Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:26]=1[NH2:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][O:24][C:25]1[CH:31]=[C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2ccc(N3CCOCC3)cc2OC)ncc1C(F)(F)F

Procedure:
Method C was applied to a mixture of 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (23 mg, 0.070 mmol), 2-methoxy-4-morpholinoaniline (23 mg, 0.11 mmol), Pd2(dba)3 (9 mg, 0.0098 mmol), xantphos (8 mg, 0.014 mmol) and cesium carbonate (34 mg, 0.10 mmol) in dioxane (3 ml). The title compound was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]C)=[O:7])=[CH:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[O:13]1[CH2:18][CH2:17][CH:16]([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 21 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (500 mg, 3.0 mmol), tetrahydro-2H-pyran-4-ol (307.3 mg, 3.0 mmol) and PPh3 (944 mg, 3.6 mmol) in THF (15 mL) was added DEAD (627 mg, 3.6 mmol) at 0° C. The mixture was the warmed to 21° C. and stirred for 16 h. The mixture was treated with water and the organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was purified by column chromatography to give the title compound (320 mg, Yield 45%). 1H NMR (CDCl3, 400 MHz): δ 7.92 (d, J=8.9 Hz, 1H), 6.75-6.94 (m, 1H), 4.44-4.59 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 3.83-4.00 (m, 2H), 3.46-3.60 (m, 2H), 1.88-2.05 (m, 2H), 1.67-1.83 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+]C2CCCCC2)CCCCC1.CC(C)(N)CCl>>[CH3:38][N:7]([CH3:1])[CH:8]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:13]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(N)CCl
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C

Procedure:
that N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl-ammonium salt is reacted with dimethyl-aminoethylchloride to form N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.ClC(Cl)(Cl)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 75 %

Procedure:
Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (739 mg), trifluoroacetic anhydride (0.29 mL) as a dehydrating agent and trichloroacetic acid (327 mg) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 524 mg, yield: 75%) by the same method of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[CH:6]=[C:5]2[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC1C=CC=CC=1)=[O:26].O1CCOCC1.O>CO.[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:6]1)=[O:21]
Reactant: O=C(CCCc1cn(C(=O)c2cccc([N+](=O)[O-])c2)c2ccc(Cl)cc12)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3cc(Cl)ccc32)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
To a solution of benzyl 4-[5-chloro-1-(3-nitrobenzoyl)indol-3-yl]butyrate (1.3 g) in a mixture of methanol (35 ml), 1,4-dioxane (35 ml) and water (5 ml) was added 10% palladium on activated carbon (400 mg), and the mixture was stirred under hydrogen atmosphere (3 atm) at 20° C. for 4 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel (40 g) eluting with 2% methanol in chloroform to give 4-[1-(3-aminobenzoyl)-5-chloroindol-3-yl]butyric acid (731 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[I-].[K+]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccccc1F
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [I-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Temperature: 23 °C

Procedure:
A mixture of 2-fluoroaniline (13.0 ml), 2-fluoronitrobenzene (14.2 ml) and potassium iodide (5.5 g) was heated at 180° for 18 h. The mixture was cooled to 23° C.; the solid materials were filtered off and the solution was concentrated in vacuo. The residue was purified by flash chromatography (eluting with CH-EA 7:3) then crystallized from absolute ethanol to give the title compound as an orange solid (9.30 g). T.l.c. CH-EA (7:3), Rf =0.69. M.p. 76°-77° C. IR: 3352 (NH), 1609 (C=C), 1510 and 1350 (NO2) cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:9](=[O:12])[CH:10]=[CH:11][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Temperature: 110 °C

Procedure:
A mixture of 2-amino-5-bromopyridine 10-1 (10 g, 58 mmol), tert-butyl acrylate (50 mL, 344 mmol), triethylamine (50 mL, 359 mmol), tri-o-tolylphosphine (3.0 g, 9.8 mmol) and Pd(OAc)2 (1.0 g, 4.5 mmol) in 150 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was then cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:1) to afford the desired product 10-2 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N:16]#[C:17]Br.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:17]#[N:16])[CH2:9][CH2:10]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: N#CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CN1CCC(Oc2cc(F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (2.0 g, 7.30 mmol) in THF (24.3 ml) was added cyanogen bromide (0.77 g, 7.30 mmol) followed by triethylamine (1.01 ml, 7.3 mmol) at 0° C. The mixture was warmed to rt and further stirred for 1 h. Solvent was evaporated and the residue was diluted with 1N HCl (20 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic fractions were washed with water (20 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford the title compound as a solid which was used in the next step without further purification.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][OH:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A THF solution (1.00 L) of trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (29.70 g, 101.1 mmol) was cooled to −78° C. and was charged with LAH (1M in THF, 25.3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture was charged with additional LAH (25.3 mmol) at −78° C. and then, allowed to stir at −78° C. for 1.5 h. The reaction was slowly warmed up to r.t. and stirred for additional 30 min. Ethyl acetate, Na2SO4.10H2O, and silica gel were added to the reaction mixture and concentrated in vacuo to give an orange solid. The crude mixture was purified by a silica gel glass column chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) to obtain the title compound as a slightly yellow-tinted white solid; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (mc, 1H), 1.84 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br, —OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d, J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS (ES+): m/z 266.21/268.17 (100/89) [MH+]. HPLC: tR=2.38 min (OpenLynx, polar—5 min). MS (ES+): m/z 266.21 (100) [MH+], 268.17 (80) [MH+2}, 289.18 (20) [MH+3]; tR(polar-5 min/openlynx) 2.36 min.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[C:40]1([S:46]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH2:56][CH2:57][N:58]([CH3:75])[C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CN(C)C=O.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:72]([C@@H:60]([C:59](=[O:74])[N:58]([CH2:57][CH2:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:49][S:46]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)(=[O:48])=[O:47])[CH3:75])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:73])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
{(3E)-4-[N-((1R)-1-{N-[2-(2-(Phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}-2-2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester ##STR165## At 0° C., N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of (2E)-5-(tert.-butoxycarbonylamino)-5-methylhex-2-enoic acid (175 mg, 0.72 mmol) and 1-hydroxy-7-azabenzotriazole (98 mg, 0.72 mmol) in dichloromethane (3 ml) and N,N-dimethylformamide (3 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)-N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (363 mg, 0.72 mmol) in dichloromethane (3ml) and ethyldiiso-propylamine (0.13 ml) were added successively. The reaction mixture was stirred for 3 d, while it was warming up to room temperature. It was diluted with ethyl acetate (60 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (60 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (60 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using ethyl acetate/heptane 1:1 as eluent, to give 363 mg of {(3E)-4-[N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: Br.[S:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:37][C:38]1[CH:39]=[C:40]([C:46]2([C:64]([F:67])([F:66])[F:65])[CH2:50][C:49]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[C:53]([C:60]([F:63])([F:62])[F:61])[CH:52]=3)=[N:48][CH2:47]2)[CH:41]=[C:42]([Cl:45])[C:43]=1[Cl:44]>C(OC)(C)(C)C>[S:2]1[CH2:5][CH:4]([NH:6][C:55](=[O:56])[C:54]2[CH:58]=[CH:59][C:51]([C:49]3[CH2:50][C:46]([C:40]4[CH:39]=[C:38]([Cl:37])[C:43]([Cl:44])=[C:42]([Cl:45])[CH:41]=4)([C:64]([F:65])([F:66])[F:67])[CH2:47][N:48]=3)=[CH:52][C:53]=2[C:60]([F:63])([F:62])[F:61])[CH2:3]1
Reactant: NC1CSC1
Reactant: O=C(O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CSC1)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To the solution of thietan-3-amine hydrobromide (40 mg, 0.23 mmol) in 1,2-dichloromethane was added triethylamine (60 mg, 0.59 mmol) at 0° C. After that 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg, 0.23 mmol), 1-hydroxybenzotriazole monohydrate (32 mg, 0.23 mmol), and 4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzoic acid (100 mg, 0.19 mmol) were added to the solution at 0° C. Then the reaction mixture was stirred overnight at room temperature and diluted with t-butylmethylether, and washed with water, and dried over magnesium sulfate anhydrous. After evaporation, the residue was purified with silicagel column chromatography to give 75 mg of N-(thietan-3-yl)-4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=CC(S(Cl)(=O)=O)=C[CH:18]=1.C([O-])(O)=O.[Na+]>CC(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:17]([CH3:27])([CH3:22])[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid (500 mg, 3.154 mmol) was suspended in 2-methylpropan-2-ol (20 ml), followed by addition of pyridine (3 ml) and p-toluenesulfonyl chloride (1.2 g, 6.308 mmol), and then resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was neutralized by slow addition of a saturated aqueous NaHCO3 solution, and then concentrated under reduced pressure, followed by addition of distilled water (5 ml). The precipitated solid was filtered, followed by vacuum drying, to obtain 420 mg of pale yellow solid (62%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27](O)=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:39](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+].CN(C)C(=O)C>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:27]([NH2:39])=[O:28])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(N)=O)cc1OCC2
Reaction time: 1 h

Procedure:
A mixture of 55 mg (0.135 mmol) of (S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid, N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (57.0 mg, 0.150 mmol), N,N-Diisopropylethylamine (52.2 uL, 0.300 mmol) and Ammonium chloride (8.02 mg, 0.150 mmol) in N,N-Dimethylacetamide (3.0 mL, 32 mmol) was stirred for 1 hour. The mixture was concentrated in vacuum, the residue triturated with water, 0.01 N aq HCL, water, dried in vacuum and subjected to RP HPLC and then chiral purification to give 375. Yield 12 mg. M/z 408.2, calc. 407.21. 1H NMR (400 MHz, DMSO) δ 8.19 (d, J=8.9, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.04 (s, 1H), 6.36 (dd, J=9.0, 2.4, 1H), 6.07 (d, J=2.4, 1H), 5.91 (dq, J=13.3, 6.5, 1H), 4.44 (d, J=6.5, 4H), 4.01-3.93 (m, 1H), 3.57 (t, J=7.0, 1H), 3.24 (d, J=9.0, 1H), 2.23 (dd, J=12.1, 6.9, 1H), 1.98 (dd, J=14.8, 11.3, 3H), 1.47 (dd, J=6.6, 3.3, 6H)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1)[CH2:1][CH3:2]
Reactant: C=C(C)COc1ccc(Cl)cc1CNCC
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(N)=O)nn1
Yield: 58 %

Procedure:
A mixture of N-ethyl-5-chloro-2-(2-methylprop-2-en-1-yloxy)benzylamine (reference example 16) (13.8 g, 50 mM), 6-chloropyridazine-3-carboxamide (7.9 g, 50 mM) and di-isopropylethylamine (20.0 ml, 115 mM) in DMF (50 ml) was stirred at reflux for 16 hours. The mixture was cooled and diluted with water (200 ml) giving an oil which was allowed to settle out (1 hour). The supernatant liquor was decanted and the residual brown gum dissolved in dichloromethane (250 ml) and washed with 2N hydrochloric acid (100 ml). The product was obtained by eluting the organic layer through silica, adjusting the solvent to dichloromethane/isopropanol (19:1) and collecting relevant fractions, which were combined and evaporated to give the title compound as a gum (10.5 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:28])([F:27])[F:26])[CH:3]=1.[Cl:32]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:31])[CH:23]([F:29])[O:24][C:25]([F:26])([F:27])[F:28])[C:3]=1[Cl:32]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2N)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.17 h

Procedure:
0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 30 mL of acetonitrile, and 0.27 g of N-chlorosuccinimide was added under cooling with ice. After stirring for 10 minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole. Then, the obtained pyrazole derivative was dissolved in 30 mL of tetrahydrofuran, and 0.3 mL of t-butyl nitrite was added under cooling with ice. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 0.75 of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1>>[F:40][C:37]([F:38])([F:39])[C:32]([C:14]1[CH:15]=[C:16]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)=[CH:12][CH:13]=1)([OH:41])[C:33]([F:36])([F:35])[F:34]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2cccc(F)c2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-fluorophenylboronic acid (20.23 mg, 0.145 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-fluoro-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=4.2 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.53 (s, 1H), 7.42-7.31 (m, 1H), 7.27 (d, J=4.0 Hz, 3H), 7.17 (d, J=8.6 Hz, 1H), 7.09-6.97 (m, 1H), 2.96 (br. s, 8H). m/z (ESI, +ve ion) 568.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.67 μM; GK-GKRP EC50 (LC MS/MS)=1.84 μM.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].[N:10]1[CH:11]=[CH:12][N:13]2[C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=12>C(#N)C>[N:10]1[CH:11]=[CH:12][N:13]2[C:18]([C:19]([NH:9][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[C:7]#[N:8])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: O=C(Cl)c1cccc2nccn12
Reactant: N#CC(N)c1ccco1
Solvent: CC#N
Product: N#CC(NC(=O)c1cccc2nccn12)c1ccco1
Yield: 61 %

Procedure:
α-(2-Furyl)-α-aminoacetonitrile (0.7 g, 5.5 m moles) was dissolved in acetonitrile (20 ml), and imidazo[1,2-a]pyridine-5-carboxylic acid chloride (1.0 g, 5.5 m moles) was added thereto and reacted at room temperature for 2 hours. After completion of the reaction, the solvent was removed from the reaction mixture. To the residue were added water (20 ml), saturated aqueous solution of sodium bicarbonate (50 ml) and chloroform (50 ml), and the mixture was stirred. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography on silica gel (eluent: methanol/chloroform=1/9) to give the object compound (0.9 g, yield 64%) as amorphous solid.