Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:9][CH:8]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:3]([OH:6])([CH3:5])[CH:2]([C:7]1[S:11][C:10]([C:12]2[NH:40][C:15]([CH:16]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=3)[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:9][CH:8]=1)[OH:1]
Reactant: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(O)C(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.51 g), ammonium acetate (0.39 g) and acetic acid (5 mL) was stirred at 90° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.38 g, yield 77%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 505 (MH+).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:19][O:20][C:21](=[O:40])[C@H:22]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[N:23]1[CH2:28][CH:27](O)[C:26]2[S:30][CH:31]=[CH:32][C:25]=2[CH2:24]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:19][O:20][C:21]([C@@H:22]([N:23]1[CH2:24][C:25]2[CH:32]=[CH:31][S:30][C:26]=2[CH2:27][CH2:28]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])=[O:40]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC#N
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium iodide in acetonitrile is added chlorotrimethylsilane. The mixture is stirred at room temperature under nitrogen for 1 hour. (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate para toluenesulfonic acid salt (55.0 g, 108 mmol) is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 17 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oily product (30.6 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.O[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:51][CH2:52][C@@H:53]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH3:54])[CH:47]=1)=[O:45]>C(#N)C.O>[OH:42][C:39]1[CH:40]=[CH:41][C:36]2[O:45][C:44]([C:46]3[O:50][N:49]=[C:48]([O:51][CH2:52][C@@H:53]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH3:54])[CH:47]=3)=[N:43][C:37]=2[CH:38]=1
Reactant: C[C@@H](COc1cc(C(=O)Nc2cc(O)ccc2O)on1)NC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
Triethylamine (2.83 mL) was added to a solution of triphenylphosphine (2.0 g) and hexachloroethane (1.5 g) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was further added a solution of tert-butyl [(1S)-2-({5-[(2,5-dihydroxyphenyl)carbamoyl]isoxazol-3-yl}oxy)-1-methylethyl]carbamate (1.0 g) in acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (503 mg).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O-:19])=[O:18]>>[CH3:7][C:5]1[S:4][C:3]([CH:8]=[O:9])=[C:2]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])[CH:6]=1
Reactant: Cc1cc(Br)c(C=O)s1
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccccn2)c(C=O)s1

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-bromo-5-methylthiophene-2-carbaldehyde and pyridine-2-sulfinate sodium salt.
Reaction SMILES: O1CCCC1.[Si]([O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:26][C:27](=[O:41])[C:28]4[N:33]([CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)[N:32]=[C:31]([CH3:40])[C:29]=4[N:30]=3)=[C:21]([O:42][CH3:43])[CH:20]=2)[CH2:15]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH:34]1([N:33]2[C:28]3[C:27](=[O:41])[NH:26][C:25]([C:22]4[CH:23]=[CH:24][C:19]([N:16]5[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]5)=[CH:20][C:21]=4[O:42][CH3:43])=[N:30][C:29]=3[C:31]([CH3:40])=[N:32]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1cc(N2CC[C@@H](O[Si](C)(C)C(C)(C)C)C2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CC[C@@H](O)C2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 3 ml tetrahydrofuran solution of 243 mg (0.452 mmol) of the compound obtained in Example 269, 0.54 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution 0.54 mmoml) was added, and the mixture was stirred at room temperature for 2 hours. Then, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1˜20/1) to obtain 191 mg (quant.) of the captioned compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[O-:15])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Temperature: 25 °C

Procedure:
A solution of 22.69 g (110 mmol, 1.1 equivalents) of 2,6-di-t-butylphenol in 10 mL of toluene was treated with 100 mL (100 mmol) of a 1M solution of tetrabutylammonium hydroxide in methanol under nitrogen with stirring at ambient temperature. The resulting dark green solution was stirred for 1 hour and concentrated under vacuum to a thick residue. Two 100 mL portions of toluene were added and removed by evaporation under vacuum yielding 52.08 g of wet, crude title compound as a green solid which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:39]=[CH:40][CH:41]=2)[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35](=[O:38])(=[O:37])[NH2:36])=[O:27])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1>[C:13]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:39]=[CH:40][CH:41]=2)[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:36][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:37])=[O:38])=[O:27])=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuan (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 535 mg (yield: 99.0%) of the title compound.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[N:16]1.Br[C:30]1[C:31](N2CC[C@@H](O)C2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37]C1C=CC(OC(F)(F)C)=CC=1)=[O:36].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:49]=2)[C:35]([NH2:37])=[O:36])=[CH:18][CH:17]=[N:16]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1
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: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1cncc(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
K3PO4 (113 mg, 0.532 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (99 mg, 0.355 mmol) and Pd(PPh3)4 (10.24 mg, 8.86 mmol) were added to a solution of (R)-5-bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 30.1, 80 mg, 0.177 mmol) in toluene (1.5 mL) under argon atmosphere. and the RM was stirred at 110° C. for 1 h. The RM was diluted with EtOAc (20 mL) treated with sat. NaHCO3 solution (20 mL). and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried with Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g DCM/EtOH from 97:3 to 95:5) to afford N-(4-(1,1-difluoroethoxy)phenyl)-6-(R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide which (66 mg, 0.129 mmol) was dissolved in DCM (1.5 mL) and treated with TFA (0.546 mL, 7.09 mmol) and stirred for 2 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. NaHCO3 solution (25 mL) and extracted with EtOAc (20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with 0.5 g NaHCO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with DCM to give the title product as a white solid. HPLC (Condition 5) tR=5.42 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=430.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.87 (m, 2H) 1.93 (t, J=13.67 Hz, 3H) 2.94 (d, J=11.71 Hz, 1H) 3.15-3.33 (m, 2H) 3.38-3.48 (m, 1H) 4.19 (br. s, 1H) 6.37 (s, 1H) 7.15 (d, J=9.37 Hz, 2H) 7.65-7.83 (m, J=9.37 Hz, 3H) 8.03 (d, J=2.34 Hz, 1H) 8.73 (d, J=2.34 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[N+:3]([CH:6]=[CH:7][NH:8][C:9]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)([O-:5])=[O:4].CO>O>[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:10]([C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)([O-:5])=[O:4]
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC=C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cnc2ccc(C(F)(F)F)cc2c1-c1ccccc1
Yield: 85.9 %

Procedure:
2N-Sodium hydroxide solution (9.0 ml) was added dropwise to a mixture of 2-(2-nitrovinylamino)-5-trifluoromethylbenzophenone (6.0 g) and methanol (60 ml) under stirring. After stirring further for 30 mins. at room temperature, the mixture was diluted with water to give 3-nitro-4-phenyl-6-trifluoromethylquinoline as crystals (4.88 g, 4.5 %). It was recrystallized from a mixture of chloroform and methanol to give pale yellow needles (4.50 g, 79,2 %). m.p 192°-193° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][CH2:9][CH2:10][N:11]=2)[CH:2]=1.[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: c1cncc(C2=NCCN2)c1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: c1cncc(-c2ncc[nH]2)c1
Yield: 65.6 %

Procedure:
2-(3-pyridyl)imidazoline (7.2 g, 0.049 M), and barium manganate (52.5 g) in CH2Cl2 (500 ml) were refluxed for 24 hrs. The reaction mixture was then filtered through diatomaceous earth, washed with ethylacetate (3×200 ml) and methanol (3×100 ml). The combined filtrates were concentrated to yield an oil which was purified on silica gel column, eluted with 20% by volume methanol 80% by volume methylene dichloride, to give 3-(1H-imidazol-2-yl)pyridine (4.66 g, 64.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2SC.S(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CSC1C(=O)Nc2c(F)cccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1Cc2cccc(F)c2N1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 95 %

Procedure:
7-Fluoro-3-(methylsulfanyl)-1,3-dihydro-2H-indol-2-one (270.5 g) was dissolved in water (2000 g) and admixed with sodium bisulfite (300 g). The mixture was heated to reflux, in the course of which it was vigorously stirred. After 2.25 h, the mixture was cooled to 25° C. and isolated by filtration on a suction filter. It was washed twice with water (500 g each time) and then dried under reduced pressure (<50 mbar, 50° C.). This gave 7-fluoro-1,3-dihydro-2H-indol-2-one as a white solid (206.3 g, 95.1% by weight, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:23])[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: c1cn[nH]c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cn2cccn2)c1
Yield: 99 %

Procedure:
3-((1H-Pyrazol-1-yl)methyl)-N-(2-(5-Chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), pyrazole (0.034 g; 0.5 mmol) and sodium iodide (0.090 g; 0.6 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.054 g (99%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].N1C=CC=CC=1.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30]([C:37](=[O:53])[NH:38][C:39]1[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:42]=[C:41]([S:49]([OH:52])(=[O:51])=[O:50])[CH:40]=1)=[C:31]2[OH:36].CN(C)C(=O)C>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([S:15]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30]([C:37](=[O:53])[NH:38][C:39]2[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:42]=[C:41]([S:49]([OH:52])(=[O:51])=[O:50])[CH:40]=2)=[C:31]3[OH:36])(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)([OH:2])=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2c(O)c(C(=O)Nc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c3)ccc12
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(C(=O)O)cc(S(=O)(=O)Nc2cccc3c(O)c(C(=O)Nc4cc(S(=O)(=O)O)cc(S(=O)(=O)O)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.8 %

Procedure:
3,5-Dimethoxycarbonylbenzenesulfonyl chloride (1.9 grams) and 2 ml of pyridine were added to 2.7 grams of 5-amino-2-(3,5-disulfophenylcarbamoyl)-1-naphthol and 27 ml of N,N-dimethylacetamide. The mixture was stirred for 1 hour at room temperature and then 50 ml of ethyl alcohol were added, and the crystals which precipitated out were recovered by filtration. 30 ml of methyl alcohol, 2 grams of sodium hydroxide and 10 ml of water were added to the crystals and, after boiling under reflux for 1 hour, 5 grams of 5-(3,5-dicarboxyphenylsulfonamido)-2-(3,5-disulfophenylcarbamoyl)-1-naphthol were obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([O:13]C)[CH:9]=[CH:10][C:11]=1[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].Cl>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([C:9]2[CH:10]=[C:11]([CH3:12])[C:6]([Cl:5])=[CH:7][C:8]=2[OH:13])=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)c2cccc(Br)c2)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Aluminum chloride (20.4 g) was added to a solution of 3-chloro-4-methylanisole (20 g) in chlorobenzene (56 ml) at 20-30° C., and then 3-bromobenzoyl chloride (28 g) was further added dropwise over about 30 minutes at 25 to 30° C. After completion of addition, the mixture was stirred at 25° C. for 1 hour, and then heated at 40° C. for 1 hour. After the reaction was completed, the mixture was cooled, and toluene/tetrahydrofuran (1:1, 200 ml) was added dropwise at 20 to 30° C. Then, 4N hydrochloric acid (80 ml) was added dropwise. The organic layer was separated, washed successively with 2N hydrochloric acid (60 ml) and a 10% aqueous sodium chloride solution. The organic layer was concentrated to 80 g. After methanol (100 ml) was added, the mixture was concentrated again to 90 g. Methanol (80 ml) was added to the residue, the mixture was stirred at room temperature for 30 minutes, and below 5° C. for 1 hour. Crystals were collected, washed with cooled methanol (40 ml) and dried under reduced pressure to obtain the title compound (35.4 g, yield 85.1%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1B(O)O>>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4Cl)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 2-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.02 (br s, 1H), 12.92 (br s, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=6.6 Hz, 1H), 7.71 (s, 1H), 7.67-7.62 (m, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.55-7.47 (m, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].C(Cl)Cl.O1CCOCC1>[C:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)c2ccccc12
Temperature: 85 °C

Procedure:
A pressure bottle was charged with 4-bromonaphthalen-1-amine (500 mg, 2251 μmol), phenylboronic acid (357 mg, 2927 μmol), PdCl2(dppf)-CH2Cl2 adduct (91.9 mg, 113 μmol), 2.0 M sodium carbonate (2251 μl, 4503 μmol) and 9.0 mL of dioxane. The bottle was sealed and the mixture was heated at 85° C. for 2 h. LCMS showed desired product as the major component. The mixture was diluted with DCM and washed with water. The organic portion was dried, filtered and concentrated. The crude material was purified by silica gel chromatography, DCM to 2% MeOH/DCM to provide 4-phenylnaphthalen-1-amine. MS: [M+H]=220.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)=[C:8]([F:24])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([F:24])[C:9]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:12]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)c(Cl)cc(F)c1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
0.24 ml (5.8 mmol) of 100% strength nitric acid was added to 1.9 g (5.8 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-chloro-5-trifluoromethylpyridine in 50 ml of concentrated sulfuric acid. The reaction mixture was stirred at about 20° C. for 10 hours and then poured into 100 ml of ice-water. The solids were subsequently removed and dried at 40° C. in a vacuum drying cabinet. Yield: 79%; m.p.: 67-72° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:25]([C:16]2[CH:15]=[C:14]([O:13][CH:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[O:7][CH2:6][CH2:5]3)[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=2)=[O:27])[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Reactant: C1CNC1
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCC3)cc2n1C
Yield: 80 %

Procedure:
The title compound was prepared as a colorless amorphous in 80% yield (1.4 g) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (1.6 g, 4.2 mmol, STEP 2 of Example 19) and azetidine hydrochloride (0.79 g, 8.4 mmol) by the same manner in STEP 3 of Example 11.