Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[O:4]1.[H][H]>[Co].CO>[C:3]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:5][O:4]1)=[O:2]
Reactant: [H][H]
Reactant: COC1OC(=O)c2ccccc21
Agent: [Co]
Solvent: CO
Product: O=C1OCc2ccccc21
Temperature: 120 °C
Yield: 99 %

Procedure:
The autoclave described in Example 1 is filled with 106.6 g of 3-methoxyphthalide, 400 ml of methanol and 15 g of RCH 45/20 cobalt catalyst (commercial product of Hoechst AG). After the addition of hydrogen to a pressure 100 bars, the autoclave is heated at 120° C., the pressure increasing to about 113 bars. After a temperature of 120° C. is reached, the pressure drops to 100 bars and is brought back up to 120 bars by another injection of hydrogen. After 2 hours of reaction at 120° C., the pressure has dropped again to 100 bars; the mixture is cooled, relieved of pressure, and filtered of catalyst. After withdrawal of the solvent, 86.2 g of phthalide (99% of the theory) is obtained having a melting point of 72°-73° C. (GC analysis 99.2% phthalide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([OH:24])=[N:12][CH:13]=[CH:14]2)=[N:9]1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:13]=[CH:14]2)=[N:9]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol (I-9A-1b: 150 mg, 0.421 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (107 mg, 0.463 mmol) and Cs2CO3 (151 mg, 0.463 mmol) in DMF (2.1 ml) were stirred overnight at room temperature. The reaction mixture was extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo, and then purified on a Biotage™ Flash 12M column using 0-40% ethyl acetate in hexanes as eluant to give the title compound 9A-1 (145 mg, 79%) as a colorless solid: +ES MS (M+1) 438.3; 1H NMR (CD2Cl2) 67 7.70 (d, J=6.2 Hz, 1H), 7.59-7.56 (m, 1H), 7.52-7.43 (m, 3H), 7.38-7.34 (m, 2H), 7.29-7.25 (m, 3H), 5.03 (br s, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20][CH3:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[C:8]([NH2:22])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:23]1([CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:20][CH3:21])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:22])[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCC3)c2n1
Temperature: 50 °C

Procedure:
2-(Butyloxy)-9-(4-chlorobutyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.305 mmol), azetidine (0.021 ml, 0.305 mmo1) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 48 hours. LCMS indicated the reaction to be incomplete and additional azetidine (0.021 ml, 0.305 mmol) and N,N-diisopropylethylamine (0.107 ml, 0.610 mmol) were added and the reaction mixture heated at 50° C. for a further 48 hours. The mixture was then partitioned between DCM (4 ml) and water (4 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (4 ml) and the combined organic extracts were concentrated and the residue purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (7.6 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH:46]([S:48]([CH3:51])(=[O:50])=[O:49])=C.FC(F)(F)C(O)=O>CCO>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH3:32])[CH:26]2[CH2:31][CH2:30][N:29]([CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:28][CH2:27]2)=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: C=CS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
To 40 mg (0.07 mmol) of amine 7-2 in EtOH was added 15 μL (0.11 mmol) of triethylamine and 10 μL (0.11 mmol) of methyl vinyl sulfone. After stirring for 60 min, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 13-1 as a white solid. Data for 13-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.3 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.15 (m, 2H), 3.05 (s, 3H), 3.0 (m, 2H), 2.9 (s, 3H), 2.85 (m, 2H), 2.2 (m, 2H), 1.9-1.7 (m, 4H) ppm. HRMS (ES) calc'd M+H for C27H33F2N3O4S1: 534.2233. Found: 534.2218.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].II>C(OCC)C.C1(C)C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[OH:12]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(F)cc(F)cc21
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(O)CCc2c(F)cc(F)cc21
Reaction time: 24 h
Yield: 110.7 %

Procedure:
A mixture of 4,6-difluoro-1-indanone (12.6 g, 0.08 mol), ethyl bromoacetate (19.0 g, 0.11 mol, Aldrich), activated zinc powder (7.5 g, 0.11 mol, Aldrich; Org. Syn., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether:toluene (1:1, 300 mL) was heated at 30°-35° C. under a nitrogen atmosphere for 24 h. A few more crystals of iodine were added, the temperature was adjusted to 40°-45° C., and the mixture was kept at that temperature for an additional 24 h. The reaction mixture was filtered and concentrated in vacuo. The residue was treated with a mixture of diethyl ether (450 mL), concentrated ammonium hydroxide (135 mL) and water (135 mL). The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 22.7 g of crude Ethyl 2-(4,6-difluoro-1- hydroxy-1-indanyl)acetate which was Chromatographed on silica gel with dichloromethane:hexanes (9:1) as eluent gave 12.7 g (66%) of a yellow oil; NMR (CDCl3): d 6.67-6.88 (m, 2H), 4.22 (q, 2H), 3.02 (m, 1H), 2.75 (2 m's, 3H), 2.31 (m, 2H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[CH2:25][C:26]([NH:28][NH:29][C:30](=O)[CH3:31])=[O:27].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[CH2:25][C:26]1[O:27][C:30]([CH3:31])=[N:29][N:28]=1
Reactant: CC(=O)NNC(=O)Cc1nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(C)c1C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nnc(Cc2nnc(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(C)c2C)o1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
Acetic acid N′-(2-{4,5-dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazin-3-yl}-acetyl)-hydrazide (114 mg, 0.248 mmol) is added to a round-bottom flask under N2 followed by acetonitrile (3 mL), diisopropylethylamine (0.27 mL, 1.43 mmol) and triphenylphosphine (115.5 mg, 0.44 mmol) and the reaction is stirred for 30 min. Hexachloroethane (77.5 mg, 0.329 mmol) is then added and the reaction is stirred for 16 h. The crude mixture is purified via HPLC (ammonium hydroxide as a modifier) to afford the title compound (8 mg, 7%).
Reaction SMILES: C([NH2:5])(C)(C)C.C(O)C.[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10].[OH2:16]>>[OH:16][NH-:5].[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10]
Reactant: CC(C)(C)N
Reactant: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: [NH-]O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of compound 25.4 (0.027 g), ethanol (1.5 mL), TFA (0.6 mL) and water (0.5 mL) was stirred at 60° C. for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC to afford compound 25.6 as a TFA salt (0.014 g, 51%). 1H NMR (CD3OD): δ 1.4 (t, J=8 Hz, 6H), 2.9 (M, 4H), 3.2 (m, 2H), 3.58 (brs, 2H), 3.65 (m, 2H), 4.25 (m, 4H), 4.42 (d, J=10 Hz, 2H), 4.85 (m, 2H), 6.75 (d, J=9 Hz, 2H), 6.9 (m, 4H), 7.0 (d, J=9 Hz, 2H), 7.4-7.6 (m, 6H), 8.1 (brs, 2H). 31P NMR (CD3OD): δ 20.8. MS: 769 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:37][CH:47]([CH3:51])[CH3:48])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCCC(C)C)c4)cc23)CC1
Yield: 49.4 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.6 mg of the title compound (49.4%).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])C)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:38]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH2:22]([O:29][C:30](=[O:37])[C:31]([CH3:38])([NH:32][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:21])=[O:20])=[CH:15][CH:14]=1)[CH2:33][CH2:34][CH3:36])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(C)(NC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1)C(=O)OCc1ccccc1
Yield: 77.7 %

Procedure:
To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (3.0 g), L-leucine benzyl ester (4.2 g), triethylamine (1.6 ml), and HOBT (1.6 g) in dry DMF (50 ml) at room temperature was added EDCl (2.4 g). After 16 h the mixture was poured into water (400 ml) and extracted with EtOAc (400 ml×2). The combined organics were washed with 5% citric acid (100 ml); saturated NaHCO3 (100 ml); water (100 ml), brine (100 ml); dried over MgSO4; filtered, and concentrated under reduced pressure to about 100 ml. The resulting suspension was filtered to give 4.0 g of the title compound as a white solid. MS [M+1]+ 488.2; 1H nmr (400 MHz, DMSO-d6) δ0.79 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 1.45-1.63 (m, 3H), 2.21 (s, 3H), 3.37 (s, 2H), 4.26-4.31 (m, 1H), 5.07 (s, 2H), 6.91 (t, 1H), 7.09-7.15 (m, 4H), 7.29-7.37 (m, 7H), 7.81 (d, 1H), 7.86 (s, 1H), 8.44 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]([CH3:12])(O)[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(O)=O.C1(C=CC(O)=CC=1)O>C(OC(=O)C)(=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH2:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(C)(O)C1=O
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: C=C1NC(=O)N(CCCC)C1=O
Temperature: 120 °C

Procedure:
3-n-Butyl-5-methyl-5-hydroxyhydantoin (5.1 g 0.027 mole) was added to an ice-cold solution of 80% formic acid (50 ml) in acetic anhydride (60 ml) containing a small amount of hydroquinone (0.1 g) and the mixture heated on an oil-bath at 120° C. for 15 minutes. The mixture was then cooled to room-temperature and the solvents removed on the rotary evaporator under reduced pressure, yielding an oil which readily crystallised. The title product was crystallised from ethyl acetate-light petroleum (b.p. 40°-60° C.) to yield the product as prisms, m.p. 73° C. Yield=4.3 g=94%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])O[N:5]([C:9]2[CH:14]=[CH:13]C(Cl)=C(Cl)C=2)[C:3]1=[O:4].CC([C:21]1OC(=O)N(C2C=C(OCC#N)C(Cl)=CC=2Cl)[N:22]=1)(C)C.[CH3:39]C(OC1C=C(N2N=C(C(C)(C)C)OC2=O)C(Cl)=CC=1Cl)C>>[CH3:39][CH:14]([CH2:9][NH:5][C:3]([N:2]1[C:7](=[O:8])[NH:22][CH2:21][CH2:1]1)=[O:4])[CH3:13]
Reactant: CC(C)(C)c1nn(-c2cc(OCC#N)c(Cl)cc2Cl)c(=O)o1
Reactant: Cn1c(=O)on(-c2ccc(Cl)c(Cl)c2)c1=O
Reactant: CC(C)Oc1cc(-n2nc(C(C)(C)C)oc2=O)c(Cl)cc1Cl
Product: CC(C)CNC(=O)N1CCNC1=O

Procedure:
methazole, oxadiargyl, oxadiazon
Reaction SMILES: C(OC([NH:11][C@H:12]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[C:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH2:11])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])([CH3:22])([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
Under nitrogen atmosphere, palladium-activated carbon (10% Pd, 0.30 g) was added to a solution of 2.75 g of the compound obtained in Step 78-1 in EtOH (30 ml) and the inside of the reaction system was displaced with hydrogen gas. The solution was stirred at room temperature for two hours, then, the reaction solution was filtered, and the solvent was filtered out under reduced pressure to obtain 1.97 g of residue (pale yellow oil). The present compound was used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:38][CH:37]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)cc1
Yield: 53.9 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxybenzylamine (0.27 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 53%) as a white solid. MS (ISP) 590.2 [(M+H)+]; mp 126° C. (dec.).
Reaction SMILES: CC1CCCO1.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]3[CH2:20][CH2:21][CH:16]2[CH2:17][CH2:18]3)=[CH:11][C:10]=1[C:22]([F:25])([F:24])[F:23].[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[C:37]([F:40])([F:39])[F:38])[NH:30][CH:29]=[C:28]1[C:41](O)=[O:42].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>O>[CH:16]12[N:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:41]([C:28]4[C:27](=[O:26])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][C:35]=5[C:37]([F:40])([F:38])[F:39])[NH:30][CH:29]=4)=[O:42])=[C:10]([C:22]([F:25])([F:23])[F:24])[CH:11]=3)[CH:19]([CH2:18][CH2:17]1)[CH2:20][CH2:21]2
Reactant: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 45 °C

Procedure:
2-Methyltetrahydrofuran (1 vol) was charged into a 30 L jacketed reactor vessel followed by the addition of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11B) (1.2 eq) and 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7) (573 g, 2.228 mol). An additional 2-methyltetrahydrofuran (9 vol) was charged into the vessel and stirring commenced. T3P in 2-methyltetrahydrofuran (2 eq) was added to the reaction mixture over a period of 15 min. Pyridine (3 eq) was added rapidly in a dropwise fashion using an addition funnel. Under stirring, the mixture was then heated to 45° C. over a period of about 30 min and this temperature was maintained for about 5 h. The mixture was cooled to room temperature. 2-Methyltetrahydrofuran (4 vol) was added, followed by the slow addition of water (6.9 vol), and the temperature of the reaction was kept below 30° C. The water layer was removed and the organic layer was washed twice with NaHCO3 saturated aqueous solution. The organic layer was then carefully washed with 10% w/w citric acid (5 vol) and water (7 vol), polished filtered, and then transferred into another dry vessel. 2-Methyltetrahydrofuran (10 vol) was added and stirring commenced. Heptane (10 vol) was rapidly added in a dropwise fashion with stirring. The mixture was stirred for a period of about 12 h, and then was vacuum filtered. The solid filter cake was introduced into another vessel. Water (15 vol) was charged into the vessel and the suspension was stirred vigorously for 48 h, and then filtered. The solid cake was washed with water (5 vol) and dried at 45° C. to constant weight to give Compound I, Form B.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:17]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1)=[O:6].[OH-:32].[Na+].[CH3:34][C:35](O)=O.O>>[CH3:14][CH2:13][CH:16]([CH2:17][CH2:18][C:19]([OH:32])([CH2:35][CH3:34])[CH3:20])[CH3:21].[O:6]1[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: [OH-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: O
Product: CCC(C)CCC(C)(O)CC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ncno4)ccn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine. HCl (30 mg, 0.43 mmol) was added to 3-{3-[3-(2,2,2-trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (135 mg, 0.3 mmol) and 5N NaOH (75 μl, 0.38 mmol) in AcOH/H2O (7:3, 1 ml) at RT. The reaction mixture was stirred at room temperature for 2 h before being heated at 60° C. for 7 h. The reaction mixture was allowed to cool then the volatiles removed in vacuo. The residue was purified by preparative HPLC to afford the desired product (35 mg). MS: [M+H]+ 403.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=2)[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(I)cn1)S(C)(=O)=O
Reactant: OB(O)C1=CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCC2)cn1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
Ethyl (2R)-4-(4-iodo-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (100 mg, 0.25 mmol, 1 eq) was weighed into a 40 mL vial equipped with a septa cap. Cyclopent-1-en-1-ylboronic acid (97 mg, 0.5 mmol, 2 eq) and potassium phosphate (159 mg, 0.75 mmol, 3 eq) was added, followed by PdCl2(PPh3)2 (18 mg, 0.025 mmol, 0.1 eq). The vial was evacuated and backfilled 3 times with nitrogen gas. 2-MeTHF (9 mL) and water (1 mL) were added to the vial and the mixture heated at 100° C. overnight. The reaction mixture was then filtered through celite and eluted with MeOH. The crude product mixture was then purified by flash chromatography on a 25 g silicycle silica gel column eluting with 20% EtOAc/Hpt to give ethyl (2R)-4-[4-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate which was used without further purification. LC-MS M+H+341.4.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].Cl.[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[C:12]([F:14])=[CH:13][C:2]=1[Cl:1])[CH3:9]
Reactant: COC(=O)CCN
Reactant: CC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CCNC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-[2-Chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]propionic acid (20 g) and β-alanine methyl ester hydrochloride (8.2 g) were dissolved in dichloromethane (200 mL). After slowly adding 4-methylmorpholine (14.8 g) dropwise to the reaction mixture, stirring was performed for 1 hour. After adding (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (18.5 g) for 30 minutes, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (24 g) including a trace amount of impurities, which was recrystallized twice using a mixture solvent of ethyl acetate and hexane to give the target compound (18.2 g).