Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3][CH2:2]1.[F:11][C:12]([F:42])([F:41])[C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17].C(N(C(C)C)CC)(C)C.CN(C)C=O>O>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:41])[F:42])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH2:7][CH2:6][C:4]2([CH3:5])[O:10][CH2:1][CH2:2][O:3]2)[CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17]
Reactant: CC1(CCCCl)OCCO1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(CCCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)OCCO1
Temperature: 90 °C
Yield: 39.9 %

Procedure:
A mixture of 5-chloro-2-pentanone ethylene ketal (0.54 g), (2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.37 g), diisopropylethylamine (0.6 mL), and dimethylformamide (25 mL) was heated overnight, at 90°C. After cooling to room temperature the mixture was poured in water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 95/15) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]piperazine (0.7 g, 40%). MH+ 584.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([NH2:35])(=[O:34])[CH2:32][OH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[N:23]=[CH:24][C:25]([NH:35][C:31](=[O:34])[CH2:32][OH:33])=[N:26][C:27]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: NC(=O)CO
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NC(=O)CO)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g), glycolamide (0.066 g) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.075 g.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24][CH3:25])[CH:17]=1)=O)(C)(C)C.F[C:40]([F:45])([F:44])C(O)=O.ClCCl>C(#N)C>[C:29]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=[C:27]([N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:40]([F:44])[F:45])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3ccccc3)c2)cc1OC
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(C(=O)N(C[C@@H]2CCCN2)c2cccc(-c3ccccc3)c2)ccc1OC(F)F

Procedure:
Experimental condition analogous to Example 1, from 1 g (1.94 mmol) of 2-(S)-{[biphenyl-3-yl-(3,4-dimethoxy-benzoyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 25 mL of trifluoroacetic acid and 100 mL of dichloromethane. Gave 0.75 gram of white semi solid: LC-MSD, m/z for: C26H26F2N2O3 [M+H]: 452.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 7 minutes: 3.54.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=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.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Ethynylpyridine (250 mg, 2.42 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]-acetate (500 mg, 0.91 mmol; example 7) in a mixture of tetrahydrofuran (8 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:24])=[O:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=1
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1cccc(-c2c(C=O)cccc2OC)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Aldehyde 4a (0.512 g., 1.80 mmol, 1 equiv.) is dissolved in 17 mL of THF and 13 mL of H2O. The solution is cooled to 0° C. Sulfamic acid (0.525 g., 5.41 mmol, 3 equiv. ) is then added, followed by a solution of sodium chlorite (80% tech., 0.612 g., 5.41 mmol, 3 equiv. ) in 4 mL of H2O. The mixture is stirred for 15 min. at 0° C., and then poured into EtOAc and water. The aqueous layer is extracted thrice with EtOAc, and the combined organic-phase is washed with brine. The organic phase is dried (MgSO4) and then concentrated in vacuo to afford 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxylic acid (5a) as a pale yellow oil (0.583 g., 1.80 mmol, 100%): 1H NMR (300 MHz, CDCl3) δ 10.17 (br, 1H, C2H), 8.02 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.94 (s, 1H, ArH), 7.56 (d, J=8 Hz, 1H, ArH), 7.41 (m, 3H, ArH), 7.15 (d, J=8 Hz, 1H, ArH), 4.19 (q, J=7 Hz, 2H, CO2CH2), 3.,73 (s, 3H, OCH3), 1.39 (t, J=7 Hz, 3H, CH2CH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][C:16]1([CH3:30])[CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18][CH:17]1[C:27]([O-:29])=[O:28].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[CH3:15][C:16]1([CH3:30])[CH2:21][CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][CH2:18][CH:17]1[C:27]([O:29][CH3:31])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CC(OS(C)(=O)=O)CCC1C(=O)[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1(C)C
Temperature: 90 °C
Reaction time: 22 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (700 mg, 3.61 mmol), 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (1.50 g, 3.97 mmol), and cesium carbonate (1.29 g, 3.97 mmol) were added to an oven-dried flask. DMF (12 mL) was added and the mixture was stirred at 90° C. for 22 hours. The mixture was cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL), and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 to 80% EtOAc/hexanes) to afford racemic methyl 2,2-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.54 (s, 1H), 4.10 (q, J=7.3 Hz, 1H), 3.54 (s, 3H), 2.20-1.98 (m, 1H), 1.83-1.65 (m, 2H), 1.64-1.49 (m, 2H), 1.43-1.38 (m, 1H), 1.34-1.31 (m, 1H), 1.22 (s, 12H), 0.90 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)O)CC3)cc12
Reaction time: 0.33 h

Procedure:
A solution of Example 226A (0.43 g, 0.983 mmol) and trifluoroacetic acid (1.817 mL, 23.59 mmol) in dichloromethane (9.83 mL) was stirred at ambient temperature for 24 hours. The mixture was concentrated, dissolved in 5 mL dichloromethane and 2N hydrogen chloride in ether (20 mL) was added. The suspension was stirred for 20 minutes, treated with ether (50 mL), and filtered. The solid was washed with ether and dried under vacuum to afford the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 2.84-2.92 (m, 2H), 3.50-3.63 (m, 2H), 3.74 (s, 3H), 4.03-4.11 (m, 2H), 4.14 (s, 2H), 6.40 (s, 1H), 6.46-6.56 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.16-7.29 (m, 3H), 8.26 (d, J=5.1 Hz, 1H), 12.07 (bs, 1H). MS (ESI+) m/z 382.1 (M+H)+.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C1(C)C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].C([N:25](CC)CC)C>>[CH3:7][O:6][Si:5]([CH2:4][CH2:3][CH2:2][CH2:20][C:19]([NH2:25])=[O:21])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CO[Si](CCCN)(OC)OC
Solvent: Cc1ccccc1
Product: CO[Si](CCCCC(N)=O)(OC)OC

Procedure:
A three-neck round-bottomed flask, equipped with a mechanical stirrer, a refluxing condenser and a dropping funnel, was charged with 3-aminopropyltrimethoxysilane (18 gram, Gelest Inc.), toluene (40 mL, Aldrich) and triethylamine (13 gram, Aldrich). Stirring was started, and an appropriate acyl chloride such as acetyl chloride (18 mL, Aldrich) was added dropwise to the flask. The mixture was stirred at room temperature under an argon atmosphere for 16 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-:23][Si](C)(C)C)(C)C.[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:23])=[NH:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
A solution of 4-benzyloxy-2-fluoro-benzonitrile (84 g, 0.37 mol) in THF (450 mL) under an atmosphere of nitrogen, was cooled to −70° C. The resultant suspension was treated with a solution of 1M LiHMDS in THF (440 mL, 0.44 mol) over 10 min to reach a maximum temperature of −55° C. The reaction mixture was allowed to warm to RT and stirred for three days. Reaction progress was monitored by TLC analysis. The reaction mixture was poured onto ice/1M HCl mixture, the pH adjusted to ˜1 by addition of 6M HCl and washed with EtOAc (500 mL). The organic layer was extracted with 1M HCl and the combined aqueous extracts washed with EtOAc (500 mL). The acid aqueous extracts were concentrated to low volume in vacuo and the resultant solid filtered off, washed with H2O and dried in vacuo to give 4-Benzyloxy-2-fluoro-benzamidine hydrochloride as a pale cream crystalline solid (74.5 g, 72%). 1H NMR (400 MHz, d6-DMSO): 9.30 (4H, d, J=10.39 Hz), 7.64 (1H, t, J=8.59 Hz), 7.49-7.35 (5H, m), 7.19 (1H, dd, J=12.88, 2.41 Hz), 7.06 (1H, dd, J=8.77, 2.41 Hz), 5.25 (2H, s).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[I:14][C:15]1[CH:20]=[C:19](OC)[N:18]=[C:17]([NH2:23])[CH:16]=1>O.C(OCC)(=O)C>[I:14][C:15]1[CH:4]=[C:3]([O:2][CH3:1])[N:23]2[CH:20]=[CH:19][N:18]=[C:17]2[CH:16]=1
Reactant: COC(CBr)OC
Reactant: COc1cc(I)cc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(I)cc2nccn12
Temperature: 80 °C

Procedure:
To a mixture of bromoacetaldehyde dimethylacetal (4.50 ml, 37.1 mmol) in water (126 ml) was added a 1M solution of hydrochloric acid (8.40 ml, 8.40 mmol). After 2.5 h the reaction mixture was heated to 80° C. resulting in a clear solution. After 40 minutes the reaction mixture was cooled to ambient temperature and sodium bicarbonate (3.83 g, 45.6 mmol) and 4-iodo-6-methoxypyridin-2-amine (5.25 g, 21.0 mmol) were added. After 16 hours the reaction mixture was diluted with ethyl acetate, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to give 7-iodo-5-methoxyimidazo[1,2-a]pyridine. LRMS (ESI) calculated for C8H8IN2O [M+H]+, 275.0 found 274.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Clc1ccc2c(c1)Oc1ccccc1N2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 3-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-270° C. (dec.)(corr.), from ethanol-ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH3:17])=[C:15]([C:18]([NH:20][C:21]3[CH:22]=[N:23][C:24]([CH:28]4[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]4)=[C:25]([CH3:27])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.FC1C(N2C(C)=C(C(NC3C=NC(C4CCC(=O)CC4)=C(C)C=3)=O)C=N2)=NC=C(C(F)(F)F)C=1>>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH3:17])=[C:15]([C:18]([NH:20][C:21]3[CH:22]=[N:23][C:24]([C@H:28]4[CH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][CH2:33]4)=[C:25]([CH3:27])[CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2C)cnc1C1CCC(=O)CC1
Agent: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1CCC(=O)CC1
Product: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2C)cnc1[C@H]1CC[C@H](O)CC1

Procedure:
1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-N-[5-methyl-6-(4-oxocyclohexan-1-yl)pyridin-3-yl]-1H-pyrazole-4-carboxamide (234 mg) described in Example F36 was used in place of 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-N-[5-methyl-6-(4-oxocyclohexan-1-yl)pyridin-3-yl]-1H-pyrazole-4-carboxamide in Example 29, and reacted and treated in a similar manner to give the titled compound (72 mg) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.O1C2C=CC=CC=2N=C1C1C(N)=NC=C([Br:55])C=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14]([Br:55])[CH:15]=1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate used as starting material was prepared as follows: N,N-dimethylpyridin-4-amine (42.1 mg) was added to 3-(1,3-benzoxazol-2-yl)-5-bromo-pyridin-2-amine (500 mg) and di-tert-butyl dicarbonate (1.069 g) suspended in DMF (5 ml). The resulting mixture was stirred at 25° C. for 48 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (15 ml). The resulting precipitate was collected by filtration, washed with water and dried. The crude was taken up into ethylacetate and filtered through a pad of silica gel. The resulting filtrate was concentrated to afford tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-bromo-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (710 mg) as a brown solid. NMR Spectrum: (CDCl3): 1.32 (s, 18H), 7.37-7.44 (m, 2H), 7.60 (dd, 1H), 7.80 (dd, 1H), 8.70 (d, 1H), 8.81 (d, 1H); Mass spectrum: M+H+ 491;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:44])([CH3:43])[CH2:7][N:8]([S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[CH2:9][C@@H:10]([OH:31])[C@@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[CH3:54][N:55]([CH3:59])[C:56](Cl)=[O:57]>C1COCC1>[CH2:12]([C@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:10]([OH:31])[CH2:9][N:8]([CH2:7][C:6]([CH3:44])([CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:56]([N:55]([CH3:59])[CH3:54])=[O:57])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 55 mg (0.087 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((6-amino-2,2-dimethylhexyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.091 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 8.4 μL (0.091 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 49 mg (80%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.32-7.12 (m, 6H), 7.02 (d, 1H), 6.92 (s, 1H), 6.76 (d, 1H), 5.60 (m, 2H), 4.96 (q, 1H), 4.51 (m, 1H), 4.32 (s, 1H), 4.20 (br s, 1H), 4.01 (m, 1H), 3.88 (dd, 1H), 3.79 (m, 2H), 3.62 (m, 2H), 3.30-2.92 (m, 6H), 2.91-2.64 (m, 12H), 1.65-1.40 (m, 3H), 1.38-1.20 (m, 5H), 0.91 (s, 3H), 0.85 (s, 3H). MS(ESI): 704(M+H).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](F)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35].C(=O)(O)[O-].[Na+]>CS(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:9][CH2:8][C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: OCc1cccs1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(OCc4cccs4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
To a mixture of sodium hydride (37 mg, 1.54 mmol) in 3 mL of dimethylsulfoxide is added 2-thiophenemethanol (48 mg, 0.42 mmol). The solution is stirred at room temperature for 45 minutes. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.38 mmol) is added and the reaction mixture is heated at 100° C. overnight, then cooled to room temperature. The reaction mixture is poured into saturated sodium bicarbonate and the solids are collected by filtration. Purification by flash column chromatography eluting with 1:1 hexane:ethyl acetate provides 61 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(2-thienylmethoxy)-3-quinolinecarbonitrile, mp 194-196° C.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-].[Na+].Cl.[C:7]1([C@H:17]([NH:19][CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[C:33]([O:36]CC)(=[O:35])[CH3:34]>>[C:33]([OH:36])(=[O:35])/[CH:34]=[CH:7]/[C:1]([OH:3])=[O:4].[C:7]1([C@H:17]([NH:19][CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Agent: C[C@@H](NCC=Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Product: O=C(O)/C=C/C(=O)O
Reaction time: 1 h

Procedure:
Aqueous solution of sodium bicarbonate (5% in water; 30 mL) was added to a solution of N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride (5.0 g) in ethyl acetate (30 mL) at room temperature and stirred for 1 hour. After completion of the reaction, product was extracted with ethyl acetate (50 mL). The organic layer was washed with water (30 mL), passed through hyflo bed and hyflo bed was washed with ethyl acetate (10 mL). The ethyl acetate layer was concentrated to about 30 mL. Fumaric acid (2 g) was added to the concentrated ethyl acetate layer at room temperature and stirred for about one hour to obtain the precipitates of N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine fumarate. The solid was filtered, washed with ethyl acetate twice (2×10 mL) and dried under vacuum.