Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.151 g, 0.43 mmol), benzylamine (0.05 mL, 0.48 mmol), and sodium cyanoborohydride (0.041 g, 0.65 mmol) were combined in CH2Cl2 (3 mL). Acetic acid (2 drops) was added, and the reaction was stirred overnight at room temperature. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[CH:26]1([C:13]2[C:12]([O:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:17][N:16]3[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[N:19][N:20]=[C:15]3[CH:14]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: OCc1ccccn1
Reactant: Clc1nn2c(-c3cccs3)nnc2cc1C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2nn3c(-c4cccs4)nnc3cc2C2CCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
b 2-Hydroxymethylpyridine (56 mg) was dissolved in dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 21 mg) was added followed after 5-10 minutes by 6-chloro-7-cyclopentyl-3-(thiophen-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction was stirred at room temperature for 18 hours, partitioned between ethyl acetate and water, organic phase separated dried (MgSO4) and evaporated to dryness. Recrystallized in ethyl acetate in ether or methanol to give pure product. 1H NMR (250 MHz, CDCl3) δ1.73 (6 H, m), 2.16 (2 H, m) 3.38 (1 H, m), 5.68 (2 H, s), 7.21 (1 H, m), 7.28 (1 H, m), 7.51 (2 H, m), 7.77 (1 H, m), 7.88 (1 H, d, J=1.1 Hz), 8.15 (1 H, m), 8.65 (1 H, m); MS (ES+) m/e 377 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH:14](/B(O)O)=[CH:15]\[CH3:16].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)C.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH:14]=[CH:15][CH3:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Reactant: C/C=C/B(O)O
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: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC=Cc1cc(C(=O)OCC)cc(C)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 109.6 %

Procedure:
To a solution of 2-chloro-6-methylisonicotinic acid ethyl ester (2.0 g, 10.0 mmol), and trans-propenyl boronic acid (1.30 g, 15.13 mmol) in DME (20 mL), a solution of 2 M aq. K2CO3 (3 mL) followed by Pd(PPh3)4 (150 mg, 0.205 mmol) and triphenylphosphine (265 mg, 0.99 mmol) is added. The mixture is stirred at 100° C. for 15 h before it is cooled to rt, diluted with diethyl ether and washed with sat. aq. Na2CO3 (2×30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g) as a colourless oil; LC-MS: tR=0.65 min, [M+1]+=206.33.
Reaction SMILES: C([NH:8][C:9](=[NH:33])[NH:10][C:11]1[CH:32]=[CH:31][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:19](=[O:30])[CH2:18]2)=[O:16])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[OH-].[Na+]>O1CCOCC1>[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:19](=[O:30])[CH2:18]2)=[O:16])=[CH:31][CH:32]=1)[C:9]([NH2:33])=[NH:8]
Reactant: CCOC(=O)CCN1CCN(C(=O)c2ccc(NC(=N)NC(=O)OC(C)(C)C)cc2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N=C(N)Nc1ccc(C(=O)N2CCN(CCC(=O)O)C(=O)C2)cc1
Reaction time: 5 h

Procedure:
A mixture of 10 g of ethyl 3-(4-(4-(3-BOC-guanidino)benzoyl)-2-oxopiperazin-1-yl)propionate (m.p. 143°; FAB 462; obtainable by condensing 4-(3-BOC-guanidino)benzoic acid with ethyl 3-(2-oxopiperazin-1-yl)propionate), 400 ml of dioxane and 56 ml of 1 N aqueous NaOH solution is stirred for 5 hours at 20°. It is evaporated, the residue is dissolved in water, the solution is washed several times with ethyl acetate, and HCl is added to pH 4. Extraction is carried out with ethyl acetate, the extract is dried and evaporated, the resulting crude 3-(4-(4-(3-BOC-guanidino)benzoyl)-2-oxopiperazin-1-yl)propionic acid is dissolved in 200 ml of 4 N HCl in dioxane and the solution is stirred for 3 hours at 20° and worked up in conventional manner to give 3-(4-(4-guanidinobenzoyl)-2-oxopiperazin-1-yl)propionic acid, m.p. 110° (decomposition).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14](Cl)[N:13]=1)=[O:11].Cl>O>[CH:3]1([CH2:6][O:7][C:14]2[N:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:17]=[CH:16][C:15]=2[C:18]([F:21])([F:19])[F:20])[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(Cl)n1
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Sodium hydride (1.1 g, 31.4 mmol) was added in portions to cyclopropylmethanol (20 mL) and the mixture was stirred at room temperature for 0.5 hours. 6-Chloro-5-(trifluoromethyl)-pyridine-2-carboxylic acid methyl ester (1.5 g, 6.3 mmol) was added and the resulting solution was stirred at 80° C. for 1 h. Water (20 mL) was added; the solution was acidified with 6 N hydrochloric acid and then concentrated to give a residue which was partitioned between water (30 mL) and ethyl acetate (20 mL). The aqueous solution was extracted with ethyl acetate (2×20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude target compound. The crude target compound was purified by column chromatography (silica gel, 10 g, 15% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 85%) as white solid; MS (EI): m/e=262.0 [M+H]+.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=O.[Na+].[I-:16].[K+]>Cl.O>[Cl:10][C:8]1[CH:9]=[C:2]([I:16])[CH:3]=[C:4]([Cl:11])[C:5]=1[C:6]#[N:7]
Reactant: [I-]
Reactant: N#Cc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1c(Cl)cc(I)cc1Cl
Temperature: 25 °C

Procedure:
4-amino-2,6-dichlorobenzonitrile (1.65 g, 8.82 mmol) was stirred in 7.5 mL of 12M HCl solution. The reaction mixture was cooled with ice-bath. Sodium nitrite (0.6 g, 8.82 mmol) dissolved in 6 mL of water was added drop-wise to the flask under cold condition, followed by the drop-wise addition of cold potassium iodide (5.86 g, 35.3 mmol) solution in water (12 mL). The mixture was allowed to stir at RT for a day. After the completion of the reaction, the mixture was extracted with ethyl acetate, washed with 10% Na2SO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated. The solid obtained was washed with heptane-ethyl acetate mixture (5:1) and dried under vacuum. Yield 1.09 g. 1H NMR (400 MHz; d6-DMSO): δ 6.71 (s, 1H), 6.81 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[C:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2.[OH:22][CH2:23]C1C(C(O)=O)=CC2C(C=1C1C=CSC=1)=CC=C(O)C=2>>[OH:22][CH2:23][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2.[OH:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[C:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2
Reactant: O=C(O)c1cc2cc(O)ccc2c(-c2ccsc2)c1CO
Agent: Cc1c(C(=O)O)c(O)c(-c2ccoc2)c2ccc(O)cc12
Product: O=C(O)c1cc2cc(O)ccc2c(-c2ccoc2)c1CO

Procedure:
Following the procedure described in Example 7, but substituting 6-[4-(4-hydroxy)tetrahydropyranyl]pyridin-2-ylmethanol (Alcohol 2) for 5-[4-(4-hydroxy)tetrahydropyzanyl]pyridin-3-ylmethanol (Alcohol 1), and substituting 3-hydroxymethyl-4-(3-thienyl)-7-hydroxy-2-naphthoic acid, lactone form (Lactone 4), for 3-hydroxymethyl-4-(3-furyl)-7-hydroxy-2-naphthoic acid, lactone form (Lactone 1), the title compound was obtained as a solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
In a flask, 25 g of benzyl bromide, 36.4 g of 4-bromo-4'-hydroxybiphenyl, 40.4 g of potassium carbonate, and 300 ml of 2-butanone were placed, and stirred under reflux for 6 hours. The reaction solution was poured into water, and an organic layer was extracted with toluene. After the toluene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was recrystallized from acetone to give 42.5 g of 4-bromo-4'-benzyloxybiphenyl (Y: 85.8%). The purity of the compound thus obtained was 99.0% by GC.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[F:6][C:7]([F:12])([F:11])[C:8](O)=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1.O>[NH2:5][C:3]1[S:4][C:8]([C:7]([F:12])([F:11])[F:6])=[N:1][N:2]=1
Reactant: NNC(N)=S
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(C(F)(F)F)s1
Temperature: 20 °C
Yield: 72.1 %

Procedure:
A three-liter reaction flask fitted with a mechanical stirrer, heating mantle, dropping funnel, thermometer and water-cooled condenser connected to a caustic trap was charged with 228 g (2.5 mole) of thiosemicarbazide, 1260 ml of 1,4-dioxane and 285.1 g (2.5 mole, 193 ml) of trifluoroacetic acid. The dropping funnel contained 383.8 g (2.5 mole, 229 ml) of phosphorus oxychloride which was added to the reaction flask over a period of 30 minutes. The resulting thick slurry was heated slowly to reflux with rapid evolution of hydrogen chloride gas. The slurry thinned with separation of the product as a heavy syrup. Total reflux time required about four hours until the gas evolution ceased. The dioxane was decanted and then 1700 ml of water was added to the residue. The mixture was cooled to 20° C. and made basic with 50% sodium hydroxide (~225 ml) to pH 9. The slurry was cooled to 10° C. and collected on a filter funnel. The cake was washed with cold water and dried in the oven. There was obtained 305 g, Mp 219°-220.5°, yield 72.1%. The proton NMR recorded in Me2SO-d6 consisted of a peak at 7.9∂ (NH2) with respect to tetramethylsilane.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11]C)=[O:10])[CH:3]=1.O.[OH-].[Li+]>CO.O>[F:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (0.876 g, 5.12 mmol) in MeOH (33 mL) and water (11 mL), was added lithium hydroxide hydrate (1.074 g, 25.6 mmol). The resulting mixture was then stirred at rt for 5 h. The mixture was concentrated and the pH was adjusted to pH=5 using concentrated HCl. The mixture was then concentrated and dried in vacuo. The resulting residue was dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried. The solid mixture was then purified by silica gel flash column chromatography (30%-100% EtOAc/hexane, then 0%-100% MeOH/DCM) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 158 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][N:17]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(OC2CN(C(=O)NC(C)(C)C)C2)c2ccccc2C(F)(F)F)cc1
Yield: 68.7 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]azetidine (157) (100 mg, 0.30 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (3.01 mmol/g; 100 mg, 0.30 mmol) and tert-butyl isocyanate (35 μL, 0.30 mmol). The resultant mixture was shaken at ambient temperature for 5 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (6 mL) followed by DCM-MeOH (6 mL), then evaporated. Purification by flash column chromatography [SiO2; ethyl acetate-iso-hexane (35:65→50:50)] afforded the desired product as a colourless glass (90 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14]Br)[CH3:2].[Br:17][C:18]1[C:19](=[O:34])[N:20]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:21]([CH3:25])=[CH:22][C:23]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][O:24][C:23]1[CH:22]=[C:21]([CH3:25])[N:20]([C:26]2[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=2[F:32])[C:19](=[O:34])[C:18]=1[Br:17])[CH3:2]
Reactant: Cc1cc(O)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CCOC(=O)COc1cc(F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Reaction time: 2 h

Procedure:
To a solution of ethyl[2-(bromomethyl)-5-fluorophenoxy]acetate (from Step 2) (0.59 g, 2.03 mmol) and 3-bromo-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.61 g, 1.93 mmol) in DMF (3.0 mL) was added K2CO3 (0.34 g, 2.43 mmol). After 2 h at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid, extracted in DCM, dried over Na2SO4, filtered, and concentrated onto silica gel. Purified by flash column chromatography using 50% EtOAc/hexane as the eluent. Obtained product as a pale yellow solid (0.45 g, 42%). 1H NMR (CD3OD/400 MHz) δ7.21 (q, 3H, J=8.4 Hz), 6.80 (m, 2H), 6.69 (s, 1H), 6.15 (s, 1H), 5.40 (s, 2H), 4.84 (s, 2H), 4.23 (q, 2H, J=6.8 Hz), 2.08 (s, 3H), 1.26 (t, 3H, J=6.8 Hz). ESHRMS m/z 526.0446 and 528.0414 (M+H calculated for C23H20BrF3NO5 requires 526.0471 and 528.0454).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:33])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:28][CH2:29][N:30]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:31][CH:32]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:33])=[O:10])=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCNCC3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCN(S(C)(=O)=O)CC3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 39 (80 mg, 0.172 mmol) and TEA (0.048 ml, 0.344 mmol) in DCM was added methanesulfonyl chloride (0.021 ml, 0.258 mmol) dropwise. The resulting mixture was stirred at r.t. for 16 hrs, then quenched with water, and extracted with EtOAc. The organic layer was dried with Na2SO4 and filtered. The solvents were removed in vacuo, and the crude product was purified by flash chromatography (silica gel, EtOAc/MeOH/N H3 gradient) to yield Example 44.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([Cl:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12]
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)Cc1ccc(Br)cc1Cl
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a solution of 4-bromo-2-chlorophenylacetic acid (240 g) of Reference Example 15 in N,N-dimethylformamide (3000 mL) were added potassium carbonate (399 g) and iodomethane (164 g) at 7° C., and the mixture was stirred at the same temperature for 3 hr and stirred at room temperature for 19 hr. The reaction mixture was poured into water, and partitioned and extracted with ethyl acetate. The organic layer was washed 3 times with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (259 g) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:53])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=3)[N:28]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:27]=2[CH2:49][CH2:50][CH2:51]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:53])[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=3)[N:28]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:27]=2[CH2:49][CH2:50][CH2:51][NH:11][S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCCBr)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCc2c(CCCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
33.3 mg of α-toluenesulfonamide (0.0002M, 1.2 eq.) was dissolved in 0.5 mL of DMF and added to a slurry of 8.0 mg of 60% sodium hydride (0.0002M, 1.2 eq.) in 0.5 mL of DMF. The reaction was stirred for 30 min. at which point 100 mg of 4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0002M, 1.0 eq.) in 0.5 mL of DMF was added and the solution was stirred for an additional 1 hour. The reaction was quenched with water and diluted with 10 mL of ethyl acetate. The organic layer was washed with water(2×5 mL) and brine (2×5 mL), dried over magnesium sulfate and evaporated to a yellow oil. The residue was purified via column chromatography (ethyl acetate/hexanes 5:95) to give 20 mg (17%) of 4-{2-[1-Benzhydryl-5-chloro-2-(3-phenylmethanesulfonylamino-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:17]=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][C@H:10]1[CH2:14][O:13]C(C)(C)[O:11]1)=[O:6].C(O)(C(F)(F)F)=O.ClCCl>>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:17]=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[O:6]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccnc(Cl)c2Nc2ccc(I)cc2F)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOC[C@H](O)CO)c1ccnc(Cl)c1Nc1ccc(I)cc1F

Procedure:
Deprotection of 2-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide with 50:50 mixture of TFA/dichloromethane at room temperature for 30 minutes afforded the desired product. Purification by reverse phase LC/MS [7.94 min; 482 (M+1)].
Reaction SMILES: [Cl:1][C:2]1N=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[Cl-].Cl[C:33]1C=CC(C[Zn+])=CN=1>>[Cl:1][C:2]1[CH:33]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Cl-]
Product: O=c1c2cc(Cc3ccc(Cl)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O

Procedure:
6-(4-Chlorobenzyl)-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 1, substituting 4-chlorobenzylzinc chloride for (2-chloro-5-pyridyl)methylzinc chloride.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH:19][C:20]3[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][CH:21]=3)[C:16]([O:28][CH3:29])=[CH:15][N:14]=2)=[N:6]1.S(=O)(=O)(O)[OH:35].[OH-].[Na+]>>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH:19][C:20]3[C:25]([C:26]([NH2:27])=[O:35])=[CH:24][N:23]=[CH:22][CH:21]=3)[C:16]([O:28][CH3:29])=[CH:15][N:14]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1C(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 80 mg of 4-({2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinonitrile 2-1-7 (0.181 mmol, 1.00 eq.) were given at rt with caution 0.28 mL of sulfuric acid. The mixture was stirred for 3 days at rt. Then the reaction mixture was dropped into ice water and set with aqueous 2M sodium hydroxide solution to an alkaline pH. The suspension was filtrated and the resulted solid was dried at 65° C. to provide 86 mg (0.18 mmol, 83%) of the analytically pure target compound.