Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N(C)CCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: C=CC(=O)N(C)CCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
A mixture of 113a (80 mg, 0.115 mmol) and LiOH.H2O (24 mg, 0.573 mmol) in THF/i-PrOH/water (3.0 mL/1.0 mL/1.0 mL) was stirred at rt for 6 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (EA/MeOH=25/1) to give 113 (50 mg, 67%) as white solid. 1H NMR (300 MHz, DMSO-d6, 80° C.): δ 8.42 (s, 2H), 8.35 (s, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.33-7.30 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.68-6.59 (m, 1H), 6.19 (d, J=8.1 Hz, 1H), 6.05-5.99 (m, 1H), 5.56 (m, 1H), 4.37-4.32 (m, 2H), 3.68 (t, J=5.4 Hz, 2H), 3.62 (s, 3H), 3.07 (s, 3H), 2.95-2.86 (m, 6H), 1.91-1.89 (m, 4H). ESI-LCMS: m/z=657.3 [C34H33FN6O5S+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:25]=[CH:26][N:27]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 17 h
Yield: 65.6 %

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.47 mmol, from Example 62, Step 2) and 4-(tributylstannyl)-1-trityl-1H-imidazole (0.28 g, 0.47 mmol, Synthonix) in toluene (9.0 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) was added and the reaction was stirred at 110° C. for 17 h. Solvent was removed in vacuo and the product was purified by flash chromatography, eluting with a gradient from 0-35% EtOAc in hexanes to afford product as a white solid (0.17 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Cl)=[N:5][C:6]([Cl:12])=[N:7]2.C(N(CC)CC)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:24][CH2:23][CH2:21][OH:22])=[N:5][C:6]([Cl:12])=[N:7]2
Reactant: Clc1nc(Cl)c2c(Br)cccc2n1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCNc1nc(Cl)nc2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5-bromo-2,4-dichloroquinazoline (2.3 g, 8.2 mmol) and triethylamine (1.5 ml, 11 mmol) in dichloromethane (100 ml) was added ethanolamine (0.64 ml, 11 mmol), and the mixture was stirred for 30 min. The solvent was evaporated and the residue treated with a mixture of water (30 ml) and ether (20 ml) giving the title compound as a crystalline precipitate which was collected by filtration and dried, m.p. 165°-67° C.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:44])[C@@H:18]([NH:29][C:30](=[O:43])[CH2:31][CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:44])[C@@H:18]([NH:29][C:30](=[O:43])[CH2:31][CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCCc1c[nH]c2ccccc12)NOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCCc1c[nH]c2ccccc12)NO
Reaction time: 4 h
Yield: 410.4 %

Procedure:
(Method J15F) 6-[3-(1H-Indol-3-yl)-2-(4-1H-indol-3-yl-butyrylamino)-propionylamino]-hexanoic acid benzyloxy-amide (19/97) (1.654 g, 0.274 mmol) was dissolved in ethanol (20 ml), 10% Pd/C (50 mg) was added and the reaction mixture was hydrogenated at room temperature for 4 hours. The catalyst was filtered off, the solvent was evaporated and the residue was chromatographed on silica gel with acetonitrile-acetic acid (60:1) and acetonitrile-acetic acid-water (30:1:1) as eluent to give the title product (0.582 g, 41%) as white powder. M.p. 94-96° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.06-1.55 (m, 6H); 1.68-1.97 (m, 4H); 2.04-2.27 (m, 2H); 2.42-2.67 (m, 2H overlapped with DMSO) 2.80-3.15 (m, 4H); 4.44-4.57 (m, 1H); 6.87-7.17 (m, 6H); 7.31 (d, 2H, J=7.6 Hz); 7.44 (d, 1H, J=7.6 Hz); 7.58 (d, 1H, J=7.6 Hz); 7.80-8.03 (m, 2H); 8.67 (s, 1H); 10.33 (s, 1H); 10.72 (s, 1H); 10.76 ppm (s, 1H). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm; sample concentration 0.5 mg/ml, flow rate 1.0 ml/min). Anal. Calcd for C29H35N5O4: C, 67.29; H, 6.82; N, 13.53. Found: C, 67.06; H, 6.86; N, 13.66.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)#[N:21]
Reactant: Nc1ccccc1O
Reactant: N#Cc1cccc(CBr)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2OCc2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 33A and 33B except starting from 2-hydroxyaniline, p-anisoyl chloride and 3-cyanobenzyl bromide, the title compound was obtained as a solid (700 mg, 48%); MS(FD): 358.1.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:13][Cl:14])([CH3:12])OC(C)C)=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([Li])CCC>O1CCCC1.CCCCCC>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([SiH:7]([CH2:13][Cl:14])[CH2:12][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: CC(C)O[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1ccc(C[SiH](CCl)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g (32.8 mmol) of (1,1'-biphenyl-4-yl)(chloromethyl)methyl(2-propoxy)silane and 3.6 ml (32.8 mmol) of 4-bromofluorobenzene in 30 ml of dry tetrahydrofuran was cooled to -60° under nitrogen and stirred while 20.5 ml (32.8 mmol) of 1.6 molar n-butyllithium in hexane was added at a rate that held the mixture below 50°. After stirring at -70° for another 30 minutes, the solution was allowed to warm to room temperature and was worked up as in Example 8. The resulting crude product was subjected to distillation at 130°-150° (0.2 mm) to remove unreacted starting material, leaving the title compound as an oil: nD23 1.5128; nmr (CDCl3): 0.7 (3H, s), 3.1 (2H, s), 7.1 (2H, t), 7.2-7.8 (11H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: COc1c(Br)cccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
3-Bromo-2-methoxybenzoic acid (2 g, 8.65 mmol, 1.0 eq) was dissolved in dry DCM and stirred for 10 minutes, cooled to 0° C. and slowly treated with oxalyl chloride (3.3 g, 25.9 mmol, 3 eq). Methanol in pyridine was added dropwise and the reaction mixture was stirred at ambient temperature. The solvents were evaporated under reduced pressure and the reaction mass was diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to afford the desired product (1.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 3.93 (s, 6H), 7.02-6.06 (t, 1H), 7.72-7.76 (m, 2H). MS (ESI): 247.0 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])C)([CH3:3])C.C([Li])CCC.[CH3:13][O:14][CH2:15][O:16][C:17](=[O:37])[CH2:18]/[C:19](/[C:33]([O:35][CH3:36])=[O:34])=[C:20](/[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([Cl:32])[CH:23]=1)\[CH3:21].[Cl-].[NH4+].[O:40]1CC[CH2:42][CH2:41]1>CCCCCC>[CH3:13][O:14][CH2:15][O:16][C:17](=[O:37])[CH:18]([CH:41]([C:42]1[CH:3]=[CH:1][N:4]=[CH:5][CH:7]=1)[OH:40])/[C:19](/[C:33]([O:35][CH3:36])=[O:34])=[C:20](/[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([Cl:32])[CH:23]=1)\[CH3:21]
Reactant: COCOC(=O)C/C(C(=O)OC)=C(\C)c1cc(Cl)c(OC)c(OC)c1
Reactant: C1CCOC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: COCOC(=O)C(/C(C(=O)OC)=C(\C)c1cc(Cl)c(OC)c(OC)c1)C(O)c1ccncc1
Temperature: -78 °C

Procedure:
To a solution of diisopropylamine (1.33 ml) in tetrahydrofuran (20 ml) is added gradually and dropwise a 1.6 N solution of n-butyl lithium in hexane (5.91 ml) at 0° C., and the mixture is stirred at the same temperature for 30 minutes. The solution is cooled to −78° C., and thereto is added gradually and dropwise a solution of (Z)-4-(3-chloro-4,5-dimethoxyphenyl)-4-methyl-3-methoxycarbonyl-3-butenoic acid methoxymethyl ester (2.94 g) in tetrahydrofuran (20 ml), and the mixture is further stirred at the same temperature for 30 minutes. The reaction mixture is cooled to −90° C., and thereto is added gradually and dropwise a solution of isonictinaldehyde (1.01 g) in tetrahydrofuran (10 ml), and the mixture is stirred at −90° C. for 20 minutes. To the reaction mixture is added a saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The organic layer is washed, dried, and concentrated under reduced pressure to remove the solvent to give (Z)-4-(3-chloro-4,5-dimethoxyphenyl)-4-methyl-3-methoxycarbonyl-2-(4-pyridylhydroxymethyl)-3-butenoic acid methoxymethyl ester.
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:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[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:25]([CH2:26][C:27]([CH3:29])=[CH2:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)CN1CCCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)CN1CCCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To methyl 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (1.65 g) were added tetrahydrofuran (45 ml) and methanol (45 ml), followed by adding an aqueous 1N sodium hydroxide solution (15 ml), and the mixture was stirred at 60° C. overnight. After cooling down to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated water and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (0.97 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].CC([O-])(C)C.[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Br.O>C1COCC1>[CH3:30][O:31][C:32](=[O:35])[CH2:33][N:19]1[CH:20]=[CH:21][C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])=[CH:17][C:18]1=[O:22]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cn1ccc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) was dissolved in THF (10 mL), and treated with t-BuOK (34 mg). After 5 minutes stirring, bromo-acetic acid methyl ester (0.03 mL) was added and the reaction mixture was stirred at 55° C. for 17 h. The reaction mixture was then cooled down to r.t., poured into water (50 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 30:70) to give the title compound as colorless waxy solid (49 mg). MS (m/e)=438.1 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:20])([F:22])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[CH:36][N:35]=[N:34]4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-[1,2,3]-triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M118) (0.33 g, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (115 mg, 44%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH:23]=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1COCC1.CCO>O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH2:23][OH:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C=O)c2ccccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CO
Temperature: 100 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 14 μmol), NaBH4 (1.5 mg, 40 μmol), THF (250 μL), and EtOH (absolute, 500 μL) was stirred at 23° C. for 1 h. H2O (500 μL) and LiOH monohydrate (50 mg, 1.18 mmol) were added. The reaction was sealed and heated to 100° C. After 2 h, the reaction cooled to 23° C., filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (2.6 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.72-7.65 (m, 2H), 7.58-7.48 (m, 2H), 7.39-7.33 (m, 2H), 7.18 (d, J=8.6 Hz, 1H), 5.07 (s, 1H), 5.01 (d, broad, J=2.7 Hz, 2H), 2.62 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH:5]([C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH:14](N(C)C(N)=S)[CH2:13][CH2:12]1)=[O:9])([CH3:7])[CH3:6].Br[C:23](Br)=O.C(N(C(C)C)CC)(C)C>CCO>[CH:5]([C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:23][NH:1][C:2]([NH2:4])=[S:3])[CH2:13][CH2:12]1)=[O:9])([CH3:7])[CH3:6]
Reactant: CC(C)C(=O)NC1CCC(N(C)C(N)=S)CC1
Reactant: NC(N)=S
Reactant: O=C(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)C(=O)NC1CCC(CNC(N)=S)CC1

Procedure:
A thiourea such as N-[4-(isopropylformylamino)cyclohexyl]-methylthiourea (0.029 mmol, 1 equivalent), a bromoketone (0.044 mmol, 1.5 equivalent) and 2 equivalents of diisopropylethyl amine in 10 ml of EtOH were heated at reflux temperature for 2 days. The reaction mixture was concentrated in vacuo and the crude product chromatographed (silica) to obtain the desired product. This procedure was used to prepare examples 101–102.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]1[C:30](=O)[C:31](=[O:36])[C:32]=1[O:33]CC)[CH3:27]>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][P:17]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:18])[C:30]2[C:31](=[O:36])[C:32](=[O:33])[C:29]=2[O:28][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCNCCCNC(=O)OCc1ccccc1)OCC
Solvent: CCO
Product: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CCP(=O)(OCC)OCC)c(=O)c1=O
Yield: 88.9 %

Procedure:
A solution of [3-[[2-(diethoxyphosphinyl)ethyl]amino]propyl]carbamic acid phenylmethyl ester (3.17 g, 8.5 mmol) in absolute ethanol (40 mL) was added over 45 minutes to 3,4-diethoxy-3-cyclobutene-1,2-dione (2.3 mL, 16 mmol) dissolved ethanol (55 mL). After leaving overnight, the reaction mixture was preadsorbed onto silica gel and purified by flash chromotography (7 cm diameter, gradient elution was 2.5-10% methanol in dichloromethane) to yield [3-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester as a viscous oil (3.75 g, 89%); 1H NMR (CDCl3, 400 MHz): δ 7.35 (m, 5H), 5.45 (br m, NH), 5.09 (s, 2H), 4.80-4.71 (m, 2H), 4.16-4.09 (m, 4H), 3.90-3.48 (m, 4H), 3.23-3.20 (m, 2H), 2.16-2.05 (m, 2 H), 1.85-1.79 (m, 2H), 1.47, 1.41 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: -12 °C
Reaction time: 0.33 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g (45.42 mmol) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)fluoromethoxyiminoacetic acid were stirred at room temperature to completely dissolve the latter in the former, followed by cooling to -12° C. Added dropwise to the reaction mixture was a chlorinating reagent, which had been prepared beforehand by gradually adding 7.65 g (49.89 mmol) of phosphorus oxychloride at 5° C. into a mixture of 20 ml of THF and 3.7 g (49.93 mmol) of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. Subsequent to their reaction for 60 minutes with the temperature maintained at -15° C., the reaction mixture was poured into 150 ml of ice water and was then stirred for 20 minutes to precipitate crystals. The crystals were collected by filtration, washed twice with 15 ml aliquots of ice water and then, under reduced pressure, dried, whereby the title compound was obtained. Yield: 8.50 g (77.9%). Purity: 95.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:33]3[CH:32]=[C:31]([CH2:30][C:29]([OH:39])=[O:28])[CH:36]=[CH:35][CH:34]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(Cl)cccc23)c1
Reactant: COC(=O)Cc1cccc(C=O)c1
Product: O=C(O)Cc1cccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-chloro-quinolin-3-yl]-phenyl-methanone and (3-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 507.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[CH3:27][Mg+].[Br-].O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(C)O)cc2=O)cc1
Temperature: -30 °C
Yield: 58 %

Procedure:
To a solution of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (3.0 g, 7.25 mmol), in dry THF (50 mL) was added MeMgBr (7.25 mL of a 3 M solution in THF, 21.8 mmol) dropwise at −30° C., and the reaction mixture was stirred at −30° C. then warmed to room temperature and stirred for another 2 h. The reaction mixture was cooled to 0° C., 2 mL water was added, and the mixture was diluted with ethyl acetate. The layers were separated, and the organic fraction was dried (MgSO4), concentrated under reduced pressure, and purified by Prep-HPLC to give 1.8 g (58%) of 1-(3-bromophenyl)-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one. Chiral resolution of 12.0 g 1-(3-bromophenyl)-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was accomplished by SFC of racemic material using a Chiral Technologies ChiralPak AD-H column (25% MeOH in CO2, 3 cm diameter×25 cm length, 70 mL/min flow, 200 mg per injection), and afforded (80%) of the first eluting enantiomer and (79%) of the second eluting enantiomer. 1H-NMR (CD3OD, 400 MHz) δ 7.76 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.51-7.41(m, 2H), 7.38-7.35 (m, 2H), 7.33-7.31 (m, 2H), 6.88-6.86 (m, 2H), 6.76 (s, 1H), 4.95 (s, 2H), 4.39-4.34 (m, 1H), 3.76 (s, 3H), 1.26 (d, J=6.0 Hz, 2H). MS (ESI) m/z (M+H)+ 430.1/432.1.