Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 67.1 %

Procedure:
3-Methyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.925 g, 2.4573 mmol) and ethyl formate (0.59 mL, 7.33 mmol) were dissolved in anhydrous ethanol (25 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.583 mL, 12.28 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.6659 g, 1.65 mmol, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:13][CH2:14][C:15]#[N:16].Cl>O1CCOCC1>[Cl:13][CH2:14][C:15]1[NH:16][C:4](=[O:6])[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([CH3:12])[CH:8]=2)[N:1]=1
Reactant: COC(=O)c1cc(C)ccc1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2nc(CCl)[nH]c(=O)c2c1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
1. 91.4 g of methyl 2-amino-5-methylbenzoate and 23.4 ml of chloroacetonitrile are dissolved in 1.01 of absolute dioxan and the solution is cooled to 10° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 15° C. After 4 h., a further 23.4 ml of chloroacetonitrile are added thereto. The mixture is stirred at room temperature for a further 18 h. The suspension is subsequently evaporated in a vacuum. The crystalline residue is suspended with 2.51 of ice/water, adjusted to pH 8 to 9 with about 100 ml of 25% ammonia, stirred at 5° C. for 1 h. and then filtered. The crystals are washed with water and dried in a vacuum. There are obtained 114.1 g of 2-chloromethyl-6-methyl-3H-quinazolin-4-one of m.p. 263°-265° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([Br:34])[N:26]=2)=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1>[Br:34][C:27]1[N:26]=[C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:14]3[NH:13][C:2](=[O:4])[O:17][C:16](=[O:18])[C:15]=3[CH:19]=2)=[O:24])[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12
Reactant: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C(c1ccc2[nH]c(=O)oc(=O)c2c1)c1nc(Br)c2ccccn12
Yield: 97.9 %

Procedure:
1.30 g (4.37 mmol) of triphosgene dissolved in 10 ml of dioxane are added, under an inert atmosphere at ambient temperature, to 1.05 g (2.91 mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid. The reaction medium is refluxed for 4 hours, and then concentrated under reduced pressure. 100 ml of water are added to the residue. The precipitate obtained is filtered off under reduced pressure at 40° C. for 18 hours. 1.1 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15].C(C1C(=O)C(Cl)=C(Cl)C(=[O:21])C=1C#N)#N.C1(C=CC(O)=CC=1)O>O1CCOCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]=[CH:14][CH:15]=[O:21]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1cc(OC)c(OC)cc1OC
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(OC)c(OC)cc1C=CC=O
Temperature: 95 °C
Yield: 82 %

Procedure:
A solution of 2,4,5-Trimethoxyphenylpropane (5 g) in 70 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of acetic acid (2-4 drops) and 16 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 5 to 9 hrs. The solution, which was initially deep green, turned into pale yellow with the formation of hydroquinone (DDQH2). The mixture was cooled and the solid DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (80 ml) and the ether layer was washed with aqueous NaOH (15%, 2×15 ml). The combined aqueous layers are further extracted with ether (3×15 ml). The ether layers were combined and washed with saturated sodium chloride (3×15 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (70-80 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 2,4,5-trimethoxycinnamaldehyde in 82% yield as a yellow solid; mp 140° C.; UV (MeOH) λmax 244, 298, 366 nm; IR (film) νmax 1648 (conjugated carbonyl), 1602, 1504, 1466, 1448, 1350, 1254, 1120, 1024, 856 cm−1; 1H NMR δ 9.65 (1H, d, J=7.8 Hz, H-3′), 7.81 (1H, d, J=15.8 Hz, H-1′), 7.03 (1H, s, H-6), 6.64 (1H, dd, J=15.8 Hz, J=7.8 Hz, H-2′), 6.51 (1H, s, H-3), 3.95 (s, 3H, 2-OCH3), 3.91 (s, 3H, 4-OCH3), 3.87 (s, 3H, 5-OCH3); 13C NMR δ 194.1 (C-3′), 154.1 (C-1′), 153.2 (C-2), 147.6 (C-4), 143.3 (C-5), 126.4 (C-2′), 114.5 (C-1), 110.5 (C-6), 96.5 (C-3), 56.4 (5-OCH3), 56.2 (2-OCH3), 56.0 (4-OCH3); EIMS m/z 222 [M]+ (44), 207 (18), 191 (100), 179 (14), 171 (27), 151 (14), 147 (7), 69 (58), 58 (80).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#N.O.C(Cl)Cl.N([O-])=O.[Na+].[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1ccc(C#N)cc1
Yield: 84 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Acetic acid (18 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over a one hour period. The mixture was stirred at the same temperature for four hours. The reaction mixture was subjected to extraction with methylene chloride, and the organic solvent was concentrated. Water was added to the concentrated solution, and the residual organic solvent was removed through distillation, to thereby obtain 14.7 g of p-cyanobenzyl acetate (yield 84%). The purity of the product was 98%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:24]1([C:2]2[C:7]([C:8]([C:10]3[CH:11]=[N:12][N:13]([CH3:22])[C:14]=3[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CCC3)cnn2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (200 mg, 0.576 mmol) in acetonitrile (6.0 mL) were added azetidine (39.0 μL, 0.576 mmol) and N,N-diisopropylethylamine (151 μL, 0.867 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The product was carried to Step 7 without further purification. LCMS m/z 368.4 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].CC(C)=O.O.C(=O)(O)[O-].[Na+].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][C@H:4]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7])[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:33]=[CH:34][C:26]=1[O:25][CH3:24]
Reactant: C=CC[C@H](CNC)c1ccccc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CC[C@H](CN(C)C(=O)c1cc(-n2cnnn2)ccc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (S)-N-methyl-(2-phenylpent-4-enyl)amine (1.93 g, 11.0 mmol), acetone/water (4/1, 125 mL), and sodium bicarbonate (3.0 g, 35.5 mmol). Cool in an ice bath with vigorous stirring. Add portionwise, 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (2.86 g, 11.8 mmol). After the addition is complete, warm to ambient temperature. After 1.5 hours, evaporate in vacuo to remove most of the acetone. Extract the evaporated reaction mixture with ethyl acetate. Extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (S)-N-methyl-N-(2-phenylpent-4-enyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1)=[CH2:2].[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14]>C1COCC1>[F:11][C:12]([F:18])([F:17])[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)=[O:14]
Reactant: C=Cc1ccc([Mg]Br)cc1
Reactant: COC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
The (4-vinylphenyl)magnesium bromide solution of Example 1 was cooled to −78° C. using a dry ice /acetone bath and a solution of methyl trifluoroacetate (20.00 g, 156.19 mmol) in THF (25 mL) was added dropwise over 15 min. The reaction mixture was stirred in the cooling bath for 1 h, then quenched by pouring into cold 1N H2SO4. The aqueous solution was extracted with ether and the combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 17.81 g of a pale yellow oil. This material was purified by vacuum distillation to provide 12.65 g (46%) of a colorless oil: bp 59-60° C. (1.4 mm); 1H NMR (CDCl3) δ 8.05 (d, 2ArH), 7.55 (d, 2ArH), 6.79 (dd, CH═), 5.97 (dd, ═CHH), 5.51 (dd ═CHH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8].Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C([O-])([O-])=O.[K+].[K+].N#N>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:9][C:6]1[CH:5]=[C:4]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:3]=[C:2]([Br:1])[C:7]=1[Cl:8]
Reactant: CC1(C)OB(c2cc(Br)c(Cl)c(Br)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Br)c(Cl)c(Br)c1)C(F)(F)F
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 2-(3,5-dibromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260 mg, 0.66 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (172 mg, 0.98 mmol), Pd(dppf)Cl2 (91 mg, 0.13 mmol), K2CO3 (182 mg, 1.32 mmol) in THF (2 mL) and water (0.5 mL) was heated at 80° C. in a sealed vial under N2 atmosphere for 12 h, cooled to rt, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with PE to give 1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (135 mg, yield 56%) as oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Reactant: NCc1ccccc1
Product: c1ccc(CNc2nccc(-c3nn4c(NCc5ccccc5)cccc4c3-c3ccnc(NCc4ccccc4)n3)n2)cc1

Procedure:
N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with benzylamine as described in Example 7. 1H NMR, (400 MHz, CDCl3): δ 8.37 (d, 1H), 8.02 (d, 1H), 7.16–7.40 (m, 16H), 7.12 (t, 1H), 7.02 (bs, 1H), 6.63 (d, 1H), 6.48 (t, 1H), 5.96 (d, 1H), 5.58 (bs, 1H), 5.46 (1H), 4.65 (d, 2H), 4.38–4.62 (m, 4H); MS m/z 590 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[CH:9]2)C=CC=CC=1.ClC(Cl)(Cl)C(=N)O[C:32]([CH3:35])([CH3:34])[CH3:33].B(F)(F)F.CCOCC>C1CCCCC1.ClCCl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OCCc1c[nH]cn1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
2 mmol of 2-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol and 4 mmol of tert-butyl trichloroacetimidate are dissolved in 4 ml of cyclohexane and 2 ml of dichloromethane. After the addition of 120 μl of boron trifluoride etherate, the solution is stirred at 60-70° C. for 18 hours. Filtration of the reaction mixture and evaporation of the solvent are followed by a detritylation in 2 ml of ethanol, 2 ml of acetone and 15 ml of 2N HCl at 70° C. The ethanol and acetone are removed under reduced pressure and triphenylmethanol is extracted with diethyl ether. The aqueous layer is alkalized with ammonia and extracted with diethyl ether. Evaporation of the solvent and final purification by column chromatography (eluent: dichloromethane/methanol, 90:10) yield the product in the form of an oil, which is crystallized in the form of the hydrogen oxalate in ethanol and diethyl ether.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[C:16]2[CH:17]=[C:18]([C:33]([O:35]C)=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl>CO.C(Cl)Cl>[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[C:16]2[CH:17]=[C:18]([C:33]([OH:35])=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
An aqueous NaOH 2N (2.55 ml, 5.10 mmol) solution was added to methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylate (0.79 g, 1.68 mmol) in a mixture of MeOH (9 mL) and DCM (6 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and an aqueous HCl 2N (2.5 mL, 5.0 mmol) solution was added dropwise to the reaction mixture until pH ˜3. After dilution with water (9 mL), the reaction mixture was concentrated to half volume. The aqueous phase was extracted with DCM, the organic phase was concentrated to dryness, leading to a foam, which was triturated in EtAc, collected by filtration, washed with EtAc, diethyl ether, dried under vacuum at 50° C. to afford 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (0.638 g, 83%) as an off-white solid. Mass Spectrum: m/z [M+H]+=457.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].O.O.[Sn](Cl)Cl>C(O)C>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCC1COc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCCCN1CCCC1COc1ccc(N)cc1

Procedure:
In a manner similar to Preparation 44 react 1-butyl-2-[(4-nitrophenoxy)methyl]pyrrolidine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[C:38]1(/[C:44](/[C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)=[CH:45]\[C:46](O)=[O:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>C(Cl)Cl>[C:38]1(/[C:44](/[C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)=[CH:45]\[C:46]([N:28]2[CH2:29][CH2:30][N:25]([C:23](=[O:24])[C:22]3[CH:21]=[C:20]([O:19][CH3:18])[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=3)[CH2:26][CH2:27]2)=[O:47])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)/C=C(\c1ccccc1)c1ccncc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(C(=O)/C=C(\c3ccccc3)c3ccncc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
1 ml of a methylene chloride solution containing 0.330 g of diphenylphosphoryl azide and then 0.280 g of 1-(3,4,5-trimethoxybenzoyl)piperazine were added to 5 ml of a methylene chloride solution containing both 0.224 g of (E)-3-phenyl-3-(4-pyridyl)acrylic acid (prepared as described in Preparation 3) and 0.28 ml of triethylamine. The mixture was then stirred for 4 hours at room temperature, after which the reaction solution was diluted with 20 ml of methylene chloride. It was then washed with a 5% w/v aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the oily residue (0.686 g) was purified by silica gel flash chromatography. 0.419 g of the title compound was obtained as a white powder from the fractions eluted with mixtures of methylene chloride and methanol ranging from 100:2 to 100:3 by volume.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20].B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20]
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1I
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
To a solution of 2-(4′-methylamino-3′-iodophenyl)-6-methoxy benzothiazole (12 mg, 0.03 mmol) dissolved in CH2Cl2 (4 mL) was added BBr3 (400 μl, 0.4 mmol, 1M in CH2Cl2) under N2. The reaction was allowed to stir at room temperature for 18 hr. Water was then added to quench the reaction and the solution was neutralized with NaHCO3, extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over MgSO4 and evaporated. The residue was purified with preparative TLC (Hexane:EA=7:3) to give 2-(4′-methylamino-3′-iodophenyl)-6-hydroxy benzothiazole (5 mg, 43%) as brown solid. 1HNMR (300 MHz, CDCl3) δ(ppm): 8.37 (d, H=2.0 Hz, 1H), 7.88 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 6.96 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 2.96 (s, 3H, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([N:15]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[N:26]=[CH:25]4)[S:17][C:16]2=[O:43])[CH2:9]1)=O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:27]2[C:28]3[C:24](=[CH:23][C:22](/[CH:21]=[C:18]4/[C:19](=[O:20])[N:15]([CH:10]5[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]5)[C:16](=[O:43])[S:17]/4)=[CH:30][CH:29]=3)[CH:25]=[N:26]2)=[C:33]([C:39]([F:41])([F:42])[F:40])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCNCC1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.2 mmol) in DCM (2 mL) was added Dess-Martin periodinane powder (0.25 mmol). The mixture was stirred at rt for 18 h, then purified by silica gel chromatography (0-30% EtOAc/hexanes). The product was obtained as pale yellow solid, which was treated with TFA/DCM following General Procedure M to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].I[CH2:38][C:39]([F:42])([F:41])[F:40].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[O:26])([C:16]2[CH:21]=[C:20]([O:22][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OCC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 58 %

Procedure:
To a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 254, 15 mg, 0.03 mmol) in DMSO (0.15 mL) was added ICH2CF3 (0.02 mL) and K2CO3 (20 mg, 0.2 mmol). The reaction mixture was heated at 70° C. overnight. The reaction was cooled to rt and diluted with CH3CN, filtered and purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 255) as white solid (10 mg, yield 58%). LCMS: RT=2.18 min [M+H] 601.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.43 (2H, m), 7.21 (1H, d, J=6.60 Hz), 7.12-7.19 (2H, m), 6.68 (2H, d, J=7.70 Hz), 6.54-6.63 (3H, m), 4.19-4.30 (2H, m), 3.73-3.84 (4H, m).