Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][NH2:16])=[O:14])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23](Cl)=O)[CH3:18].O>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[O:14][C:13]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[N:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Reactant: NNC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc(-c2nnc(-c3ccncc3)o2)cc1OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of 3,4-diethoxybenzoylchloride (prepare above) in NMP (0.8 mL) The reaction was stirred for 12 h at room temperature, poured to 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuo. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured in an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by C.C. using CH2Cl2:MeOH (9:1) to yield the product in 67% yield (150 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10]2)[CH:4]=1.[CH3:27]I>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=3)=[CH:11][N:10]2[CH3:27])[CH:4]=1
Reactant: CI
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.7 grams α,α,α-trifluoro-3-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 grams 1,4-bis-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 207°-208° C. A 1.8 gram portion of the above pyrazolinone was alkylated with 2 grams methyl iodide to produce 1.25 grams of the desired product, m.p. 110°-111° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.CN(C)C=O>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:4]=1[O:3][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:7]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OCc2ccccc2)ccc1C#N
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
9.7 g (0.20 mol) of 50% sodium hydride are slowly added portionwise to a solution of 46 g (0.20 mol) of 2-hydroxy-4-(phenylmethoxy)benzonitrile in a mixture of 450 ml of tetrahydrofuran and 450 ml of dimethylformamide. The mixture is stirred for 30 minutes and then 22.4 ml (0.20 mol) of ethyl bromoacetate are added dropwise. Reaction is allowed to take place for 30 minutes, the reaction mixture is then poured into ice-cold water and the product is extracted with ethyl acetate. The organic phase is then washed with water, dried over sodium sulphate and concentrated under reduced pressure. After trituration of the residue in diisopropyl ether, 50 g of product are obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(F)cc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.26 mmol) was added to a stirred solution of {6-chloro-4-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 100%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H) 8.19-8.28 (m, 1 H) 8.13 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.92 (s, 1 H) 7.60-7.68 (m, 1 H) 7.57 (d, J=7.82 Hz, 2 H) 7.41-7.52 (m, 2 H) 6.96 (s, 1 H) 3.85 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C25H16ClF2O4S [(M−H)−] 485, obsd. 485.3.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:28][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cccc(C)c4)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.075 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-methylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.42 mmol) and methylamine (0.129 g, 4.2 mmol). mp 165-167° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: Cc1csc2[nH]c(=O)nc(-c3ccccc3F)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2F)c2c(C)csc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 13.57 g of 4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 271 ml of dimethylformamide is added 2.8 g of 63% sodium hydride. The mixture is stirred at room temperature for 1 hour. Then, 22.15 g of methyl iodide in 66 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-5-methyl-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 177° - 179°C. From the second fraction, 1-methyl-4-(o-fluorophenyl)-5-methyl-1,2-dihydrotheino[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 275° - 277°C. From the the third fraction, 3-methyl-4-(o-fluorophenyl)-5-methyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 176° - 178°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].[CH3:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[CH:11]1[CH2:12][CH2:13][S:14][CH2:15][CH2:16]1)=[O:4]
Reactant: CC1CCC(C(=O)Cl)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1

Procedure:
Amidation of 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.2 g, 0.6 mmol) and 4-Methyl-cyclohexanecarbonyl chloride was carried out as described for example 19, step 2 gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.208 g, 75.7%). NMR 1H (CDCl3, 400 MHz): 7.68-7.62 (m, 2H), 7.5-7.4 (m, 3H), 7.04 (s, 1H), 4.68-4.58 (m, 1H), 3.86 (s, 3H), 2.9-1.2 (m, 16H), 0.78 (d, 3H), 0.76-0.56 (m, 2H). s
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[CH:18]=[CH:19][C:20]=1[CH:21]=[O:22])[CH3:13].O>CN(C=O)C>[Br:1][C:18]1[CH:19]=[C:20]([CH:21]=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: CCOc1cc(-c2ccc(F)cc2F)ccc1C=O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(F)cc2F)c(Br)cc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 148.8 %

Procedure:
Dibromoisocyanuric acid (3.39 g) was added to a solution of 3-ethoxy-2′,4′-difluorobiphenyl-4-carbaldehyde (5.16 g) in DMF (30 mL) at room temperature. The mixture was stirred at room temperature for 4 hours. Water (6 mL) was added to the mixture. Then the crystalline seed was added to the mixture. The mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with DMF-water (8 mL-2 mL), and dried at 70° C. to give the title compound (6.00 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[CH2:7][NH2:8].C(N=[C:14]=[S:15])C=C>BrC1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:7][NH:8][C:14](=[S:15])[NH:9]1
Reactant: NCC(N)c1cccs1
Reactant: C=CCN=C=S
Solvent: Brc1ccccc1
Product: S=C1NCC(c2cccs2)N1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
. . A solution of 140 mg (1.0 mmol) of 2-thienyl-1,2-diaminoethane and allyl isothiocyanate (99 mg, 1 mmol) in bromobenzene (5 mL) was heated for 40 min and allowed to cool to room temperature and then cooled to −5° C. The title compound (160 mg, 83% yield) was obtained upon filtration and washing with hexane.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[C:15]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([O:8][C:10]2[C:15]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCC1
Reactant: NS(=O)(=O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccnc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.9 g of a 55% dispersion of sodium hydride are suspended in 40 ml of dimethylformamide and then 13.6 ml of cyclopentanol are added dropwise. Then a solution of 19.24 g of 2-chloropyridin-3-ylsulfonamide in 40 ml of dimethylformamide is added dropwise and the reaction mixture is stirred for 2 hours at 35°-40° C. and then taken up in a mixture of 250 ml of ethyl acetate, 250 ml of ice-water and 125 ml of 1N hydrochloric acid. After extraction with 3×100 ml of ethyl acetate the combined organic phases are washed with 4×100 ml of water. The organic solution is washed and dried, affording an oily residue which crystallises after trituration with 50 ml of ether to give 19.64 g of 2-cyclopentyloxypyridin-3-ylsulfonamide with a melting point of 134°-135° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:33]([N:25]([CH2:24][C:15]2[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=2)[CH2:26][CH3:27])=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CCC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CCC1

Procedure:
{2′-[(Cyclobutanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-206) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclobutanecarbonyl chloride.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([Cl:38])[CH:20]=1>C(Cl)Cl>[Cl:38][C:21]1[CH:20]=[C:19]([NH:18][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
According to Scheme 5 Step 3: Picolinoyl chloride hydrochloride (3.68 mmol, 656 mg) and Et3N (7.37 mmol, 1.03 mL) were added to a solution of tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46 mmol, 766 mg) in DCM (40 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford tert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol, 1.02 g, 100%).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH:12]1[C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2ccccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of diethyl carbonate (200 g) in toluene (800 ml) was added 60% sodium hydride (27.4 g), and the mixture was stirred at 50° C. for 30 minutes, and thereto was added dropwise a solution of 3,4-dihydro-1(2H)-napthalenone (50 g) in toluene (200 ml). The mixture was refluxed for one hour, and poured into ice-water, and the mixture was neutralized with acetic acid. The toluene layer was collected, washed successively with an aqueous potassium carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate (47 g) as an oily product, b.p. 135°-145° C./2 mmHg.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1cccnc1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminopyridine (25 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 10-50 EtOAc in dichloromethane. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-3-yl)benzamide as a white solid. Yield: 48 mg (47%). 1H-NMR: 10.66 (s, 1H), 8.89 (d, J=2.5 Hz, 1H) 8.33 (dd, J=4.5, 1.5 Hz, 1H), 8.15 (ddd, J=8.0, 2.5, 1.5 Hz, 1H) 8.08 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.41 (ddd, J=8.5, 4.5, 0.5 Hz, 1H), 7.24-7.08 (m, 3H), 3.85-3.81 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=O)[CH3:24])[CH:18]=1)(=O)[CH3:15].[OH-].[K+]>C(O)C>[N:1]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:12]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:24]=[CH:12][C:3]3[C:2](=[C:11]4[C:6](=[CH:5][CH:4]=3)[CH:7]=[CH:8][CH:9]=[N:10]4)[N:1]=2)[CH:18]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: CC(=O)c1cccc(C(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(-c2ccc3ccc4cccnc4c3n2)cc(-c2ccc3ccc4cccnc4c3n2)c1
Yield: 83 %

Procedure:
101 g of 8-amino-7-quinoline carboaldehyde was reacted with 45 g of 1,3-diacetylbenzene and 100 g of 85% potassium hydroxide in 1800 ml of ethanol for 10 hours while refluxing and a reactant was treated by a normal method to obtain 100 g of 1,3-di(1,10-phenanthroline-2-yl)benzene. 40.8 g of this 1,3-di(1,10-phenanthroline-2-yl)benzene was reacted with 400 ml of phenyl lithium (0.94 M cyclohexane-ether solution) in 750 ml of toluene for 2.5 hours while cooling with ice and a reactant was treated by a normal method. The obtained product was reacted with 118 g of nitrobenzene at 110° C. for 3 hours and a reactant was treated by a normal method to obtain 22.8 g of E-20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([CH2:10][C@H:11](S(C)(=O)=O)[CH3:12])[C:3]=1[F:17].[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C@@H:11]([CH3:12])[CH2:10][C:4]1[C:5]([F:9])=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[F:17])=[N+:19]=[N-:20]
Reactant: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-1,2,4,5-tetrafluoro-3-(2-(methylsulfonyl)propyl)benzene (2.3 g, 8.03 mmol) in anhydrous DMF (10 mL) was added sodium azide (1.045 g, 16.07 mmol) and the solution was heated to 80° C. and stirred for 2 h. Then, the temperature was cooled to rt and 20 mL of water was added, extracted with EtOAc/hexane (1/1 v/v), dried over anhydrous MgSO4 and evaporated to give crude oil, which was passed through silica gel pad and evaporated under reduced pressure to give the product. This was used as starting material for next reduction without more purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]=[C:30]=[O:31]
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=C(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H).
Reaction SMILES: [F:1][C@:2]12[C@@H:26]([OH:27])[CH2:25][C@@:24]3([CH3:28])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:23])[CH2:17]OS(C)(=O)=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[Cl-:31].[Li+].O>CN(C)C=O>[Cl:31][CH2:17][C:16](=[O:23])[C:15]1[C@:24]2([CH3:28])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:26]([OH:27])[CH2:25]2)[C@:3]2([CH3:30])[C:8](=[CH:7][C:6](=[O:29])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][CH:14]=1
Reactant: [Cl-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
To a solution of 17.5g of 9-fluoro-11β-hydroxy-21-methanesulfonyloxypregna-1,4,16-triene-3,20-dione in dry dimethylformamide (250 ml) is added lithium chloride (30g). The mixture is heated, with stirring, from 30° to 100° C. over a 30-minute period. It is cooled and poured into cold water (1.51) and the precipitated solid is isolated and crystallized from methanol to afford 12g of the title compound, melting point 258°-260° C.(dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:13].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: [F-]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-3-nitropicolinonitrile (6.84 g, 30 mmol) in dimethylsulfoxide was cooled to −25° C. and treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (60 mL, 60 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. It was quenched with water and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to provide crude title compound.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[SH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][S:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: BrCc1cccnc1
Agent: Br
Product: COC(=O)c1ccc(SCc2cccnc2)cc1

Procedure:
1 g of 3-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl 4-(pyridin-3-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate. 760 mg of methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.