Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].[CH3:22][C:23]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)([CH3:27])[C:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(#N)C>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH:11]([NH:13][C:24](=[O:25])[C:23]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)([CH3:27])[CH3:22])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: Cc1ccc(OC(C)(C)C(=O)O)nc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(O)cc1)c1cccc(C#N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(OC(C)(C)C(=O)NC(C)C(Cc2ccc(O)cc2)c2cccc(C#N)c2)nc1
Temperature: 25 °C

Procedure:
To a solution of N-(1S, 2S)-[2-(3-cyanophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]amine hydrochloride (Reference Example 8, 0.17 g, 0.49 mmol), 2-methyl-2-(5-methyl-2-pyridyloxy)propionic acid (Reference Example 12, 96 mg, 0.49 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.11 g, 0.59 mmol) in acetonitrile (2 mL) at 0° C. was added pyridine (91 uL, 1.1 mmol). The reaction was allowed to warm up to room temperature overnight, and was quenched with saturated with sodium bicarbonate (2 mL). The resulting mixture was partitioned between tert-butyl methyl ether (20 mL) and water (20 mL). The organic layer was separated, washed with 1 M hydrochloric acid, water and brine and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 10 to 70% ethyl acetate in hexane to afford N-[2-(3-Cyano-phenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylpropanamide. 1H NMR (500 MHz, CD3OD): δ 7.85 (br d, 1H), 7.81 (d, 1H), 7.53-7.80 (m, 2H), 7.38 (t, 1H), 7.34 (br d, 1H), 7.32 (br s, 1H), 6.80 (d, 1H), 6.51 (ABq, 4H), 4.26 (m, 1H), 3.01 (dd, 1H), 2.81 (td, 1H), 2.54 (dd, 1H), 2.12 (s, 3H), 1.73 (s, 3H), 1.67 (s, 3H), 0.83 (d, 3H). LC-MS: m/e 444 (M+H)+ (3.3 min).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(C1NC=CN=1)(C1[NH:33]C=CN=1)=O>>[C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:33])=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12
Reactant: CCCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: CCCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
The procedure of Example 65 is utilized starting with 3-phthalimido-3-(4'-butoxy-3'-methoxyphenyl)propionic acid and carbonyl diimidazole to afford 0.742 g (74%) of crude product as a pale yellow powder. The crude product was recrystallized from ethyl acetate (16 mL) to afford 0.517 (52%) of 3-phthalimido-3-(4'-butoxy-3'-methoxyphenyl)propionamide as fine fluffy white needles: HPLC 99.1%; 1H NMR (DMSO-d6) δ 7.95-7.75 (m, 4 H, Ar), 7.54 (br s, 1 H, CONH), 7.04 (s, 1 H, Ar), 7.0-6.75 (m, 2 H), 6.86 (br s, 1 H, CONH), 5.67 (t, 1 H, J=8 Hz), 3.90 (t, 2 H, J=6 Hz), 3.73 (s, 3 H), 3.20 (d, 1 H, J=8 Hz, CH2CO), 1.8-1.55 (m, 2 H) 1.5-1.3 (m, 2 H), 0.91 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 171.2, 167.6, 148.8, 147.7, 134.5, 131.6, 131.2, 123.0, 119.4, 112.8, 111.4, 67.8, 55.5, 50.3, 36.9, 30.7, 18.6, 13.6.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:48][C:49]([F:52])([F:51])[F:50])(=O)=O>O1CCCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:48][C:49]([F:52])([F:51])[F:50])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(CC(F)(F)F)CC1
Yield: 43.7 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (180 mg, 0.41 mmol), (prepared as described for the starting material in Example 11), was suspended in tetrahydrofuran (15 ml), and diisopropylethylamine (108 μl, 0.45 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (98 mg, 0.62 mmol) were added. The mixture was heated at reflux for 1.5 hours. Diisopropylethylamine (36 μl, 0.21 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (45 mg, 0.21 mmol) were added and the mixture was heated at reflux for a further 2 hours. The mixture was concentrated under reduced pressure and column chromatography of the residue, eluting with 1% methanol/methylene chloride gave a sticky solid. This was triturated with diethyl ether and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-ylmethoxy]quinazoline (93 mg, 44%).
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.O>[N:21]([CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(N=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.1 %

Procedure:
Ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.55 g) was dissolved in N,N-dimethylformamide (30 ml); a solution of sodium azide (0.88 g) in water (5 ml) was added at 0° C. After the reaction mixture was stirred at room temperature for 50 minutes, it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9, v/v) to yield ethyl 5-azido-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.70 g, 74.2%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 118-119° C.
Reaction SMILES: C([O-])(=O)C.[CH:5]1([NH3+:8])[CH2:7][CH2:6]1.C([O:11][C:12](=O)[CH2:13][S:14][C:15]#[N:16])C>>[CH:5]1([NH:8][C:15]2[S:14][CH2:13][C:12](=[O:11])[N:16]=2)[CH2:7][CH2:6]1
Reactant: [NH3+]C1CC1
Reactant: CCOC(=O)CSC#N
Agent: CC(=O)[O-]
Product: O=C1CSC(NC2CC2)=N1
Temperature: 90 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A solution of ethyl chloroacetate (20 g, 0.16 mol) and potassium thiocyanate (12.7 g, 0.13 mol) in ethanol (100 ml) was refluxed for 3 h. The solution was filtered and concentrated under reduced pressure to afford 18.7 g of thiocyanato-acetic acid ethyl ester (97%). A mixture of cyclopropylammonium acetate (0.50 g, 4.27 mmol) and thiocyanato-acetic acid ethyl ester (0.62 g, 4.27 mmol) was heated to 90° C. for 3 h, and left at rt overnight. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then concentrated to dryness. The crude was triturated with dichloromethane and the solution separated from the solid by filtration. This solution was dried over sodium sulfate and concentrated to dryness. The crude was purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylamino-thiazol-4-one (244 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.Br[CH2:16][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:16])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C[C@H](CBr)NC(=O)OC(C)(C)C
Reactant: Cn1nccc1-c1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 53.3 %

Procedure:
4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (500 mg, 2643 μmol), (R)-tert-butyl 1-bromopropan-2-ylcarbamate (755 mg, 3171 μmol) and cesium carbonate (1205 mg, 3700 μmol) were weighed into a vial with anhydrous acetone (3.0 mL). The reaction was heated in a microwave at 100° C. for an hour. After this time, the crude LC/MS showed that the reaction was nearly complete. Thus, the solvent was evaporated and the resulting material was extracted (3 mL each of H2O and CH2Cl2). The aqueous layer was extracted again with CH2Cl2 (3 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (0, 20, 50, 70, 100% EtOAc/Hexanes) to yield tert-butyl(R)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate (487 mg, 1.41 mmol, 50.7%) as a light brown colored oil. LCMS m/z 347.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 0.92 (d, J=6.57 Hz, 3 H), 1.32 (s, 9 H), 3.60 (s, 3 H), 3.69-3.76 (m, 1 H), 3.79-3.94 (m, 2 H), 6.13 (d, J=1.77 Hz, 1 H), 6.57 (d, J=2.78 Hz, 1 H), 6.72 (dd, J=8.59, 2.78 Hz, 1 H), 6.83 (d, J=8.84 Hz, 1 H), 7.36 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]([C:11]1[CH:15]=[C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)[N:13]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[N:12]=1)([CH3:10])[CH3:9]>ClCCl>[ClH:1].[CH:8]([C:11]1[CH:15]=[C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH2:23])=[CH:18][CH:17]=2)[N:13]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[N:12]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCN)cc2)cc1

Procedure:
4M Hydrochloric acid/dioxane (2 ml) was added to a solution of tert-butyl 2-{4-[3-isopropyl-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamate obtained by Example 2 (382 mg) in dichloromethane (3 ml) at 0° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Yield: 33.9 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.0 g, 40.9 mmol, 1.0 eq) and 4-fluorobromobenzene (14.3 g, 81.7 mmol, 2 eq) in pyridine was added K2CO3 (8.5 g, 61.4 mmol, 1.5 eq) followed by copper powder (1.3 g, 20.5 mmol, 0.5 eq). The reaction mixture was refluxed for 60 h before being filtered to remove the copper powder. The filtrate was then distilled under reduced pressure to remove pyridine. The resultant residue was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under in vacuo. The residue was purified by silica gel column chromatography eluting with 10-20% ethyl acetate in hexane to afford the desired compound (3.0 g, 35%). 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.61-7.58 (t, 1H), 7.50-7.48 (t, 1H), 7.42-7.41 (t, 1H), 7.28-7.24 (m, 1H), 7.11-6.99 (m, 4H). MS (ESI): 218.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.P(Br)(Br)[Br:11]>C(OCC)C>[Br:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: OCc1ccccc1I
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccccc1I
Yield: 91 %

Procedure:
To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-water bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91%) of the title material of Step A as a solid, mp 55-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>>[Cl:26][C:20]1[N:19]=[C:18]([C:14]2([C:12]3[C:7]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=4)[CH2:9][CH2:10][N:11]=3)[CH2:17][CH2:16][CH2:15]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccn3)CCC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2

Procedure:
N-[2-(4-methoxyphenyl)ethyl]-1-(pyridin-2-yl)cyclobutanecarboxamide (679 mg, 1.969 mmol) was reacted with phosphorusoxychloride (2.7 ml, 29.5 mmol) in the microwave at 140° C. for 60 min. The reaction mixture was poured on ice water. After 10 min 10% aqueous sodium hydroxide solution was added until pH 8 was reached. The aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 560 mg (1.71 mmol, 87%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:9]=3[N:28]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CCO>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:9]=3[N:28]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12

Procedure:
methyl 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 81 mg, 0.219 mmol) was stirred in EtOH (3 ml) and 6N NaOH (1 ml) at 60° C. for 15 hours. Water was added and the mixture acidified using 6 N HCl. The solid was filtered, washed with water and dried. After trituration in MeOH and filtration, 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylic acid was isolated as yellow solid (57 mg, 73% yield)). LCMS (ES): >95% pure, m/z 357 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[C:43]([F:46])([F:45])[F:44])[C:26]2=[O:47])=[C:20]([F:48])[CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pt]=O.C(O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([C:43]([F:44])([F:45])[F:46])=[C:34]([N:27]2[C:26](=[O:47])[N:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:19][C:20]=3[F:48])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: [H][H]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 66.6 %

Procedure:
A mixture of 185 mg (0.267 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C), 25 mg of platinum oxide, 2 mL of ethyl acetate, and 10 mL of ethanol was shaken with hydrogen at approximately 3 atm for 2 hours. The mixture was centrifuged, and the supernatant was concentrated. Flash chromatography of the residue on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) yielded 118 mg (67%) of the title compound as a white foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 664 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(C=Cc2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2cc(C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 97.8 %

Procedure:
Methyl 4-[2-(1,1-dimethyl-3-phenyl-1H-inden-5-yl)-vinyl]benzoate (294 mg, 0.77 mmol) and 0.77 mL of 10N NaOH in 7 mL of tetrahydrofuran and 5 mL of methanol were stirred at reflux for 1 hour. The mixture was concentrated and acidified with 1N HCl (10 mL), extracted with ethyl acetate (30 mL×2). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in hot methanol to give 276 mg (90% yield) of the title compound which contained a molecule of methanol; 1H-NMR (DMSO-d6) δ1.34 (s, 6H), 3.14 (s, 3H), 6.58 (s, 1H), 7.25 (d, J=16.4 Hz, 1H), 7.37-7.71 (m, 11H), 7.90 (d, J=8.3 Hz, 2H); MS m/e 367 (MH+).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[BH4-].[Na+]>C(O)(=O)C.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)CNc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Pivalaldehyde (20.4 g, 236 mmol, 25.6 mL) was added to a solution of 4-chloroaniline (30.2 g, 236 mmol) in concentrated acetic acid (475 mL) at ambient temperature. After 1.5 hours, the reaction mixture was cooled to 0° C. and sodium borohydride (11.7 g, 307 mmol) was added portionwise over 15 minutes. After stirring for 1 hour, the resulting mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed successively with water (3×), aqueous 2N sodium hydroxide (2×), saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 47.2 g (99%) of the title compound as an off-white solid which was taken on crude to the next step.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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>[CH:33]1([C:2]2[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[N:10][CH:9]=4)[CH2:35][CH2:34]1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C[C@@H](COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 50.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A), cyclopropylboronic acid (28.1 mg, 0.327 mmol), tetrakis(triphenylphosphine)palladium (17.2 mg, 0.015 mmol) and Cs2CO3 (291 mg, 0.892 mmol) in toluene (5 mL) and water (0.43 mL) mixture was purged with nitrogen for 5 min then heated at 90° C. overnight (16 h). After cooling, toluene was removed under reduced pressure and the product was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (EtOAc-hexane) to afford (S)-tert-butyl (1-((9-cyclopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (70 mg, 0.150 mmol, 51% yield) as an off-white gummy solid. LC/MS (ESI) m/z 466.4 [(M+H)+, calcd for C27H36N3O4 466.3]; LC/MS retention time (method E): tR=1.19 min.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]4[CH2:28][O:27]4)[N:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]>O.CS(C)=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:1])[CH2:28][OH:27])[N:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: [OH-]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CO)n3)cs2)cc1OCC
Temperature: 100 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
A solution of 505 mg of potassium hydroxide dissolved in 30 ml of water was added to a solution of 700 mg of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole dissolved in 30 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 7 hours. The reaction mixture was subjected to extraction three times with 50 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=20/1) and then recrystallized from ethyl acetate-n-hexane to obtain 350 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1,2-dihydroxyethyl)-2-pyridyl]-thiazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][C:12](=[O:13])NC2=O)=[CH:4][CH:3]=1.[OH-:15].[Na+]>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:12]([OH:13])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(O)cc2)C(=O)N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNc1ccc(O)cc1
Temperature: 50 °C
Yield: 6.9 %

Procedure:
Example 1 of U.S. Pat. No. 4,436,910 was generally repeated as follows: p-hydroxyphenyl hydantoin (100 mM, 19.2 g) was treated with NaOH (100 mM, 4.0 g) and Ca(OH)2 (200 mM, 14.2 g) in 200 ml water at 140° C. for four hours in an autoclave. After cooling to 50° C., the precipitated CaCO3 which separated out was filtered off. The recovered mother liquor was analyzed by HPLC. It was found to contain 1.16 g p-hydroxyphenyl glycine (7% yield) in solution. Substantial amounts of decomposition (by-product) was indicated by HPLC analysis. This control experiment demonstrates that the p-hydroxyphenylglycine product when subjected under the reaction conditions [Ca(OH)2, NaOH, 140° C., H2O] suffers severe decomposition to several unwanted and unidentified products. It was quite unexpected then to find that the use per se of only a calcium base material like calcium hydroxide facilitates the production of the corresponding hydantoic acid salt in very high yields. The hydantoic acid salt can then be subjected to decarbamoylation with nitrous acid under acidic conditions to produce p-hydroxyphenylglycine, and which can in turn be optically resolved by processes such as described in U.S. Pat. Nos. 5,120,855 and 3,094,741, both of which are incorporated herein by reference in their entirety.