Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:42]1[CH2:43][CH2:44][CH:45]([NH:48][C:21]([N:11]2[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:37])[N:9]=[C:10]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:25]=2[O:34][CH2:35][CH3:36])=[O:22])[CH2:46][CH2:47]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methanesulfonyl-piperidin-4-ylamine (prepared as described by Bartkovitz, D. J. et al. WO2004069139) to give the title compound. HR-MS (ES, m/z) calculated for C33H36N4O4SF3Cl2 [(M+H)+] 711.1781, observed 711.1778.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[CH3:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:27])([F:28])[CH3:26])=[C:17]([Cl:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(OCC(C)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (1200 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1000 mg, 3.6 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (1030 mg, 3.6 mmol, Amine-63, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O>>[Cl:12][C:11]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)c(Cl)cc2c1

Procedure:
Followed Scheme 3 where the starting materials were 2,3-dichloro-6-methoxyquinoline (Intermediate 4) and 4-boronobenzoic acid.
Reaction SMILES: [OH-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([C:19]3[N:23]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[N:22]=[CH:21][CH:20]=3)=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=2)[CH2:5]1>CO>[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([C:19]3[N:23]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[N:22]=[CH:21][CH:20]=3)=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH2:5]1
Reactant: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aq. NaOH (180 mL of 2.6 M) was added to a solution of methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (Stage 9.5, 111 g, 299 mmol) in MeOH (270 mL) and the RM was stirred at RT for 14 h. The MeOH was evaporated off under reduced pressure and the aq. residue was treated with brine (90 mL), extracted with MeTHF twice (540 mL+360 mL) and the combined organic layers were washed with water (90 mL). MeTHF was added to the combined aq. layers, the biphasic mixture was cooled to 0° C. and acidified (pH=4-4.5) with aq. HCl solution (18%) and extracted with MeTHF. The combined organic extracts were washed with brine and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from a EtOAc/TBME (1:1) to afford the title compound as a white solid. HPLC (Condition 7) tR=4.74 min, LC-MS (Condition 8) tR=3.37 min, m/z=359.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.44 (br. s, 2H), 1.51 (d, J=11.54 Hz, 2H), 1.64-1.86 (m, 4H), 1.90 (br. s, 1H), 2.31 (d, J=9.29 Hz, 1H), 2.77 (br. s, 1H), 3.10 (br. s, 1H), 3.21 (d, J=8.78 Hz, 2H), 3.27-3.51 (m, 4H), 3.87 (d, J=11.54 Hz, 1H), 4.16 (br. s, 1H), 4.75-4.93 (m, 1H), 5.04 (br. s, 1H), 6.35 (d, J=17.32 Hz, 1H), 7.51-7.64 (m, 1H), 7.64-7.82 (m, 1H), 8.67 (d, J=2.26 Hz, 1H), 12.58 (br. s, 1H).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40](=[S:47])[N:41]([CH3:46])[CH2:42][C:43](O)=[O:44].N>CN(C=O)C.O1CCCC1>[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:36])([F:37])[F:35])[C:25]=1[C:40]([N:41]([CH2:42][C:43]([NH2:2])=[O:44])[CH3:46])=[S:47]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc2c(C(=S)N(C)CC(=O)O)c(F)ccc2c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=S)N(C)CC(N)=O)c(F)ccc2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
1-Hydroxybenzotriazole (0.84 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 1.2 eq) were added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine (1.50 g, 4.15 mmol) in anhydrous DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 13/4 hours, a saturated solution of ammonia in tetrahydrofuran (100 mL) was added to the reaction mixture at room temperature. After 1 hour, the reaction was cooled to 0° C. and ammonia gas was bubbled directly into the reaction mixture for 15 minutes. While still cool, the reaction mixture was filtered and the solid was washed with THF (2×10 mL). The solvent was removed from the filtrate and the residue was diluted with water (500 mL). The aqueous phase was extracted with ether (6×100 mL). The extracts were combined and preabsorbed onto silica gel. The absorbate was flash chromatographed (19:1 chloroform:methanol, silica) and the resulting product was re-flash chromatographed (chloroform to 49:1 chloroform:methanol, silica) to provide the title compound as a light yellow solid (0.30 g, 20%), m.p. 222°-224° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
To a solution of (1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.85 g, 3.22 mmol) in THF (7 mL) was added a solution of LiOH (0.385 g, 16.1 mmol) in water (7 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH 2 using dilute hydrochloric acid. The mixture was concentrated to remove THF and the white precipitate collected and washed with water to give pure product as a white powder (0.571 g, 75.1%); mp 157-158° C. 1HNMR (400 MHz, DMSO-d δ 9.10 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=1.76 Hz, 1H), 5.42 (dd, J=9.67, 2.64 Hz, 1H), 3.73 (s, 3H), 3.01 (dd, J=15.38, 2.49 Hz, 1H), 2.24 (s, 3H), 2.03 (dd, 1H). MS (ESI) m/z=235 [M−H]−.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9].O.O.[I:36](O)(=O)(=O)=O.II>C(O)(=O)C.O>[CH2:6]([O:10][C:11]1[C:20]([I:36])=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1I
Yield: 378.2 %

Procedure:
(The following is performed in a draft chamber.) A mixture of concentrated sulfuric acid (1.5 ml), water (10 ml), and glacial acetic acid (50 ml) was dropped for about 10 minutes into a suspension of 7-butoxy-3-[2-(trans-4-propylcyclohexyl)ethyl]-1,2-difluoronaphthalene(21.4 g, 0.053 mol), periodic acid dihydrate (2.6 g, 0.011 mol), and iodine (5.4 g, 0.021 mol) in glacial acetic acid (100 ml) with vigorously stirring. After stirring at 60° C. for 4 hours, the reaction liquid was cooled, poured into water, and the reaction was terminated. The precipitated solid was dissolved with toluene, the organic layer was separated, and was extracted with toluene from the aqueous layer. After collecting organic layers, it was rinsed, in order, with 10% sodium thiosulfate aqueous solution, with saturated sodium hydrogen carbonate aqueous solution, and with saturated brine, and was dried with anhydrous sodium sulfate. A light yellow solid (21.4 g) was obtained by removing the solvent under reduced pressure and by recrystallizing the obtained orange solid (from acetone). (Yield 73.9%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
A mixture of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (222 g, 0.8 mol), 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (292 g, 0.96 mol) and cesium carbonate (312 g, 0.96 mol) in DMF (1.5 L) was heated at 65° C. for 28 hours. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (105 g, 0.34 mol) dissolved in DMF (150 mL) was added. The mixture was cooled to room temperature and poured into water (5 L) with stirring. The resulting taffy was separated from the supernatant and stirred with ethyl acetate (2.5 L) for 3 hours at room temperature. The resulting suspension was filtered and the filter cake was dried to yield methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate as a solid (245 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=9 Hz, 1H), 8.28 (d, J=1 Hz, 1H), 8.11 (m, 3H), 7.72 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (m, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.93 (s, 3H), 3.47 (m, 1H), 1.33 (d, J=7 Hz, 6H). ES-LCMS m/z 547 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[C:18]([C:36]([F:39])([F:38])[F:37])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[C:18]([C:36]([F:38])([F:37])[F:39])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)OC(C)(C)C)c4)n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)O)c4)n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of tert-butyl 3-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I29) (0.048 g, 0.088 mmol) in DCM (3 mL) was added TFA (0.5 mL); the reaction was then stirred for 35 minutes at room temperature before concentrating under reduced pressure. The residue was taken up in toluene (2×10 mL) and concentrated under reduced pressure. The resulting residue was taken up in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 1 hour then the volatiles removed by evaporation under reduced pressure. The residue was taken up in toluene (2×20 mL) and concentrated under reduced pressure to give the title compound (I30) in quantative yield; 1H NMR (400 MHz, d6-Acetone) b 9.14 (s, 1H), 8.62 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.74 (bs, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.44 (dd, J=7.6, 7.6 Hz, 1H), 7.34 (bd, J=8.0 Hz, 1H), 7.25 (dd, J=8.1, 8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.8 Hz, 1H), 3.60 (m, 4H), 3.47 (m, 4H), 3.20 (m, 4H), 2.94 (s, 3H). LCMS Method C: rt 4.93 min; m/z 486.2 [M+H]+.
Reaction SMILES: O=[C:2]([CH:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH3:10])[CH2:3][C:4]([O:6]CC)=O.[NH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][CH:9]([C:2]1[NH:20][C:18](=[O:19])[NH:17][C:4](=[O:6])[CH:3]=1)[CH3:10]
Reactant: CCOC(=O)CC(=O)C(C)OCC(F)(F)F
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(OCC(F)(F)F)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 160 °C

Procedure:
A mixture of ethyl 3-oxo-4-(2,2,2-trifluoroethoxy)pentanoate (3.29 g, 13.58 mmol) and urea (0.816 g, 13.58 mmol) was heated at 160° C. under nitrogen for 10 h. A solution of potassium carbonate (3.8 g) in water (30 mL) was added and the mixture was extracted with MTBE (20 mL). The aqueous phase was acidified to pH 2 and extracted with MTBE (20 mL). The organic phase was dried over sodium sulfate and concentrated in vacuum to yield the title product, 1.35 g (42%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[O:33])[CH:24]=[CH:25][C:26]=1[O:27][CH:28]([F:30])[F:29]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH:28]([F:30])[F:29]
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(OC(F)F)c(Cl)c1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)F)c(Cl)c2)cc1

Procedure:
93 mg of pale yellow solid 3-{4-[3-(3-chloro-4-difluoromethoxyphenyl)-ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-chloro-4-difluoromethoxyphenyl isocyanate.
Reaction SMILES: [CH:1]1([C:4]([OH:33])([CH3:32])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Cl)[CH:26]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.NC1C(C2C=CC([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[CH:1]1([C:4]([OH:33])([CH3:32])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:11]([C:25]3[CH:30]=[CH:29][C:28]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[CH:27][CH:26]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Product: CC(O)(CNC(=O)c1nc(-c2ccc(NS(C)(=O)=O)cc2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
This compound was prepared in analogy to example 5 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine by N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.Cl>O1CCCC1>[Br:31][C:32]1[CH:39]=[CH:38][C:35](/[CH:36]=[CH:5]/[CH2:4][N:3]([CH3:25])[CH3:2])=[CH:34][CH:33]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)C/C=C/c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2-dimethylaminoethyl)triphenylphosphonium bromide (1.12 g, 2.7 mmol) in tetrahydrofuran (10 ml) was added 2.5 M n-BuLi in hexanes (1.08 ml, 2.7 mmol) under nitrogen at 0° C. After 30 minutes 4-bromobenzaldehyde (0.5 g, 2.7 mmol) was added slowly and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was acidified with 2M hydrochloric acid and extracted with toluene. The aqueous layer was then made alkaline with 2N sodium hydroxide and extracted twice with ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the product as yellow oil. Yield 0.41 g, 63%. LCMS method: 2, RT: 2.62 min; MI: 240-242 [M+1].
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[K+].CO.Cl>C1COCC1>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: [OH-]
Reactant: O=C1CCCCCO1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Caprolactone (100 g) was added to a mixture of potassium hydroxide (145 g), methanol (110 mL), and THF (390 mL). The resulting mixture was stirred at room temperature overnight. The solution was then acidified with HCl and extracted with ethyl acetate. The combined organic layers were washed with water, dried, filtered, and concentrated to obtain 6-hydroxyhexanoic acid. 1H NMR (CDCl3, 500 MHz) δ 1.44 (m, 2H), 1.60 (m, 2H), 1.68 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 5.80 (br, 1H).
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@@H:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C:28]([OH:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C>[CH2:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:34][CH2:33][CH2:32][CH2:31][C@H:27]([NH:26][C:9]([O:11][CH2:12][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])[C:28]([OH:30])=[O:29])=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCCN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.4 %

Procedure:
A solution of 9-fluorenylmethyl N-succinimidyl carbonate (143 mg, 0.42 mmol) in DMF (1.60 mL) was added to a solution of 9 (135 mg, 0.278 mmol) in 9% Na2CO3 (655.9 mg, 0.557 mmol) at 0° C. and stirred at room temperature for 21 hours under argon. The pH was adjusted to 7.0 with 0.1 N HCl. The mixture was concentrated to an oil and purified by flash chromatography (CHCl3, then 95% CHCl3MeOH) to give 10 (115 mg, 58%) as a colorless oil: 1H NMR (19.2° C.) δ1.22-1.92 (m, 10 H), 3.08 (m, 2 H), 3.16-3.30 (m, 4 H), 4.12 (m, 1 H), 4.21 (t, 1 H, J=6.9), 4.30-4.45 (m, 2 H), 5.04(s, 2H), 5.08 (s, 2 H), 7.22-7.42 (m, 14 H), 7.66 (m, 2 H), 7.78 (d, 2 H, J=7.5); HRMS m/z calcd for C41H46N3O8 708.3285, found 708.3284. [δ]22D=+9.3°(c 1.00, CHCl3).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:18])[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[C:16]([F:18])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cc(F)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(F)cc(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 78 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-fluorobenzoate obtained in Example (175b) (50.6 mg, 0.18 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (28 mg, 0.16 mmol), WSC hydrochloride (93.7 mg, 0.49 mmol) and HOBt (22 mg, 0.16 mmol), to obtain 56 mg of the title compound as a pale yellow solid (78%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=3)[N:9]=[C:8]([C:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=3)[C:4]=2[N:5]=[CH:6][N:7]=1>[Pd].CO>[NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH3:21])[CH:12]=3)[N:9]=[C:8]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-n2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(-n2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1N
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of tert-butyl 4-[7-amino-1-(3-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate (200 mg, 0.428 mmol) and 10% palladium on carbon (100 mg) in methanol (20 mL) and hydrogenated in a Parr shaker at 55 psi for 18 hours. The catalyst was removed by filtration through a pad of diatomaceous earth and the filtrate concentrated under reduced pressure then the residue was dissolved methanol (20 mL). Platinum (IV) oxide (100 mg) was added and the mixture was hydrogenated in a Parr shaker at 55 psi for 30 hours. The catalyst was removed by filtration through a pad of diatomaceous earth and the filtrate concentrated under reduced pressure to provide the title compound as a brown solid (175 mg, 93%): 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (s, 1H), 6.96 (d, 1H), 6.84 (d, 1H), 6.74 (d, 1H), 6.5 (bs, 2H), 5.75 (bs, 2H), 4.03 (m, 2H), 3.76 (s, 3H), 3.22 (m, 1H), 2.93 (m, 2H), 1.7-2.1 (m, 4H), 1.42 (s, 9H) RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 16.93 min; MS: MH+ 440.2