Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]([NH:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)#[N:2].C(OCC)C>C(O)=O>[C:1]([C@@H:3]([NH:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: COCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)cc3)cc21
Solvent: CCOCC
Solvent: O=CO
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4)cc3)cc21
Yield: 86.9 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-cyano-2-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (38 mg) in formic acid (1 mL) was stirred at 50° C. for 10 min. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:24 2M ammonia in methanol/DCM to give, after trituration with diethyl ether, the title compound (27 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([NH:24]C(=O)C(F)(F)F)[CH:3]=1.[Cl-].[Na+]>N1CCCCC1>[NH2:24][C:4]1[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Product: Nc1cc(F)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
1.145 g (0.0027 mol) of 1-benzyl-piperidin-4-yl 4-fluoro-2-trifluoroacetamido-benzoate were suspended in 25 ml of 1N aqueous piperidine in an ultrasound bath for 1/2 hr. and subsequently stirred at room temperature for 48 hrs. The suspension was treated with semi-saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 0.82 g (92%) of 1-benzyl-piperidin-4-yl 2-amino-4-fluoro-benzoate was obtained as a colorless oil. MS:=329 (C19H22FN2O2 +).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[C:7]([CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:8][NH:9][C:10]=2[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:4].[C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=O)[CH2:26][CH2:27][CH3:28].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:25]1([CH2:26][CH2:27][CH3:28])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:15][CH2:16][O:17]1)=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=3[CH3:14])[CH3:35]
Reactant: CNC(=O)c1ccc(C)c2[nH]cc(CCO[Si](C)(C)C(C)(C)C)c12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid methylamide (100 mg, 0.289 mmol) and ethyl butyrylacetate (92 mL, 0.578 mmol) in CH2Cl2 (2 mL) was added BF3.OEt2 (0.11 mL, 0.867 mmol) dropwise at room temperature. After stirring overnight, the solution was diluted with CH2Cl2 (10 mL) and then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 88 mg (82%) of title compound as a yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.54 (bs, 1H), 7.12 (d, J=7.38 Hz, 1H), 6.89 (d, J=7.38 Hz, 1H), 6.05 (d, J=4.71 Hz, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.86 (m, 1H), 3.03–2.83 (m, 7H), 2.48 (s, 3H), 2.00 (m, 2H), 1.37 (m, 1H), 1.25 (t, J=6.84 Hz, 3H), 1.22 (m, 1H), 0.87 (t, J=7.17 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[CH2:16][Br:15])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1cccnc1
Reaction time: 2 h

Procedure:
To a mixture of 3-aminopyridine (11 g.) and triethylamine (13.0 g.) in dry ethyl acetate (300 ml.) was added a solution of bromoacetyl bromide (26.0 g.) in dry ethyl acetate (26 ml.) over a period of 30 minutes with stirring at 0° to 5° C. and stirring was continued for an additional 2 hours at the same temperature. To the reaction mixture was added a chilled aqueous solution of sodium bicarbonate. After shaking well, the ethyl acetate layer was separated, washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and then concentrated. There was obtained concentrate (200 ml.) containing the title compound. Thus obtained concentrate was used directly in the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:3]1.B.C1COCC1.Cl>C1COCC1>[NH2:16][CH2:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:17])([CH3:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: CC1(C)CCCC(Oc2ccc(C#N)cn2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCCC(Oc2ccc(CN)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Dissolve 6-(3,3-dimethyl-cyclohexyloxy)-pyridine-3-carbonitrile (9.14 g, 39.7 mmoles) in THF (20 mL) at 0° C. under nitrogen and add borane-THF complex (119 mL, 119 mmol, 1M solution in THF). Stir the resulting solution overnight while warming to room temperature. Slowly add the reaction mixture to a mixture of 5N aqueous HCl (100 mL) and THF (50 mL) at 0° C. and stir for 2 h. Concentrate in vacuo and take-up the residue in a minimum amount of methanol for filtration through a SCX-2 column (10 g) eluting with methanol followed by 3N ammonia in methanol to obtain the desired intermediate as an oil (5.85 g, 63%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1CBr
Yield: 14.7 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-thiazol-2-ylmethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.551 g, 1.61 mmol), N-bromosuccinimide (0.315 g, 1.77 mmol), and benzoyl peroxide (39 mg, 0.161 mmol) in CCl4 (20 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-60% EtOAc/hexanes) to give 100 mg of the title compound as a orange viscous oil. MS: (+) m/z 423.03 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[C:15](=[CH2:17])[CH3:16].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[CH2:14]([NH:18][CH2:11][CH2:10][C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[C:15](=[CH2:16])[CH3:17]
Reactant: O=C(CCBr)NCc1ccccc1
Reactant: C=C(C)CN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)CNCCC(=O)NCc1ccccc1
Yield: 17 %

Procedure:
N-Benzyl-3-bromopropanamide (6 g), methallylamine (1.9 g) and triethylamine (3.5 ml) in dimethylformamide (12 ml) were heated together under reflux for 21/4 hr, then poured into ethyl actate (100 ml). The organic phase was washed with water (2×100 ml), saturated brine (100 ml) and dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a yellow oil which produced the title compound in 17% yield after column chromatography using ethyl acetate:ethanol (1:1) as eluent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:1][C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCOC(=O)c1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-phenylthiazole-5-carboxylate and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (47.2 mg) with purity >90%. LCMS (pos) m/z 437.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:43]([S:49][CH2:50][CH3:51])=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:43]([S:49][CH2:50][CH3:51])=[N:42][N:41]=5)=[O:61])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(SCC)n4CC(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(SCC)n4CC(C)C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (697 mg) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→9:1 →ethyl acetate→ethanol:ethyl acetate 1:19), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 147) (574.6 mg) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH2:62])[C:57]([CH3:63])=[CH:56]2.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH:62][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[C:57]([CH3:63])=[CH:56]2
Reactant: Cc1cc2cc(F)ccc2n1N
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1c(C)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (340 mg, 1.46 mmol, prepared according to the general procedure described in Example 1, steps 3 and 4), HOAt (248 mg, 1.82 mmol), and HATU (645 mg, 1.70 mmol) in DMF (15 mL) is stirred at rt under N2 for 20 min. 5-Fluoro-2-methyl-indol-1-ylamine (237 mg, 1.44 mmol) and DIPEA (380 μL, 2.18 mmol) are added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)amide (300 mg, 55%) as a solid. MS: 379 (M+H). 1H NMR (300 MHz, CD3OD): δ 9.14 (s, 1H), 8.38-8.20 (m, 3H), 7.56-7.52 (m, 1H), 7.30-7.27 (m, 2H), 7.19-7.16 (m, 1H), 6.96-6.90 (m, 1H), 6.32 (s, 1H), 2.83 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: N#Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56) (150 mg, 0.80 mmol) was coupled to 3-amino-benzonitrile (94 mg, 0.80 mmol) using Method C. The residue was purified by column chromatography eluting with 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:46]1[CH:54]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][C:46]1[CH:54]=[CH:53][C:49]([C:50](=[O:51])[NH2:52])=[CH:48][CH:47]=1)=[O:9]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To the solution of 1 (diclofenac, 890 mg, 3.0 mmol) in 50 mL of N,N-dimethylformamide, hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 616 mg, 4.5 mmol) was added and stirred for 1 h at 0° C. and 3 hs at room temperature. After filtration, the filtrate was evaporated under reduced pressure and the oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (5) was obtained (212 mg, 17% yield).
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.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([CH2:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1CCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1CCC(F)(F)F
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (560 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.6 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (440 mg, 1.6 mmol, Amine-64, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [S:1](/[CH:4]=[CH:5]\[C:6]([OH:8])=O)[C:2]#[N:3].C(N(CC)CC)C.ClC(OCC)=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[S:1](/[CH:4]=[CH:5]\[C:6]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:8])[C:2]#[N:3]
Reactant: C1CCNCC1
Reactant: N#CS/C=C\C(=O)O
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CS/C=C\C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of compound 2 (3.06 g., 0.023 mole) in 60 ml of dry toluene, triethylamine (2.35 g., 0.023 mole) in 10 ml of dry toluene was added dropwise, keeping the temperature of the mixture at 0°-5° C. To the resulting solution was added dropwise, ethyl chloroformate (2.53 g., 0.023 mole) in 15 ml of dry toluene at 0°-5° C. After stirring the mixture for 15 minutes, piperidine (2.0 g., 0.023 mole) in 15 ml of dry toluene was added dropwise at 0°-5° C. The mixture was allowed to warm to room temperature, stirred for an additional 2 hours and filtered. The filtrate was washed with water, dried (MgSO4) and concentrated to give an oil which solidified, 2.6 g. The solid was recrystallized from ethanol: mp 88°-90° C.; IR (KBr) 2175, 1630 cm-1
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH2:27])=[C:23]([CH3:26])[CH:24]=2)[C:19]([CH3:29])([CH3:28])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH:27][C:11]3[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:23]([CH3:26])[CH:24]=2)[C:19]([CH3:29])([CH3:28])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: Cc1cc2c(cc1N)C(C)(C)CCN2C(C)C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Temperature: 100 °C
Yield: 55.2 %

Procedure:
To a solution of ethyl 4-bromobenzoate (0.98 g, 4.3 mmol) and (1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amine (Compound 19, 0.69 g, 3.0 mmol) in 15.0 mL of toluene stirring under argon was added cesium carbonate (1.84 g, 5.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol) and BINAP (68 mg, 0.11 mmol) consecutively. The reaction mixture was then heated at 100° C. for 48 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl ether (2×). The combined organic extracts were washed with brine and dried (MgSO4). The filtered solution was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound (0.63 g, 56% 2 steps) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O.ClCCl>[CH2:28]([O:27][C:21]1[CH:22]=[C:23]([N:35]2[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])=[O:30])[CH3:29]
Reactant: CN1CCCNCC1
Reactant: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 65.6 %

Procedure:
5-Fluoro-2-[4-fluoro-2-ethoxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (135 mg, 0.31 mmol) and 1-methylhexahydro-1,4-diazepine (177 mg, 1.55 mmol, 5 eq) were dissolved in 250 μL DMSO, in a 4 mL screw cap vial. The pale yellow solution was incubated at 100° C. for 36–40 hours. The solution was cooled, diluted with 12 mL of dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated in vacuo. The crude residue was purified first by chromatography on a silica gel cartridge (2 g/12 cc, Varian Sample Preparation Products, Harbor City, Calif.) using zero to ten percent methanol in dichloromethane, then by radial chromatography with zero to ten percent methanol in dichloromethane. Pure fractions were pooled, concentrated in vacuo and dried under high vacuum to yield 107 mg (65%) of the title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[O:8]=[C:9]1[O:13][N:12]=[C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OCC[Si](C)(C)C)[CH2:16][CH2:15]2)[NH:10]1>>[ClH:1].[NH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[NH:10][C:9](=[O:8])[O:13][N:12]=2)[CH2:19][CH2:18]1
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1CC[C@H](c2noc(=O)[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](c2noc(=O)[nH]2)CC1
Reaction time: 23 h

Procedure:
4N hydrochloric acid/1,4-dioxane solution (3.5 ml) was added to the compound (349 mg, 1.06 mmol) obtained in Step 6 above at room temperature and the resulting mixture was stirred for 23 hours. The reaction mixture was concentrated under reduced pressure to give 234 mg (100%) of the title compound as a colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10](=[O:19])[CH2:11][C:12]1[NH:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([C:11]1[CH:25]=[CH:24][C:23](=[O:26])[N:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[NH:13][C:12]=12)=[O:19]
Reactant: C#CC(=O)OC
Reactant: Cc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.05 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methylphenyl)ethanone hydrochloride (example XXIII), 65 mg (1.20 mmol) of sodium methylate and 88 mg (1.05 mmol) methyl propiolate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:3]=1[NH:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:74][O:75][CH2:76][CH2:77][NH2:78]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:3]=1[NH:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:78][CH2:77][CH2:76][O:75][CH3:74])=[O:40])=[CH:36][CH:35]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccc(C(=O)O)cc2)c(NS(=O)(=O)CCC)c1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccc(C(=O)NCCOC)cc2)c(NS(=O)(=O)CCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-{[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1-sulfonylamino)-phenylamino]-methyl}-benzoic acid (200 mg), TBTU (300 mg), N,N-diisopropylethylamine (536 μl) and 2-methoxyethylamine (134 μl) in DMF (2 ml) was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHCO3.