Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](OC)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[Li+].[OH-].Cl.C[O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([NH:49][CH2:48][CH2:47][C:46]([OH:50])=[O:45])=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=1)=[O:18]
Reactant: COC(=O)CCN
Reactant: COC(=O)c1cc2c(cc1Br)C(N(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1)CCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCOc3cc(C(=O)NCCC(=O)O)c(Br)cc32)CC1

Procedure:
Enantiomer A of methyl 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]chromane-7-carboxylate (25 mg) was saponified with aqueous LiOH and then coupled to β-alanine methyl ester HCl salt following the procedure described (Example 3/4) to give N-({6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-3,4-dihydro-2H-chromen-7-yl}carbonyl)-β-alanine. HPLC/MS: m/z=684.2 (M+1), Rt=2.50 min. 1H NMR (DMSO-d6): δ 12.20 (1H, br s), 8.56 (1H, s), 8.38 (1H, t, J=5.5 Hz), 7.46 (2H, d, J=9.0 Hz), 7.21 (2H, d, J=9.0 Hz), 6.72 (1H, s), 4.68 (1H, m), 4.36 (1H, dt, J=2.0 Hz, 11.5 Hz), 4.20 (1H, t, J=11.5 Hz), 3.90 (1H, m), 3.37 (2H, m), 2.73 (1H, m), 2.48 (2H, t, J=7.0 Hz), 1.98-1.72 (7H, m), 1.28-1.04 (4H, m), 0.88 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:18][C:7]1[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1
Reactant: Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
In a 50 mL round-bottomed flask, 7-chloro-3-methyl-1-phenyl-1H-quinolin-4-one (0.142 g, 0.526 mmol), NBS (103 mg, 0.579 mol) and AIBN (13.0 mg, 0.079 mmol) were combined with carbon tetrachloride (3.5 mL) to give a colorless solution. The reaction mixture was heated at 115° C. for 1 h. The reaction mixture was cooled to room temp and then cooled to 0° C. The mixture was filtered to remove succinimide and the filtrate was concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:22][C:9]1[O:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)[CH:10]=1
Reactant: O=C1CCc2cc(-c3ccoc3-c3ccncc3)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-c3cc(Br)oc3-c3ccncc3)ccc21
Temperature: 50 °C
Yield: 15.7 %

Procedure:
A solution of the product of Step 8 (1.0 g, 3.6 mmol) in dry dimethylformamide (10 ml) was treated with freshly recrystallised N-bromosuccinimide (1.42 g, 8.0 mmol) and heated at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, extracted into dichloromethane, washed twice with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (0.2 g, 16%); 1H NMR (CDCl3) 8.52 (2H, d, J 8 Hz), 7.80 (1H, d, J 11 Hz), 7.49 (1H, s), 7.38 (1H, d, J 8 Hz), 7.32 (2H, d, J 8 Hz), 6.54 (1H, s), 3.17 (2H, t, J 5 Hz), 2.75 (2H, t, 5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:10]1([CH3:29])[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[CH:16]=2)[CH2:11]1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(N3CCN(C)CC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc(C3CC(C)(C)c4cccc(C(=O)O)c4N3)c2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (200 mg, 0.5 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (180 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=380.2.
Reaction SMILES: [S:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Yield: 193.3 %

Procedure:
A solution of tert-butyl (6-(4-sulfamoylphenoxy)hexyl)carbamate (1.178 g, 3.16 mmol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at rt for overnight. After the solvent was evaporated under a steam of N2, the reaction mixture was dissolved in water (5.0 mL) and acetonitrile (5.0 mL) and lyophilized to afford 4-((6-aminohexyl)oxy)benzenesulfonamide (1.664 g) containing TFA. MS (ESI), 273.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C

Procedure:
To a solution of 5-nitroindole (0.20 g) in tetrahydrofuran (2 ml) was added sodium hydride (0.06 g of 60% dispersion in oil) and evolution of gas noted. After stirring for 30 min methyl iodide (0.086 ml) was added to the dark brown reaction mixture and the reaction mixture heated to 65° C. for 2 hr before cooling to room temperature and partitioning between dichloromethane and water. Organic phase separated, washed with sodium thiosulphate solution, dried (Na2SO4) and concentrated to leave sub-title compound as a yellow solid (0.20 g). 1H NMR (DMSO-d6) δ 8.58 (1H, d), 8.04 (1H, dd), 7.65 (1H, d), 7.61 (1H, d), 6.75 (1H, dd), 3.88 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.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>[F:19][C:14]1[CH:13]=[C:12]([F:20])[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(Br)c(F)cc1F
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2cncnc2)c(F)cc1F
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(II) chloride (0.56 g, 0.80 mmol), pyrimidin-5-ylboronic acid (0.99 g, 8.0 mmol), 5-bromo-2,4-difluorobenzaldehyde (0.88 g, 3.98 mmol), cesium carbonate (2.59 g, 7.96 mmol) in DME (13 mL), EtOH (7 mL) and water (7 mL) was heated at 100° C. for 45 min, and the crude reaction mixture was subjected to HPLC separation eluting with 0-100% A/B (A: 95% H2O/5% MeCN, 10 MM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 30 min period to give the title compound as a white solid (450 mg, 51% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 10.40-10.33 (m, 1H), 9.28 (s, 1H), 8.94 (d, J=1.2 Hz, 2H), 8.06 (dd, J=8.4, 7.8 Hz, 1H), 7.15 (t, J=9.9 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1>>[CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:20][C:21]2[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=2)=[O:18])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)Nc1nc(C(=O)O)cs1
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1

Procedure:
2-(3-Benzyl-ureido)-thiazole-4-carboxylic acid is coupled with ethyl (E)-3-(4-amino-phenyl)-acrylate in analogy to Example 11 After chromatography on silica gel with methylene chloride-ethanol 98:2 and crystallization from ether there is obtained ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, m.p. 207° C., MS: 451 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)=[O:11])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)n1

Procedure:
From 6-methoxy-2-pyridinecarboxylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+20.3° (c=1.08, CHCl3), ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:10]1[C:32]([O:34]CC)=O)[CH3:2].C(O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][CH2:8][N:9]2[C:17]3[C:12]([C:11]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:10]2[C:32]1=[O:34])=[CH:13][C:14]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:15][CH:16]=3)=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCC)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc21
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1CCCn2c(c(-c3ccccc3)c3cc(OCc4ccccc4)ccc32)C1=O

Procedure:
Twenty-three grams (46 m mole) of 5-(2-ethoxycarbonyl-5-benzyloxy-3-phenyl-1H-indole-1-yl)-valeric acid ethylester were dissolved in 150 ml of toluene and added dropwise within four hours to a boiling suspension of 5.2 g (46 m mole) of potassium-tert.-butylate in 150 ml of toluene. Then the ethanol formed was distilled off with toluene. After cooling, ice-cold dilute hydrochloric acid was added and the mixture was extracted with toluene. The toluene extracts were evaporated, and the residue was purified by chromatography on silicagel (solvent: toluene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:17])=[CH:5][C:4]([CH3:18])=[CH:3][C:2]=3[F:1])=[O:14])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)cc(C)cc2c1O
Solvent: CCOCC
Product: Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 180 °C

Procedure:
A mixture of 2-fluoro-4-methylaniline (5.0 g) and diethyl ethoxymethylene-malonate (8.64 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 75° C. and diphenyl ether (50 mL) is added. The solution is heated to 250° C. for 2 h with removal of ethanol by a Dean-Stark trap, then cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 5.564 g of ethyl 8-fluoro-4-hydroxy-6-methylquinoline-3-carboxylate. A mixture of this ester (0.50 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled and poured into 50 mL of diethyl ether. The resulting solid is filtered, dried, and purified by trituration in acetone to give the desired product (0.54 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][SH:7].C(N(C(C)C)CC)(C)C.Cl[C:23]1[CH:24]=[C:25]([CH3:33])[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][C:28]=1[CH3:29]>CN1CCCC1=O>[N+:30]([C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[CH:24][C:25]=1[CH3:33])([O-:32])=[O:31]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: FC(F)(F)c1cccc(CS)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1SCc1cccc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
A mixture of 3-trifluoromethylbenzyl mercaptan (3.42 g), diisopropylethylamine (2.3 g) and 3-chloro-6-nitro-p-xylene (3.0 g) in dry N-methylpyrrolidinone (20 ml) was heated at 130° C. for 6 hours. On cooling, the mixture was poured into ice-water and the resulting mixture was filtered to give a solid which was washed with ice-water and then air dried. The solid was purified by silica gel chromatography eluting with light petroleum (60-80° C.)/ethyl acetate (9:1) to give the title product as a solid, m.p. 85-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH3:30])[C:22]=2[CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH3:30])[C:22]=4[CH:31]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1nc2ccc(Br)cc2n1C
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCC(=O)c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 3.4 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 1-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-one (170 mg), N,N′-dimethylethylenediamine (0.046 ml), CuI (81 mg) and potassium carbonate (176 mg) in DMSO (3 ml) was stirred at 150° C. for 30 min under N2 atmosphere. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc), followed by recrystallization from IPA to give the title compound (6.1 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([N+:11]([O-])=O)[C:5]=1[CH3:14].[C:16]1([NH:22][C:23](=O)[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:23]([CH3:24])=[N:11][C:6]=2[C:5]=1[CH3:14])=[O:15]
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1C
Product: COC(=O)c1ccc2c(nc(C)n2-c2ccccc2)c1C

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 4-Bromo-2-methyl-3-nitrobenzoic acid methyl ester and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as yellow solid. 1H NMR (DMSO) δ 2.49 (s, 3 H), 2.62 (s, 3 H), 7.18 (d, J=8.6 Hz, 1 H), 7.28 (d, J=8.6 Hz, 1 H), 7.52-7.61 (m, 6 H); 13C NMR δ 13.5, 14.7, 51.8, 108.0, 123.7, 125.9, 126.9, 129.7, 130.1, 130.2, 134.0, 136.5, 138.0, 152.8, 167.2.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1Br)[CH3:3].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1(C)C=CC=CC=1.BrC(Br)C.O1CCCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCc1cc(C)cc(CC)c1Br
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 33 °C
Reaction time: 0.33 h
Yield: 118.4 %

Procedure:
To a 2 L volume four-necked flask, magnesium (cutting chip) (66.2 g), tetrahydrofuran (anhydrous) (494 g), and toluene (549 g) were added under a nitrogen atmosphere at room temperature. After starting to stir the mixture, dibromoethane (26.9 g) was added dropwise over 10 minutes at about 20° C., and then the internal temperature was raised to 33° C. The resulting mixture was stirred at 30° C. for 20 minutes. 2,6-diethyl-4-methylbromobenzene (10-a) (549.0 g) was added dropwise thereto at 40° C. over 1 hour. The resulting mixture was stirred at 50° C. for 51 hours, and diethyl oxalate (389.1 g) dissolved in toluene (550.1 g) was added dropwise thereto at about 0° C. over 1 hour. The resulting mixture was stirred at about 5° C. for 1 hour. Then, to the mixture, 3.5 w/w % of hydrochloric acid (832 g) was added dropwise at the same temperature. Then the mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with toluene (548.3 g). The organic layers were combined, washed with water (1098 g) and concentrated under reduced pressure to give 710.8 g of ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C@@H:21](O)[C:22]([F:25])([F:24])[F:23])=[O:7])(C)(C)C.[N:27]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[C:31]=1[CH3:42])=C=O>>[F:39][C:38]([F:40])([F:41])[C:32]1[C:31]([CH3:42])=[C:30]([N:27]2[C@H:21]([C:22]([F:23])([F:24])[F:25])[C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:7])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: Cc1c(N=C=O)ccc(C#N)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1C(F)(F)F

Procedure:
The title compound was prepared from (2R,3R)-3-(tert-butyl-dimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]pyrrolidine-1-carboxylic acid tert-butyl ester (66A) and isocyanate 18E following procedures analogous to those found in Example 72. LCMS: m/z 394 [M+H]+
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C[O-].[Mg+2].C[O-].CO>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nccs1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)c2ncc[nH]2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)c2ncc[nH]2)cc1
Temperature: 110 °C
Yield: 19.1 %

Procedure:
A mixture of 3-cyclopentyl-2-[4-(1H-imidazole-2-sulfonyl)-phenyl]-propionic acid ethyl ester (113.5 mg, 0.30 mmol) and 2-aminothiazole (45.3 mg, 0.45 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.86 mL, 0.60 mmol) was heated at 110° C. for 8 h. At this time, the reaction was cooled to 25° C., filtered through a plug of celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-[4-(1H-imidazole-2-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamide (24.7 mg, 19%) as a tan solid: mp 249-251° C.; EI-HRMS m/e calcd for C20H22N4O2S2 (M+) 430.1133 found 430.1133.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:16])=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(CC(=O)O)cc1
Product: CCOc1ccc(CC(=O)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70° C. for 21/2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>C1COCC1.[Br-].[Zn+2].[Br-].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>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Brc1cnc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cc(-c2cnc3ccccn23)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-imidazo[1,2-a]pyridine (1 g, 5.1 mmol) in dry THF (25 mL) under N2 at −78° C. was added n-BuLi (1.6 M in hexanes, 3.8 mL, 6.12 mmol) and the reaction mixture was stirred at that temperature for 1 hour. Then freshly dried zinc bromide (1.7 g, 7.65 mmol) in dry THF (15 mL) was added slowly and the reaction mixture was slowly warmed up to room temperature and 4,6-dichloro-pyrimidine (760 mg, 5.1 mmol) and Pd(PPh3)4 (294 mg, 0.26 mmol) was added. After 16 hours at 75° C., the reaction mixture was then concentrated and directly purified by flash chromatography (SiO2, 95:5:0.5/EtOAc:MeOH:TEA) to give 3-(6-chloro-pyrimidin-4-yl)-imidazo[1,2-a]pyridine (Int-1). MS found for C11H7ClN4 as (M+H)+ 231.45. To a solution of Int-1 (100 mg, 0.44 mmol), 4-amino-benzoic acid (72 mg, 0.52 mmol) in dioxane (3 mL) and 2-PrOH (0.5 mL), p-TSA (83 mg, 0.44 mmol) was added and heated in a microwave (Emry's Optimizer) at 130° C. After 20 minutes, the resulting solid was filtered and washed with ether and dried to give 4-(6-imidazo[1,2-a]pyridin-3-yl-pyrimidin-4-ylamino)-benzoic acid (Int-2). MS found for C18H13N5O2 (m/z): 332.39 [M++1]. To Int-2 (75 mg, 0.23 mmol) in DMF (4 mL), was added HATU (129 mg, 0.34 mmol), 1,2-phenylenediamine (49 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound as tan solid, after lyophilization. MS found for C24H19N7O as (M+H)+ 422.09. 1H NMR (400 MHz, dmso-d6): δ 9.89 (d, J=6.8 Hz, 1H); 8.71 (s, 1H); 8.19 (s, 1H); 7.92 (d, J=8.8 Hz, 2H); 7.80 (d, J=8.8 Hz, 2H); 7.61 (d, J=9.2 Hz, 1H); 7.42 (t, J=7.6 Hz, 1H); 7.13-6.97 (m, 4H); 6.83 (d, J=7.2 Hz, 1H); 6.69 (t, J=7.6 Hz, 1H).