc3)cc2c1
Reactant: COc1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Product: COc1ccc2oc(-c3ccc([N+](=O)[O-])cc3)cc2c1
Yield: 89 %

Procedure:
Compound V was synthesized from compound (IV) as same procedure for Compound II in 89% yield.
Reaction SMILES: [OH:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:14]([C:12]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cnc(O)c(C#N)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 716 mg (2.44 mmol) of ethyl 6-hydroxy-5-iodonicotinate and 573 mg (4.88 mmol) of zinc cyanide in 10 mL of DMF was added 169 mg (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0). After stirring at 80° C. overnight, the mixture was filtered through a cake of Celite. The filtrate was washed with brine (10 mL), H2O (3×10 mL), and brine (10 μL), dried over MgSO4, and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v EtOAc/hexanes as the eluant gave 222 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.29 (d, J=7.1, 3H), 4.28 (q, J=7.1, 2H), 8.31 (d, J=2.5, 1H), 8.42 (d, J=2.8, 1H).