Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.O.[OH-].[Li+]>O1CCCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1I)C=C(C(=O)O)C(C(F)(F)F)O2
Yield: 89.3 %

Procedure:
To the solution of 3.0 g (7.0 mmol) of ethyl 6-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 50 mL of tetrahydrofuran was added a solution of 1.2 g (28 mmol) of lithium hydroxide hydrate in 55 mL of water. The resulting solution was heated to reflux for four hr. The volatiles were removed. The residue was diluted with water. The resulting solution was acidified at 0° .C with dilute hydrochloric acid to pH=1.5. The product was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concd to afford 2.5 g (81%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.56(s, 1H), 7.52(s, 1H), 6.42(s, 1H), 5.60(q, J=6.8 Hz, 1H), 3.81 (s, 3H). MS (ESI+) 400.9 (M+1, 100). MS(ES−) 398.9(M−H, 100). HRMS (ES−) m/z calcd for (C12H7F3O4) M−H: 398.9336, found 398.9359.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[C:27](O)=[O:28])=[CH:21][CH:20]=2)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:36][CH:37]=3)[C:27]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:28])=[CH:21][CH:20]=2)=[N:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Prepared using General Procedure 7. A stirring solution of β-alanine tert-butyl ester hydrochloride (4.9 g, 27.4 mmol), (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid (12.0 g, 24.9 mmol) and DIEA (11.1 mL, 62.0 mmol) in DMF (200 mL) was cooled to 0° C. A solution of HATU (9.9 g, 26.1 mmol) in DMF (75 mL) was added dropwise over 20 min. The reaction mixture was allowed to warm to room temperature over 2 h, then diluted with EA and washed with NaHCO3 (sat aq). The aqueous fraction was back-extracted with EA. The combined organic fractions were dried (Na2SO4) then concentrated onto celite and purified by column chromatography (EA/hexane) to provide 11 g (65%) of tert-butyl (S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoate INT-28. LCMS-ESI (m/z) calculated for C31H37BrN4O4; 609.6. found 610.2 [M+H]+, tR=3.99 min (Method 15), and 87.1% e.e. (Chiral Method, isocratic with 20% Solvent A, 80% Solvent B). 1H NMR (400 MHz, CDCl3) δ8.80 (s, 2H), 8.32 (t, J=6.5 Hz, 2H), 7.74-7.62 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 4.93-4.81 (m, 1H), 3.52-3.34 (m, 2H), 3.34-3.14 (m, 2H), 2.46-2.24 (m, 2H), 1.34 (d, J=5.2 Hz, 9H), 1.31 (d, J=5.2 Hz, 9H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].[C:31]1(C)[C:32]([CH3:37])=[CH:33][CH:34]=CC=1>>[CH3:1][C:32]([CH3:37])([CH3:31])[CH2:33][CH:34]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=C(O)CCCCCCCBr
Reactant: Cc1ccccc1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)CC=CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-triphenylphosphonium octanoic acid bromide salt (2.43 g) was prepared by reacting triphenyl phosphine with 8-bromooctanoic acid in xylene solvent under reflux conditions, and removing the solvent. The residue was dissolved in THF (20 ml)/DMSO (2 ml) and butyllithium (2.5M; 4 ml) in hexane (4 ml) was added dropwise at 0° C. After warming to room temperature over 30 minutes 3,3-dimethylbutanal (0.5 g) in THF (5 ml) was added dropwise and the mixture stirred at room temperature for 3 hours. Water and dilute hydrochloric acid were added and the mixture extracted with diethyl ether(x3). Pure product 11,11-dimethyldodecan-8-enoic acid (0.4 g) was provided after silica gel column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH2:13]Br)=[O:5])[CH3:2].[CH2:15]([O:17][C:18](=[O:32])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:20]([CH2:13][C:7]1[C:8]([CH2:11][CH3:12])=[N:9][O:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:32]
Reactant: CCOC(=O)c1onc(CC)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(CC)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
4-Bromomethyl-3-ethyl-isoxazole-5-carboxylic acid ethyl ester (1.03 g, 3.93 mmol) was dissolved in 40 mL of acetonitrile. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.09 g, 4.32 mmol), potassium carbonate (1.63 g, 11.8 mmol) and potassium iodide (0.98 g, 5.90 mmol) were added, and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude oil was purified by flash chromatography (0-30% EtOAc/hexanes) to give 0.88 g of the title compound. MS: (+) m/z 435.53 (M+1).
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:3])[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4]1
Reactant: c1ccsc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2sccc21
Temperature: 40 °C

Procedure:
90 g of 2,5-dimethyl-2,5-dichlorohexane and 195 ml of thiophene are dissolved in 400 ml of hexane. 54 ml of titanium tetrachloride are slowly added dropwise thereto while cooling with ice, the mixture is warmed to 40° C. for 1.5 hours, again cooled with ice and the dark red mixture is treated cautiously with ice-water. The mixture is extracted three times with ether, the organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. The thus-obtained black oil is firsly filtered over silica gel (eluting agent hexane) and subsequently distilled in a water-jet vacuum. There are obtained 18.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 95°-96° C./10 mm.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1>CN(C)C=O>[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62]([NH:16][C:14]3[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:12]([CH3:17])[N:13]=3)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1
Reactant: O=C(O)c1ccc(Cn2cccn2)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)c2ccc(Cn3cccn3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 136.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.47 g, 1.88 mmol), and N-methylmorpholine (0.23 mL, 2.08 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.42 g, 2.09 mmol) and 4-pyrazol-1-ylmethyl-benzoic acid (0.42 g, 2.09 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (0/100 to 30/70) to afford the title compound (1.11 g); MS (ES+) m/z 432 (M+1).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])=[C:27]([F:46])[CH:26]=1.Cl>CN(C)C=O>[Cl:24][C:25]1[C:30]2[CH:31]=[C:32]([CH2:34][CH3:35])[O:33][C:29]=2[C:28]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[C:27]([F:46])[CH:26]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCc1cc2c(Cl)cc(F)c(NC(=O)Oc3ccccc3)c2o1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
80 ml of N,N-dimethylformamide was added to 5.8 g (32 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate and 6.6 g (43 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene, and 9.6 g (29 mmol) of 4-chloro-2-ethyl-6-fluoro-7-phenoxycarbonylaminobenzofuran was gradually added thereto at room temperature. After stirring at 60° C. for 8 hours, the reaction solution was poured into a 10% hydrochloric acid aqueous solution and acidified, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 4.8 g (yield: 44%) of the desired product as white crystals. Melting point: 154-155° C.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][OH:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35](OC)=[O:36].O1CCCC1.[H-].[Na+]>O>[Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][O:32][CH2:34][CH2:35][OH:36])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1COCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 48 (4.56 g), methyl bromoacetate (2.22 mL) and tetrahydrofuran (25 mL) were stirred at 0° C., 60% sodium hydride suspension (400 mg) was added into the solution. The reaction solution was stirred at room temperature for overnight, added water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→85:15). The obtained compound (1.46 g) was added tetrahydrofuran (20 mL), methanol (1 mL) and lithium borohydride (117 mg) and stirred at room temperature for 2 hours. The reaction solution was added water and aqueous 5% potassium sulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (1.40 g) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].[Cu][C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(Cl)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
25.0 g 4-bromo-3-chlorotoluene and 21.8 g copper (I) cyanide were dissolved in 200 ml dimethylformamide and stirred at 150° C. for three hours. The cooled reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 150 ml saturated NH4Cl solution. The precipitates were filtered off and the filtrate dried over MgSO4 and then reduced in vacuo to obtain 17.3 g 2-Chloro-4-methyl-benzonitrile. This material was used without purification in the next step.
Reaction SMILES: C([N:4]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C=C.[C:22]([Mg]Cl)(C)([CH3:24])[CH3:23].[C:28](Cl)(=[O:33])[O:29][CH:30]([CH3:32])[CH3:31].Cl>C1(C)C=CC=CC=1>[CH:30]([O:29][C:28]([N:4]([C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[C:5](=[O:13])[CH:6]([CH2:24][CH:22]=[CH2:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:33])([CH3:32])[CH3:31]
Reactant: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: C=CCC(CCCCCC)C(=O)N(C(=O)OC(C)C)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a solution of 40.0 g (0.14 mol) of (R)-N-allyl-N-octanoyl-1-phenylethylamine in 400 ml of toluene was added dropwise 105 ml (0.17 mol) of tert-butylmagnesium chloride (1.6 M) at room temperature, and the reaction was allowed to proceed at 70° C. for 6 hours. The reaction mixture was cooled to room temperature and, then, 51.0 g (0.42 mol) of isopropyl chlorocarbonate was added, and the reaction was allowed to proceed at room temperature for 15 hours. After completion of the reaction, the reaction mixture was added dropwise to 170 ml of a 1 N aqueous solution of hydrochloric acid in an ice bath. The reaction mixture was extracted with 400 ml of hexane, and the organic layer was washed with 100 ml of a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure to give 52.1 g of a crude product. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give 41.0 g of the title compound as a colorless oil (yield 78%, diastereomer ratio (1R,2S):(1R,2R)=80:20).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4].[I-].[Na+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CS(C)=O>COCCOC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([NH:16][C:14]2[N:15]=[C:11]([C:9]([O:8][CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:10])[N:12]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:13]=2)=[O:18])=[C:21]([CH3:27])[CH:22]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CBr)n1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CN2CCOCC2)n1

Procedure:
61.8 mg (0.1 mmol) of 2-[(2-bromoacetyl)oxy]ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylate (Example 24A) are dissolved in 0.4 ml of 1,2-dimethoxyethane under argon, and 15 mg (0.1 mmol) of sodium iodide and 43.6 mg (0.5 mmol) of morpholine are added. The reaction mixture is heated under reflux for 2 h and then mixed with 0.3 ml of DMSO, filtered and purified by preparative HPLC (Method 9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29].[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[C:32]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1cc2nccc(CN3CCc4c(C(=O)Cl)cccc4C3=O)c2cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(CN3CCc4c(C(=O)Nc5ccc(F)c(C(F)(F)F)c5)cccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.5 %

Procedure:
2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbonyl chloride (75 mg, 0.168 mmol) was suspended in dichloromethane (1 mL) then added a solution of 4-fluoro-3-trifluoromethylaniline (36 mg, 0.201 mmol) in dichloromethane (0.5 mL) and N,N-diisopropylethylamine (65 mg, 0.504 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was purified directly by silica gel chromatography (3% methanol/dichloromethane) to afford 2-((6,7-dimethoxyquinolin-4-yl)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (46 mg) as a pale yellow solid. MS (ESI, pos. ion) m/z: 554.2 (M+1).
Reaction SMILES: Cl.[O:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15])[CH3:3].[CH:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[CH:16]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:2][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:17]
Reactant: COc1cccc2c1CCCC2CN
Reactant: CCOC=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2CNC=O

Procedure:
The product from Example 14 was converted to its free base (3.4 g) and dissolved into toluene (30 ml). Ethyl formate (5 ml) was added and the reaction stirred at reflux for 5 hr. The solvent was removed to afford a solid. Recrystallization from Et2O/CH2Cl2 afforded 3.07 g of desired product. Anal. calcd. for C13H17NO2 ; C, 71.21; H, 7.81; N, 6.39. Found: C, 71.26; H, 7.82; N, 6.41.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[O:7])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C1CCCCC1C(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a mixture of 2-(4-fluorobenzoyl)cyclohexanone (99.0 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (75.6 g, 48.1%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33][N:20]2[CH2:19][CH2:18][CH:17]([C:10]3[C:11]4[C:12](=[CH:13][N:14]=[CH:15][CH:16]=4)[N:8]([CH2:7][C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=3)[CH2:22][CH2:21]2)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH3:24]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccncc32)s1
Product: CCOC(=O)c1cc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4cnccc34)CC2)ccc1OC
Yield: 43.4 %

Procedure:
This compound was prepared following the procedure described in example 24, part E, starting with 0.44 g (1.32 mmol) of 1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine and 0.36 g (1.32 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.3 g (43% yield) of 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl>CN(C=O)C.COCCOC>[C:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:8]1[C:9](=[O:10])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[N:6]=[C:7]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCCC(=O)OC(C)(C)C)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, a solution of 130 mg (0.38 mmol) of the compound from Example 222A in 1 ml DMF and 2 ml DME at 0° C. is treated with 505 μl of an LiHMDS solution (1 M in THF, 505 μmol). The cooling bath is removed and the mixture stirred for 15 mins at RT before addition of 113 mg (505 μmol) of tert.-butyl 4-bromobutanoate. The mixture is stirred overnight at 70° C. After cooling, 0.5 ml of 1 N hydrochloric acid are added. The reaction mixture is then directly separated by preparative HPLC (Method 20). 48 mg (30% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)cs1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Br)cs1
Temperature: 25 °C

Procedure:
25 g (131 mmol) of 4-bromo-thiophene-2-carbaldehyde were dissolved in 180 ml of pyridine, and 16.34 g (157 mmol) of malonic acid and 1.11 g (13.1 mmol) of piperidine were added. The reaction mix was boiled under reflux for 6 h. After cooling to room temperature, the mixture was poured onto a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 21.15 g.