Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[C:15]2[C:10](=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH2:20][O:21]C)[C:7]=1[C:23]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:24].O>C(Cl)Cl>[OH:5][C:6]1[C:15]2[C:10](=[C:11]([C:16]([F:17])([F:19])[F:18])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH2:20][OH:21])[C:7]=1[C:23]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:24]
Reactant: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)c1c(CO)nc2c(C(F)(F)F)cccc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 4 ml of boron tribromide in 30 ml of methylene chloride was added with stirring at -70° C. to a solution of 2.88 g of the product of Example 3 in 75 ml of methylene chloride and the mixture stood overnight with stirring while the temperature was allowed to rise to -20° C. The mixture was poured into 500 ml of ice and water and the mixture was stirred for 20 minutes and was vacuum filtered. The product was washed with water until the pH was 5 to 6 and was dried under reduced pressure at 100° C. The product was dissolved in refluxing dimethylformamide and the solution was cooled, iced and vacuum filtered. The product was washed with dimethylformamide and then with ether and dried under reduced pressure at 120° C. to obtain 2.3 g of 4-hydroxy-2-hydroxymethyl-N-(2-thiazolyl)-8-trifluoromethyl-3-quinolinecarboxamide melting at 280° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1B(O)O>>[CH:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:27]2[CH:26]=[CH:25][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (see step (a) above) and 2-naphthylboronic acid followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.ON1C2C=CC=CC=2N=N1.[C:55](O)(=[O:57])[CH3:56]>CN(C)C=O.O>[C:55]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:25]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:15]([C:13]([NH:12][C:5]5[C:4]([CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=5[CH2:10][CH3:11])=[O:14])=[N:16][N:17]([CH3:35])[C:18]=4[C:27]=3[N:26]=2)[CH2:34][CH2:33]1)(=[O:57])[CH3:56]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(C)=O)CC3)nc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dimethylformamide (1 mL), DIPEA (0.2 mL, 1.1 mmol), N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (22 mg, 0.113 mmol), 1-hydroxy-benzotriazole (18 mg, 0.113 mmol) and acetic acid (0.005 mL, 0.009 mmol) were added. The mixture was stirred at room temperature for 6 h. Water was added and the mixture extracted with ethylacetate. The organic layer was washed with brine then dried over Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 97/3) to 29 mg of the title compound. (77% yield)
Reaction SMILES: C1([P+](Cl)(Cl)[Cl:8])C=CC=CC=1.[N+]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]=12)=[O:18])([O-])=O.[OH-].[Na+]>C1(P(Cl)(Cl)=O)C=CC=CC=1>[Cl:8][C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]=12)=[O:18]
Reactant: Cl[P+](Cl)(Cl)c1ccccc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=P(Cl)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OC(=O)c2c(Cl)cccc21
Temperature: 170 °C

Procedure:
Phenyltrichlorophosphonium hexachlorophosphide (4 g, 8.8 mM) was added to phenylphosphonic dichloride (10 ml). To this solutoin, 3 nitrophthalic anhydride (1.7 g, 8.8 mM) was added. The reaction mixture was heated to 170° C. for 12 hours, then cooled to room temperature and poured onto ice. After neutralizing with 50% aqueous sodium hydroxide, the reaction was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 3-chlorophthalic anhydride (1.3 g, 81 wt. % yield) as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]=O)=[CH:7][CH:8]=2)[NH:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O.O.CC(O)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:12][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][CH2:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:20]
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Reactant: COc1cccc(C(=O)NC2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)NC2CCN(Cc3ccc4c(c3)NC(=O)CC4)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Step R1-5: To a suspension of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (135 g) in CHCl3 (1.4 L) were added 3-methoxy-N-(piperidin-4-yl)benzamide (190 g) and AcOH (45 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. After cooling to 0° C., NaBH(OAc)3 was added portionwise. The mixture was stirred at room temperature for 19 hours. After cooling to 0° C., 8 M aqueous NaOH (0.5 L) and water (0.5 L) were added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated to obtain a colorless solid. The solid was suspended in EtOAc (3.0 L) and the mixture was refluxed for 1 hour and cooled to room temperature. The precipitate was filtrated to obtain a colorless solid. The solid was suspended again in EtOAc (2.4 L), and the mixture was refluxed for 1 hour and cooled to room temperature. The precipitate was filtrated to obtain the titled compound as a colorless solid (229 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][N:35]([CH3:39])[CH2:36][C:37]#[CH:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][N:35]([CH3:39])[CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), 1-dimethylamino-2-propyne (0.070 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 4% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, toluene, methanol-ether and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.06 g of the title compound as a tan solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][N:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1.O>[Cl:32][C:4]1[N:3]=[C:2]([C:38]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:33])[CH:39]=2)[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3ccnc(C)c3)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (37B, 75 mg, 0.163 mmol), 2-methylpyridine-4-boronic acid pinacol ester (39.3 mg, 0.179 mmol), and Xphos Precatalyst 2nd generation (10.25 mg, 0.013 mmol) were taken up in THF (1.1 ml). The mixture was evacuated and back-filled with N2 gas (3×). Potassium phosphate tribasic (104 mg, 0.489 mmol) in Water (543 μl) (degassed) was then added to the reaction mixture. The reaction was allowed to stir at 60° C., for 1 hour. The reaction was then filtered through celite and loaded onto silica gel. The reaction mixture was purified by MPLC 0-50% EtOAc/DCM to give 6-chloro-3-methoxy-4-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (49B). MS: [M+H]+ m/z 517.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35](O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cc(F)ccc1F)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1cc(F)ccc1F)O2

Procedure:
2-(2,5-Difluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 420 mg of 2-(2,5-difluorophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.34-7.22 (m, 3H), 6.71-6.51 (m, 3H), 5.20 (m, 1H), 2.93 (m, 1H), 2.68 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH:7]1[NH:11]C(=O)N[C:8]1=[O:13]>O>[NH2:11][C@H:7]([C:8]([OH:13])=[O:1])[CH2:6][CH2:5][S:4][CH3:3]
Reactant: [OH-]
Reactant: CSCCC1NC(=O)NC1=O
Agent: [Na+]
Solvent: O
Product: CSCC[C@H](N)C(=O)O
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
A mixture of 13.1 g of 98% sodium hydroxide pellets (0.32 mole) and 17.4 g (0.10 mole) of 5-(beta-methylmercaptoethyl)-hydantoin in 100 ml of water-saturated n-hexanol was heated to boiling over 25 minutes and refluxed with stirring for 26 minutes, after which the reaction mixture was quenched. The cold reaction mixture was stirred with 75 ml water for 1/4 hour, and the aqueous phase was separated. The organic phase (n-hexanol) was washed with four 25 ml portions of water. The combined, filtered, aqueous phases were neutralized to pH of 6 with concentrated hydrochloric acid, stirred at room temperature for the crystallization of methionine, and stored at 5° C. The reaction product was collected, washed with water, and dried to give 3.2 g of methionine, m.p. 268° C. decomposition. The combined mother-liquor and washings were concentrated to about 80 ml during which methionine crystallized. After the mixture had been chilled at 5° C., the reaction product was collected, washed with water, and dried to obtain 3.5 g of methionine, m.p. 268° C. decomposition.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([CH3:12])=[CH:7][N:6]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:18](=[O:20])[CH3:19])[C:8]([CH3:12])=[CH:7][N:6]=1
Reactant: Cc1cnc(Oc2ccc(F)cc2F)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccc(F)cc2F)ncc1C
Yield: 99 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-5-methylpyridin-4ylamine (3.6 g) in 80 mL of methylene chloride was added 4.7 g of acetic anhydride. The mixture was heated for 24 hours on a steam bath and then poured onto 200 mL of 5% aqueous sodium carbonate. The aqueous solution was extracted with methylene chloride. The organic layers were combined, dried and concentrated to give 4.2 g of N-[2-(2,4-difluorophenoxy)-5-methylpyridin-4-yl]acetamide (99% yield). Mass. Spec. M+H=279.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[N:22]=[C:21]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:20]=1)(=[O:11])=[O:10])C1C=CC=CC=1.OS(O)(=O)=O.[OH-].[Na+]>>[C:31]([C:21]1[CH:20]=[C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([NH2:8])(=[O:10])=[O:11])[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[N:22]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1ccccc1S(=O)(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1ccccc1S(N)(=O)=O
Reaction time: 0.33 h
Yield: 64.4 %

Procedure:
N,N-Dibenzyl-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzene-sulfonamide (from Step 2, 240 mg, 0.42 mmol) was added to conc H2SO4 (3 mL), and the mixture was vigorously stirred for 20 min. The mixture was poured onto ice, and conc NaOH solution was added until a pH of ˜7.5 was reached. The aqueous layer was extracted 2× with EtOAc, and the combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography using EtOAc/hexane (1:3, v/v) afforded the title compound as a white solid (104 mg, 64%). 1H NMR (δ 400 MHz, CD2Cl2) 61.39 (s, 9H), 2.09 (s, 3H), 4.50 (br, 2H), 6.20 (s, 1H), 7.94 (t, 1H), 7.23 (m, 4H), 7.34 (m, 2H), 7.45 (t, 1H), 7.73 (d, 1H). ES-MS m/z 385.2 (MH+); HPLC RT (min) 3.11.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Br:10]Br>C(Cl)Cl.[Fe]>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([S:8][CH3:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: CSc1ccccc1C
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CSc1ccc(Br)cc1C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a 0° C. solution of 2-methylthioanisole (0.50 g, 3.57 mmol) in methylene chloride (40 mL) was added powdered Fe (20 mg, 0.36 mmol) followed by dropwise addition of bromine (0.58 g, 3.54 mmol). After 30 minutes, the starting material had been consumed (thin layer chromatography, hexanes). The excess bromine was quenched by adding a solution of NaHSO3 and stirring for several minutes. The methylene chloride layer was separated, and the aqueous phase extracted with additional methylene chloride. The combined methylene chloride solution was dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was chromatographed (flash silica gel, ethyl acetate/hexanes 1:49) to provide the product (yield: 0.74 g, 96%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 3H), 2.45 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.27-7.33 (m, 2H).
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([C:1]2[NH:8][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C:16](=[O:25])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: N=C(N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccccc2)NC(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred suspension of 8.42 g (70.2 mmol) of benzamidine and 8 mL (99.2 mmol) of pyridine in 150 mL of toluene was added dropwise over 10 min a solution of 7.68 g (46.1 mmol) of cinnamoyl chloride in 20 mL of toluene. The mixture was stirred for 10 min at room temperature and heated at reflux for 2 days. The mixture was cooled, diluted with 150 mL of ethyl acetate and extracted with two 125 mL portions of 5% aqueous HCl. The combined aqueous HCl extracts were neutralized by careful addition of 50% aqueous NaOH and extracted with two 250 mL portions of ethyl acetate. These ethyl acetate extracts were combined, dried over MgSO4 and rotovaped to afford 7.80 g of 5,6-dihydro-2,6-diphenylpyrimidin-4-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:34][NH:35]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](NC(=O)Cc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)Cc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
To N-{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}-2-phenylacetamide (105 mg, 0.236 mmol) in ethanol (2 mL) into a 5 mL sealable vial was added hydrazine (0.22 mL, 7.1 mmol), and the reaction was then capped and heated on a hot plate at 100° C. overnight. The reaction was concentrated, then redissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (30 ml/min, 15% CH3CN/H2O, 0.1% TFA to 45% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the resulting aqueous mixture was added sat. aqueous NaHCO3, and then it was extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (44 mg) as a light yellow solid. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.8 Hz, 3H), 1.61-1.76 (m, 4H), 2.57-2.68 (m, 1H), 3.44 (s, 2H), 3.59 (dd, J=7.7, 3.4 Hz, 1H), 4.38-4.84 (m, 2H), 5.38 (s, 2H), 6.11 (bs, 2H), 6.56 (s, 1H), 7.21-7.36 (m, 5H), 7.54 (dd, J=8.6, 1.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 11.51 (s, 1H).
Reaction SMILES: Cl[C:2]1C=CC=CC=1C(C1C=CC(F)=CC=1)=O.[F:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=O>>[F:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH2:2]
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Reactant: O=C(c1ccc(F)cc1)c1ccccc1Cl
Product: C=C(c1ccc(F)cc1)c1ccccc1F
Yield: 85 %

Procedure:
The procedure described in Example 1 is repeated except that the 130 parts of 2-chloro-4'-fluorobenzophenone are replaced by 168 parts of 2,4'-difluorobenzophenone, which was converted into the title compound in 85% yield. Distillation, under vacuum, gives a colourless liquid which is pure 1-(2-fluorophenyl)-1-(4-fluorophenyl)ethene (b.pt. 82°/0.2 mm Hg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][C:30](O)=[O:31].[NH3:33]>O1CCOCC1>[NH2:33][C:30](=[O:31])[CH2:29][CH:7]1[C:6]2[C:28](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:24]4[CH2:23][CH:22]5[CH2:21][CH:20]([CH2:19][CH:18]3[CH2:26]5)[CH2:25]4)=[O:27])[CH2:13][CH2:14]2)[CH2:8]1
Reactant: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared from (±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid following a procedure analogous to that described in Example 127 except that 0.5 M NH3 in dioxane was used in place of NH3 gas.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[C@@H:16]([CH3:34])[CH2:15]2)[C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[C@@H:16]([CH3:34])[CH2:15]2)[C:9]([CH:11]2[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)C3CC3)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H]1C[C@@H](N(C(=O)C2CC2)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropanecarboxamide (200 mg, 0.42 mmol, 1 equ.) in methylene chloride (0.3 mL) was added a 1 M solution of boron tribromide in methylene chloride (1.2 mL, 1.26 mmol, 3 equ.). The reaction mixture was stirred at room temperature for 4 h, then the reaction was quenched with methanol and concentrated. The residue was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropanecarboxamide as a beige powder (190 mg, 98%).