Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[N:12][CH:11]=1)(C)(C)C.COC([O:25][CH3:26])OC.[C:27]([O-])([O-])=O.[Na+].[Na+]>C(O)CO>[CH3:16][C:15]1([C:13]2[S:14][C:10]([CH2:9][OH:8])=[CH:11][N:12]=2)[O:17][CH2:27][CH2:26][O:25]1
Reactant: COC(OC)OC
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ncc(C(C)(C)O[SiH2]C(C)(C)C)s1
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2ncc(CO)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-2-yl]-ethanone (1.00 g, 3.68 mmol) in ethylene glycol (4 mL) was treated with trimethylorthoformate (0.82 mL, 7.51 mmol) followed by LiBF4 (70 mg, 0.74 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. Na2CO3 (5 mL) was added and the mixture was extracted with Et2O (3×20 mL). The org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude residue (mixture of silylated/desilylated products) in dry THF (10 mL) was treated at rt with TBAF (1.1 mL of a 1M solution in THF, 1.10 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then diluted with EA, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (4:1->1:2 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (EA)=0.47. LC-MS-conditions 02: tR=0.60 min; [M+H]+=202.46.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:23]1C=CC=C[CH:24]=1.Cl>C(Cl)(Cl)Cl>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CCOC(=O)Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 99 g. (0.29 mole) of the known (Belgian Patent 846,502, Example 22) compound ethyl 3-(4-bromophenyl)benzofuran-5-acetate in 40 g. of cuprous cyanide in 30 ml. of pyridine is heated at 160°-175° C. with stirring under a nitrogen atmosphere for 20 hours. To this solution is added 200 g. of ferric chloride, 100 ml. of concentrated hydrochloric acid, and 200 ml. of ice water with rapid stirring. Next, 300 ml. of chloroform is added, and the mixture is stirred for one hour, then filtered, and the insoluble material is extracted several times with chloroform. The combined chloroform extracts are dried and evaporated to provide a residue. The residue is recrystallized from a N,N-dimethyl formamide-water mixture to provide ethyl 3-(4-cyanophenyl)benzofuran-5-acetate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@@:9]1([CH2:42][OH:43])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:39][CH3:40])[CH2:30][N:31]([CH3:38])[S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[C:10]1=[O:41])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:43][CH2:42][C@:9]1([CH2:6][CH:7]=[CH2:8])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:39][CH3:40])[CH2:30][N:31]([CH3:38])[S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:34])[C:10]1=[O:41])(=[O:4])=[O:3]
Reactant: C=CC[C@@]1(CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@@]1(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.200 ml, 2.59 mmol) was added to a solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (1.0 g, 1.725 mmol) and triethylamine (0.480 ml, 3.45 mmol) in DCM. The reaction was stirred for 2 hours. The reaction mixture was diluted with DCM and washed with HCl (1N) and satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil. Mass Spectrum (ESI) m/z=657.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C[N+]([O-])=O>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(O)ccc1F
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
6-Fluoro-3-hydroxybenzoic acid (100mg, 0.64 mmol) was dissolved in CH3NO2 (10 mL) and cooled to 0° C. HNO3 (90%, 31 μL, 0.64 mmol) was added and the reaction was left at 0° C. for 4 h and then at room temperature over night. Evaporation and purification by flash chromatography on SiO2 (Toluene-EtOAc-HOAc) gave the product (22 mg). 1H NMR (CD3OD): δ7.32 (t, J=9.0 Hz, 1H), 7.15 (dd, J1 =9.3 Hz, J2 =4.4 Hz, 1H); 13C NMR: δ164.97, 153.68 (d, J=247 Hz), 148.78, 122.67, 122.56, 122.45, 122.13.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[CH:12]2.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl.CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[C:12]2[C:1](=[O:5])[C:2]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:37])=[CH:35][CH:34]=2)[CH2:33][CH2:32]1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Reactant: COc1cc2cc(C)[nH]c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)N3CCC(Oc4ccc(C(F)(F)F)cc4)CC3)c2cc1OC
Reaction time: 0.17 h

Procedure:
6.5 g of oxalyl chloride are added dropwise to a stirred solution of 8.8 g of 5,6-dimethoxy-2-methylindole in 160 ml. of ether at -10° C. After addition is complete, the mixture is stirred for 10 minutes and a bright orange precipitate of 5,6-dimethoxy-2-methyl-indole-3-glyoxyloyl chloride appears. The ether suspension of 5,6-dimethoxy-2-methyl-indole-3-glyoxyloyl chloride is added portion wise to a cooled stirring mixture of 12.3 g of 4-(p-trifluoromethylphenoxy)piperidine, 12.5 g of potassium carbonate, 50 ml. of chloroform and 60 ml. of water. The reaction mixture is stirred overnight and the resultant white solid is collected and dried. The solid is recrystallized twice from a methanol and water mixture to give 1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)-4-(p-trifluoromethylphenoxy)piperidine m.p. 211°-213° C.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:29]=[CH:28][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([O:26][CH3:27])=[O:25])[O:23][C:18]=4[C:17]=3[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=2[O:38][CH3:39])=[CH:4][S:3]1.[N+]([CH3:43])([O-])=O.CI>C(OCC)C.O>[CH3:39][O:38][C:8]1[C:9]([CH2:35][CH2:36][CH3:37])=[C:10]([CH:33]=[CH:34][C:7]=1[C:5]1[N:6]=[C:2]([S:1][CH3:43])[S:3][CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]2[CH2:20][CH2:21][CH:22]([C:24]([O:26][CH3:27])=[O:25])[O:23][C:18]=2[C:17]=1[CH2:30][CH2:31][CH3:32]
Reactant: C[N+](=O)[O-]
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: CCCc1c(OCCCOc2ccc(-c3csc(SC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Yield: 97.6 %

Procedure:
The compound of Example 25 (18 mg, 31.4 μmol) was added to 1.0 ml of nitromethane, and 0.3 ml of methyl iodide was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated. The crude product was chromatographed on silica gel using 20:1 to 10:1 hexane/ethyl acetate as eluant to give the product (51 mg, 87.0 μmol, 97.6% yield). High resolution mass spectrum, m/e 585.2223 (calculated for C31H39N6S2, 585.2219).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C([NH:30][CH:31]([CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)[CH2:32][CH2:33][CH3:34])(OC(C)(C)C)=O>C(#N)C>[ClH:18].[NH2:30][CH:31]([CH:35]1[CH2:39][CH2:38][N:37]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:36]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC(NC(=O)OC(C)(C)C)C1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: CCCC(N)C1CCN(c2c(F)cn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)C1
Product: Cl

Procedure:
A 238 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 5 mL of anhydrous acetonitrile, reacted with 3-(1-(N-BOC-amino)butyl)pyrrolidine (620 mg, 1.83 mmol, prepared in step 314d above), and carried forward as described in Example 253j-l to give the title product. MS (high resolution) found: 402.2199; calc: 402.2193 (M+H)+ ; 1H NMR (D6 -DMSO) δ: 0.60 (m, 2H), 0.89 (m, 4H), 1.05 (m, 1H), 1.49 (m, 5H), 1.17 (m, 1H), 2.14 (m, 1H), 2.27 (m, 1H), 2.62 (s, 3H), 3.77 (m, 4H), 3.94 (m, 1H), 7.89 (s, 1H), 8.54 (b m, 1H), 9.07 (d, 1H), 11.47 (br, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC[C:26]([N:28]([CH2:30][CH2:31][OH:32])[CH3:29])=[O:27].[C:33](=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]([C:26](=[O:27])[N:28]([CH2:30][CH2:31][OH:32])[CH3:29])[C:20]([O:22][CH3:33])=[O:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)C(=O)CCl
Reactant: O=C(O)COc1ccc(CCC(=O)OCc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(CCC(=O)OCc2ccccc2)cc1)C(=O)N(C)CCO

Procedure:
A mixture comprising 3-(4-carboxymethoxy-phenyl)-propionic acid benzyl ester (Step 2) (0.65 g, 1.93 mmol) and 2-chloro-N-(2-hydroxy-ethyl)-N-methyl-acetamide (0.35 g, 2.31 mmol) in DMF (10 ml) and sodium hydrogen carbonate (2.5 equivalents) was stirred at RT for 2 days and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-5% MeOH in DCM to afford the title product as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12]O>>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CO
Product: COC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 3,4-dihydroxybenzoic acid (5.0 g, 32 mmol) in methanol (80 mL) containing c-H2SO4 (3 mL) was heated at reflux for 4 hrs and cooled to room temperature. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with water, saturated NaHCO3, and brine. The organic fraction was dried over MgSO4 and concentrated to give 3,4-dihydroxybenzoic acid methyl ester (5.2 g, 96%). 1H NMR (DMSO-d6, 600 MHz) δ 9.77 (s, 1H), 9.35 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J=7.8 Hz), 6.79 (d, 1H, J=7.8 Hz), 3.78 (s, 3H).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: COc1ccc(CNC=C2CCOC2=O)cc1
Yield: 24.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and 4-methoxybenzylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-(4-methoxybenzylamino)methylenedihydrofuran-2-one (2.9 g, efficiency: 28%) is produced in the form of a white powder.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C.CCN(CC)CC.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>[F:9][C:10]1[C:11]([C:3]#[C:2][CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNS(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(C)(=O)=O)c21

Procedure:
Using Method C above, N-(Prop-2-ynyl)-methanesulfonamide (80 mg, 0.62 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-methanesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of pentane. (Yield 48 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.C(Cl)(Cl)Cl.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.[Fe]>[F:1][C:2]([F:6])([F:5])[S:3][C:12]1[CH:13]=[C:14]([S:3][C:2]([F:6])([F:5])[F:1])[CH:15]=[C:16]([S:3][C:2]([F:6])([F:5])[F:1])[C:11]=1[OH:17]
Reactant: FC(F)(F)SCl
Reactant: Oc1ccccc1
Agent: [Fe]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Oc1c(SC(F)(F)F)cc(SC(F)(F)F)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Condensed 32.5 g of trifluoromethylsulphenyl chloride was placed in a pressured bottle in a dry ice bath. 60 ml of chilled chloroform was added under nitrogen, followed by the addition of 5.6 g of phenol in 16 g of pyridine and 0.8 g of iron powder. The mixture was stirred in a closed bottle at room temperature for two days. The solution was then washed with water and diluted with hydrochloric acid. After removal of the solvent, the crude product was distilled with a column. The yield was 10 g. The b.p. was 51° C./0.1 mm. NMR (CDCl3), δ 8.1 (s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].C(O)C.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Into a three-necked flask of one liter, 25g (0.145 mol) of o-bromophenol, 8.7 g (0.217 mol) of sodium hydroxide and 300 ml of ethanol were charged and refluxed for two hours. Then, 49.4 g (0,289 mol) of benzyl bromide was added dropwise and the mixture was refluxed further for four hours. After the mixture was cooled to room temperature, 600 ml of diethyl ether was added. The mixture was charged into a separatory funnel. Separated organic layer was washed successively with, 100 ml of 2N-hydrochloric acid cooled with ice, 300 ml of saturated sodium thiosulfate, and water until the washings were neutral. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrate was distilled under reduced pressure to obtain 35.6 g (0.135 mol) of o-benzyloxyphenylbromide.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: N#CSC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 35 g. (0.12 moles) of α, 2'-dichloro-4-biphenylylacetic acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:14])(=[O:10])=[O:9])[C:12](=[O:13])[NH:15]2)=[CH:21][CH:22]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1F
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1F
Yield: 40 %

Procedure:
1.12 g (4.77 mmol) of 4-chloro-2-fluorobenzenesulfonylisocyanate and 819 mg (4.77 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 742 mg of the above-identified compound (yield 40.0%). Properties: colorless crystal, Melting point: 267°-268° C., PMR (δppm, DMSO-d6):7.16 (1H,s), 7.24 (1H,d), 7.56 (1H,t), 7.73 (1H,d), 7.87 (1H,d), 8.10 (1H,t), 12.2 (1H,br).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C(Cl)Cl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([Cl:30])=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
The title compound 390 (0.72 g, 2.2 mmol) and the oxalyl chloride (0.58 mL, 6.6 mmol) were mixed in DCM (10 mL) and few drops of DMF was added. The reaction mixture was stirred for 30 minutes and the solvent was evaporated (and stripped with toluene twice) to afford title compound 391 that was used crude for next step.
Reaction SMILES: [Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCN(CCCC)[Si](C)(C)C(C)(C)C
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCCCN(CCC[Si](OCC)(OCC)OCC)[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 22.8 g (0.1 mol) of N-t-butyldimethylsilyl-N-butyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 16.4 g (0.1 mol) of triethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 31.4 g of a fraction having a boiling point of 144-146° C./0.4 kPa.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:13](Cl)(=[O:15])[CH3:14].C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:13]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=C1CCc2cccc(F)c2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(F)c2c(c1)CCC(=O)N2
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a stirring solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (1.6 g, 9.69 mmol) and acetyl chloride (1.722 mL, 24.22 mmol) in carbon disulfide (20 mL, 9.69 mmol) at 0° C. was added in portions aluminum chloride (6.59 g, 49.4 mmol). The reaction mixture was stirred at 100° C. without a condensor until the solvent evaporated, then a condensor was fitted in place and stirring continued at 100° C. for 4 h. After cooling, the reaction contents were carefully poured into ice water and partitioned between DCM and water. The aqueous layer was extracted with DCM (3×150 mL). The combined organic washes were dried over MgSO4 and concentrated under vacuum to a tan solid. This was purified by flash chromatography on silica gel using 1% MeOH in DCM to give 6-acetyl-8-fluoro-3,4-dihydroquinolin-2(1H)-one as a yellow solid (1.6 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (br. s., 1H), 7.68-7.60 (m, 1H), 2.76-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.58 (s, 13H). LCMS: R.T.=1.335 min; [M+H]+=208.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:7](=[O:12])[N:8]2O)=[CH:4][CH:3]=1.CC(O)=O>C1COCC1.[Zn]>[NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]([F:16])([F:14])[F:15])([C:17]([F:18])([F:19])[F:20])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)N(O)C(=O)C2(C(F)(F)F)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NC(=O)C2(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.245 g (4.151 mmol) 6-amino-1-hydroxy-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one in 80 ml THF was added 3.565 ml (62.27 mmol) glacial AcOH and 19 g (290.6 mmol) Zinc dust (100 mesh). The reaction was stirred 40 min at RT and then 5 h at reflux. The reaction was cooled to RT. The solvent was decanted and concentrated, then dissolved in EtOAc and filtered through Celite®. The EtOAc solution was then washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated and dried under vacuum, to yield the titled compound, as a yellow solid.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2ncccc12
Product: Brc1cccc(Nc2ncnc3ncccc23)c1
Temperature: 100 °C

Procedure:
A mixture of 4-methylthiopyrido[2,3-d]pyrimidine (157 mg, 0.89 mmol, and 3-bromoaniline (1 mL) is heated to 100° C. for 2 h. On cooling a precipitate forms which is filtered then washed with EtOH and air dried to yield 4-(3-bromoanilino)pyrido[2,3-d]pyrimidine (55.5 mg, 20%. 1H NMR (DMSO) δ 10.13 (1H, s), 9.11 (1H, dd, J=1.7, 4.3 Hz), 9.01 (1H, dd, J=1.7, 8.2 Hz), 8.81 (1H, s), 8.22 (1H, s), 7.90 (1H, d, J=7.7 Hz), 7.71 (1H, dd, J=4.3, 8.0 Hz), 7.40 (2H, m).