Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[CH3:19])[CH:13]([CH3:14])[CH3:15]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then 2-methyl-benzoyl chloride (4.64 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.47 g of brown liquid. MS: m/e 333(M++1), 332(M+), 287(M+—OCH2CH3), 197(M+—CH3C6H4CO2), 119(base), 91, 77.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH2:4].CN(C)C1C=CC=CC=1.[Br:19][CH2:20][C:21](Br)=[O:22]>C(OCC)(=O)C>[Br:19][CH2:20][C:21]([NH:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])=[O:22]
Reactant: O=C(Br)CBr
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C(CBr)NCC(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
2,2,3,3,3-Pentafluoropropylamine (produced by Synquest) (389 g) was dissolved in ethyl acetate (1.56 l), and N,N-dimethylaniline (316 g) was added thereto. The resulting mixture was cooled to −10° C., and bromoacetyl bromide (500 g) was added dropwise thereto, followed by stirring the resulting mixture at a temperature between 10° C. and 0° C. for 2 hours. After completion of the reaction, the organic layer was sequentially washed with hydrochloric acid, aqueous sodium bicarbonate and with brine, and dried over magnesium sulfate, followed by evaporation under reduced pressure to obtain 678 g of 2-bromo-N-(2,2,3,3,3-pentafluoropropyl)acetamide as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 94.8 %

Procedure:
The general hydrolysis protocol, described for 195 was followed. Thus, 1,1-dimethylethyl (2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate (212) (0.190 g, 0.41 mmol) was treated with TFA in CH2Cl2 to afford 0.158 g (95%) of the title compound 213 as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.68 (s, 1H), 7. 40 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 2.83 (d, J=5.7 Hz, 4H), 2.11 (s, 3H), 1.22 (s, 12H). LCMS (ESI): m/z 405 (M−H)−. Anal. Calcd for C26H30O4, C, 76.82; H, 7.44; Found: C, 74.81; H, 7.42.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: CCCBr
Reactant: O=c1cc(I)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc(I)cc1=O
Temperature: 25 °C

Procedure:
2.00 g (9.05 mmol) 4-iodo-2-pyridone (XXII.1) are added to 1.00 mL (10.9 mmol) 1-bromopropane and 3.13 g (22.6 mmol) K2CO3 in 10 mL DMF. The mixture is stirred at rt over night. After that time, water is added and the mixture is extracted with EtOAc. The organic layer is washed with aq. NaHCO3 solution, dried over sodium sulphate and the solvent is removed in vacuo. The residue is purified by RP-HPLC (water+0.15% FA, MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)=[CH:33][CH:34]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(C(F)(F)F)c2)cn1
Yield: 76.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 2-methoxy-5-pyridineboronic acid (0.065 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.081 g) as a colorless solid. MS (ISP): 497.3 (M+H)+
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:23])([CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26][O:17][C:16](=[O:18])[CH:15]([O:19][CH2:20][CH3:21])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH3:22])([CH3:23])[O:6][SiH2:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen atmosphere 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid (0.135 g, 0.4 mmol) and 2,2,2-trichloro ethanol (0.06 g, 0.4 mmol) were dissolved in dry DCM (5 mL) and DMAP (2 mg, 0.02 mmol) was added followed by EDC×HCl (0.092 g, 0.48 mmol) at 0° C. The mixture was stirred for 18 h at ambient temperature, then diluted with DCM and extracted with aq. HCl (2N) and water. The organic layer was separated, dried (MgSO4) and evaporated to afford the crude product which was used in the next step without further purification (0.176 g, 93.6%). 1H NMR (400 MHz, CDCl3): δ 7.12-7.19 (m, 4H), 4.62-4.71 (q, 2H), 4.63 (s, 2H), 4.05-4.08 (m, 1H), 3.55-3.59 (m, 1H), 3.27-3.31 (m, 1H), 2.92-3.03 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 55 mg of 1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 80 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 62 mg of the title compound as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C=O)C.[Na+].[I-]>[O:1]1[CH2:2][CH2:3][CH:4]([S:20][C:18](=[O:21])[CH3:19])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCOCC1
Temperature: 50 °C
Yield: 81.3 %

Procedure:
To a solution of 300 g (1.175 mol) of toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester in DMF (3 L) are added 268 g (2.35 mol) potassium thioacetate, followed by a catalytic amount of NaI (0.12 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between TBME (3 L) and water (3 L), the aqueous layer is extracted with TBME (2 L), then saturated with NaCl and extracted again with TBME (2×2 L). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 153 g of thioacetic acid S-(tetrahydro-pyran-4-yl)ester. Yield: 81%; ES-MS: m/z 161 [M+H]; 1H-NMR (250 MHz, CHLOROFORM-d) δ ppm 1.47-1.98 (4 H, m), 2.30 (3 H, s), 3.41-3.74 (3 H, m), 3.88 (2 H, dt, J=11.76, 3.86 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl>>[ClH:1].[ClH:50].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][NH:27][CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCNC2
Yield: 94 %

Procedure:
tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (145 mg, 0.278 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (114 mg, 94%) as a yellow solid: mp 275-280° C.; 1H NMR (500 MHz, CD3OD) δ 8.61 (s, 1H), 7.77 (dd, J=8.3, 3.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.47 (d, J=1.6 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz, 1H), 6.37 (dd, J=7.6, 3.8 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J=6.1 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H); ESI MS m/z 421 [M+H]+; HPLC (Method B) 98.5% (AUC), tR=12.1 min
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[CH:6]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Cc1cnn(-c2cc(N)cc(C(F)(F)F)c2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4cc(C)cn4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (160 mg, 0.663 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (274 mg, 0.663 mmol) in pyridine (8 mL) was added T3P® (2111 mg, 3.32 mmol) in portions. Then the mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (200 mg, 0.263 mmol, 39.7% yield). 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=9.0 Hz, 3H), 6.91 (d, J=8.8 Hz, 2H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:8]=2[C:7](=[O:19])[C:6]=1[CH3:20])=[O:4].[OH-].[Na+]>CO>[CH3:20][C:6]1[C:7](=[O:19])[C:8]2[CH2:14][S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:9]=2[O:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c(c(=O)c1C)CSc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)oc2c(c1=O)CSc1ccccc1-2

Procedure:
A mixture of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid methyl ester (1.60 g, 5.56 mmoles, described in Example 7) in a solution of sodium hydroxide (0.5 g) in methanol (50 ml) is refluxed for 2 hr and evaporated. The residue is dissolved in water, and the solution is washed with diethyl ether and added with stirring to 3N hydrochloric acid (25 ml). The fine precipitate is collected, washed with very dilute hydrochloric acid, small amount of water and then dried (1.506 g), mp 299°-301° C. The precipitate is crystallized from dimethyl sulfoxide-water to obtain crystals of the title compound, mp 302°-303° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[N:25]([CH2:40][CH:41]4[CH2:44][NH:43][CH2:42]4)[CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=4)[N:28]=3)[CH2:20][CH2:19]2)[N:12]=[CH:11][N:10]=1.C(O)=O.C=O>C(O)C>[NH2:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[N:25]([CH2:40][CH:41]4[CH2:44][N:43]([CH3:2])[CH2:42]4)[CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:39])[F:38])[CH:30]=4)[N:28]=3)[CH2:20][CH2:19]2)[N:12]=[CH:11][N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CNC2)CC1
Agent: C=O
Solvent: CCO
Solvent: O=CO
Product: CN1CC(Cn2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C(N)=O)CC2)C1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-6-{4-[1-azetidin-3-ylmethyl-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide trifluoroacetate (2) (25.00 mg; 0.03 mmol; 1.00 eq.) in ethanol 1 ml added formic acid (0.00 1 ml; 0.08 mmol; 2.50 eq.) and formaldehyde (0.001 ml; 0.04 mmol; 1.20 eq.), stirred at 65° C. for 3 hr. lc-ms showed clean desired peak. Removed off solvent, purified by HPLC, collected title compound 14.8 mg. LC-MS (M+1=533, obsd.=533).
Reaction SMILES: [CH3:1][C:2]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:5].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:2]=1[CH3:1])=[O:13]
Reactant: NO
Reactant: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)O)c2C)c(OC)c1
Agent: Cl
Product: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)NO)c2C)c(OC)c1
Yield: 35 %

Procedure:
The procedure of the step 3 in Example 80 was repeated except that 6-(2-methyl-3-(2,4-dimethoxyphenyl)-benzamido)hexanoic acid instead of 6-(3-bromo-2-methylbenzamido)hexanoic acid, and hydroxylamine hydrochloride instead of 1,2-phenylenediamine were used and purified by a preparative HPLC (C18, 20% H2O/CH3CN, 20 ml/min) to obtain the title compound (27 mg, 35%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([N:8]2[CH2:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a solution of 4-acetamidopiperidine (2.5 g, 17.5 mmol) in DMF (10 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol) and K2CO3 (2.9 g, 21.2 mmol). The reaction was heated at 120° C. for 4 hours, diluted with H2O, and extracted with EtOAc. The organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (3.1 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
In a mixed solvent of 2 ml of ethanol and 2 ml of tetrahydrofuran was dissolved 21.8 mg of ethyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetate, followed by addition of 0.25 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, which was then neutralized with 2N hydrogen chloride. The crystalline deposited was filtered and washed in water followed by drying, to obtain 4.0 mg of 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetic acid. The spectrometric data thereof supports the structure of [39] as follows.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Cl[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([NH:4][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7])[C:2]#[CH:3]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C#CCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
5.5 g (0.1 mol) of propargylamine were added dropwise with stirring at ambient temperature to a suspension of 27.3 g (0.1 mol) of 11-chlorocarbonyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 10.0 g (0.1 mol) of triethylamine in 500 ml of chloroform, whereupon the temperature rises to 35° C. The mixture is stirred for a further 30 minutes at 40° C., then filtered over activated charcoal and the reaction solution is evaporated to dryness in vacuo. After the oily residue has been decocted with ethyl acetate the desired product is obtained in the form of a colourless crystalline mass in a yield of 20.7 g (71% of theory).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])=[CH:42][C:43](Cl)=[O:44]>C(Cl)Cl>[CH3:40][C:41]([CH3:46])=[CH:42][C:43]([NH:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32])=[O:44]
Reactant: CC(C)=CC(=O)Cl
Reactant: N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 1.18 g (2.64 mmol) of 3(R)-amino-1,3,4,5-tetrahydro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2H-1-benzazepin-2-one, hydrochloride (Example 4, Step C) in 30 mL of methylene chloride under nitrogen at -15° C. was added 0.923 mL (2.64 mmol) of triethylamine followed by 0.294 mL (2.64 mmol) of 3,3-dimethylacryloyl chloride. The reaction mixture was stirred at -15° C. for 2 hours then quenched by the addition of 1N hydrochloric acid. The mixture was diluted with 50 mL of methylene chloride and washed with 50 mL of 1N hydrochloric acid and brine. The organic layer was removed and concentrated to dryness under vacuum. The residue was redissolved in 30 mL of methanol and treated with 1.5 mL of 9N hydrochloric acid. After stirring for 30 minutes, the mixture was concentrated to dryness under vacuum to give 1.3 g (2.63 mmol, 99%) of the product as a white solid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][O:31]C5CCCCO5)[CH2:26][CH2:25]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.O>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCC(COC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCC(CO)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
4-(Tetrahydro-pyran-2-yloxymethyl)-piperidine-1-carboxylic acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.070 g) was dissolved in methanol (1 mL). Pyridinium toluene-4-sulfonate (11.0 mg) was added and the reaction mixture stirred at 55° C. for 1 h. The reaction mixtures was diluted with water and extracted with ethyl acetate. The combined organic phases were dried on sodium sulfate, evaporated and the residue was subjected to column chromatography (silica gel, dichloro methane:methanol gradient=100:0→90:10) to yield the title compound (35 mg; 60%) as an off-white solid; MS: m/e=416.7 (M+H+).