Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+].O>COCCOC.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>[N:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(Br)c2ccccc12
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12

Procedure:
4-Bromonaphth-1-ylacetic acid (J. Org. Chem., 1951, 16, 1588) (1 g, 3.78 mmole) in 1,2-dimethoxyethane (50 ml) was treated with pyridin-4-ylboronic acid (465 mg, 3.78 mmole), sodium hydrogen carbonate (952 mg, 11.3 mmole) and water (10 ml). A stream of argon was bubbled through the mixture for 15 minutes, then tetrakis(triphenylphosphine)palladium (0) (200 mg 0.17 mmole) was added and the mixture heated under reflux for 18 hours. The mixture was then concentrated in vacuo to a gum, which was partitioned between 2M sodium hydroxide solution and dichloromethane. The aqueous layer was separated, adjusted to pH 0 with 6M hydrochloric acid and washed with dichloromethane; then adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane. The dichloromethane extract was dried (Na2SO4) and concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215° C. (465 mg, 46%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[CH:21][C:20]=1[F:29].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:18][C:19]3[C:20]([F:29])=[CH:21][C:22]([O:26][CH2:27][CH3:28])=[CH:23][C:24]=3[F:25])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=2[CH3:14])[CH2:2][CH2:3]1
Reactant: CCOc1cc(F)c(CBr)c(F)c1
Reactant: CCOC(=O)c1n[nH]c(C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(C2CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
46.9 g of ethyl 5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate 1-15-1 (266 mmol, 1.0 eq.) in 588 mL THF were cooled to 0° C. and 11.6 g sodiumhydride (60%, 290 mmol, 1.2 eq.) were added in small portions. The resulting suspension was diluted with 250 mL THF. 66.7 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (266 mmol, 1.1 eq., commercially available) were added slowly. The reaction mixture was stirred at rt for 2 hours. 300 mL water was added and the THF was evaporated in vacuum. The aqueous residue was extracted with ethylacetate three times. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to provide 79.8 g (195 mmol, 81%) of 89% pure target compound.
Reaction SMILES: [CH:1]([C:4]1[C:9]([N:10]=[C:11]=[S:12])=[C:8]([CH:13]([CH3:15])[CH3:14])[CH:7]=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([NH:28][C:11]([NH:10][C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][C:6]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:7][C:8]=1[CH:13]([CH3:15])[CH3:14])=[S:12])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1NC(=S)NC(C)(C)C
Reaction time: 2 h

Procedure:
8.15 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate are diluted with 30 ml of toluene, and 2.0 g of tert.-butylamine are added dropwise. The reaction mixture is then further stirred for 2 hours at approximately +60° C. The reaction mixture is concentrated and hexane is added to the residue. The resulting solid is filtered off and subsequently washed with hexane. 1-tert.-Butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-thiourea is obtained in the form of colourless crystals, m.p. 165°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=[CH:23]1.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>CC#N>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Add MeCN (2 ml) to a flask under N2 containing 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (50 mg, 0.152 mmol), 1H-pyrrolo[2,3-b]pyridine (18 mg, 0.152 mmol), 4-Pyrrolidin-1-yl-pyridine (2 mg, 0.167 mmol), and triethylamine (17 mg, 0.167 mmol). Heat reaction to 80° C. for 16 hours. Cool the solution to room temperature, remove MeCN on rotovap. Purify crude material on silica gel to give 45 mg (73% yield) of N-(4-Fluoro-benzyl)-4-(pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide. Mass Spectrum (m/e): 410.1(M+).
Reaction SMILES: C(OC)(=O)C#C.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=[O:18])=[C:13]2[C:9]=1[C:10]([CH2:20]N(C)C)=[CH:11][NH:12]2.[N+:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([O-:26])=[O:25]>ClCCl.C(#N)C>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[NH2:19])=[C:13]2[C:9]=1[C:10]([CH2:20][CH:27]([N+:24]([O-:26])=[O:25])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][NH:12]2
Reactant: CN(C)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C#CC(=O)OC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(Cc1c[nH]c2c(C(N)=O)ccc(Br)c12)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Methyl propiolate (2.300 mL, 27.5 mmol) was added slowly to a suspension of crude 4-bromo-3-((dimethylamino)methyl)-1H-indole-7-carboxamide (6.27 g, 21.17 mmol) and ethyl 2-nitroacetate (3.66 g, 27.5 mmol) in dichloromethane (151 mL) and acetonitrile (151 mL). After 30 min, the mixture was concentrated and partitioned between EtOAc and 1 M aqueous HCl. The organic phase was washed with NaHCO3 (aq) and brine, dried and concentrated. The residue was coated subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexane (gradient from 50:50 to 80:20) to provide the desired product as a solid (4.60 g, 57% yield). LCMS (M+H)+ m/z 383.8, 385.8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][S:23]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)CCl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCl)c2n1
Yield: 98.3 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.57 g, 9.80 mmol) (Intermediate 10.1), chloromethanesulfonyl chloride (2.00 ml, 19.59 mmol), and N,N-diisopropylethylamine (11.98 ml, 68.58 mmol) in dichloromethane (100 ml) is stirred for 20 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 3.61 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.05 min (tR(SM) 6.64 min). 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.56 (m, 2H), 6.93 (dd, 1H), 6.25 (d, 1H), 5.50 (d, 1H), 5.41 (s, 2H), 4.21 (t, 2H), 3.28 (t, 2H) ppm. MS (ESI) m/z (C17H15ClN4O2S) 375.0 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1
Yield: 11 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.35 g (6.48 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 221 mg (yield 11%) of Compound 90 as pale yellow grains.
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[CH2:13]([S:15][C:16]1[N:20]=[CH:19][N:18]([C:21](Cl)=[O:22])[N:17]=1)[CH3:14].[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1.N1C=CC=CC=1>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[C:21]([N:18]1[CH:19]=[N:20][C:16]([S:15][CH2:13][CH3:14])=[N:17]1)=[O:22])[CH2:25][CH3:26]
Reactant: CCSc1ncn(C(=O)Cl)n1
Reactant: CCCNCCC
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 25.8 g. 3-ethylthio-1,2,4-triazole and 15.8 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 1 molecular proportion), with stirring and cooling to maintain the reaction temperature at 25° - 30°C. The mixture was stirred at 25° - 30°C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution of 3-ethylthio-1,2,4-triazole-1-carbonyl chloride was added dropwise a solution of 20.2 g. dipropylamine and 15.8 g. dry pyridine in 50 ml. dry tetrahydrofuran, with stirring and cooling to maintain the reaction temperature at 25° - 30°C. The mixture was stirred at 25° - 30°C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. The filtrate was evaporated under reduced pressure to remove solvent and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130°C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C=CC(CCO)=[CH:23][CH:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:2]=[CH:3][C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cc1

Procedure:
4-[2-(4-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16l) is synthesized analogous to 16a from 2-(4-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)[CH:4]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O)c(Cc2cccc(C(F)(F)F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:17]=[N:18][C:19](OC)=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON=C(Cl)C1C=NC([C:33]([F:36])([F:35])[F:34])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:17]=[N:18][C:19]([C:33]([F:36])([F:35])[F:34])=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ON=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(C(F)(F)F)nc3)[C@@H]2C1

Procedure:
The title compound was prepared in an analogous manner as the 4-methoxy-3-pyridyl cycloadduct 3c using chloro oxime 2d. 3d was isolated as a white solid after chromatography with 25% ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16].C(OCC)C>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.7 ml of chloroformic acid benzyl ester (90%) in toluene is added to 25 g of 3-amino-2(R,S)-methylpropionic acid in 533 ml of 1N sodium hydroxide at 0° C. The reaction mixture is then stirred for 30 minutes at 0° C. After the addition of 400 ml of diethyl ether, the aqueous phase is removed and 140 ml of 4N hydrochloric acid are added. The crude title compound is obtained from the organic phase by extraction with diethyl ether: Rf (dichloromethane/methanol=8:2)=0.41.
Reaction SMILES: ClC1C=C([C@H](CCN2CCC(N(C(=O)C(F)(F)F)CCNC(=O)C(F)(F)F)CC2)[CH2:10][N:11](C)[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.FC(F)(F)C(N(CCNC(=O)C(F)(F)F)C1CCNCC1)=O.ClC1C=C(C(CC=O)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl>>[CH3:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C[C@@H](CCN1CCC(N(CCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(NCCN(C(=O)C(F)(F)F)C1CCNCC1)C(F)(F)F
Product: CNC(=O)c1ccccc1

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]-butyl]-N-methylbenzamide. Using the procedure of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with 4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidine, and N-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with the (S)-enantiomer, the N-methylbenzamide was obtained as a viscous oil; MS: m/z=669(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(-c2nc(CCN3CCC[C@H]3C)c(C)o2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 67 mg (62%). MS (m/e) 377.2 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][N:8]2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1nn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a mixture of methyl 6-bromo-1H-indazole-3-carboxylate (0.50 g, 1.96 mmol) and potassium carbonate (1.28 g, 9.29 mmol) in acetonitrile (15 mL) is added methyl iodide (1.31 g, 9.29 mmol) at room temperature. The reaction mixture is stirred at room temperature for 15 h. Remove the solvent under vacuum, dilute with water, and extract with ethyl acetate (3×10 mL). The combined organics are dried over sodium sulfate and concentrated under reduced pressure. The crude is purified by flash chromatography eluting with 8:2 hexane/ethyl acetate to give 0.35 g (70%) of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 4.14 (s, 3H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.66 (s, 1H), 8.08 (d, J=8.8 Hz, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(O)c1cccnn1
Yield: 157.4 %

Procedure:
According to a similar synthesis of compound 4 described in Example 346, compound 1 (500 mg, 1.17 mmol) was alkylated with 1-Bromo-2-methoxy-ethane (180 mg, 1.3 mmol) to give compound 2 (360 mg, 65%) as a white solid. Compound 2 (200 mg, 0.43 mmol) was reacted with Lawesson's Reagent (190 mg, 0.47 mmol) to give compound 3 (84 mg, 50%) as a white solid. And compound 3 (80 mg, 0.17 mmol) was converted to hydantoin 4 (55 mg, 70%) as a white solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:45].Cl>>[ClH:45].[ClH:45].[CH2:25]([NH:32][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1cc(O)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Reactant: NCc1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=c1cc(NCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Yield: 22 %

Procedure:
4-Hydroxy-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (120 mg, 0.37 mmol) and benzylamine (0.3 mL) were irradiated in a microwave tube for min at 300 W. Purification by column chromatography (12 g ISCO column eluting with ethyl acetate and a methanol/ammonia mixture (10:1); gradient 100% ethyl acetate to 80% ethyl acetate over 30 min at 25 mL/min) provided the free-base. This was converted to the dihydrochloride as in Example 64 to provide the title compound (43 mg, 22%) as a yellow solid: mp 180-185° C.; 1H NMR (500 MHz, CD3OD) δ 8.25 (s, 1H), 7.90 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 7.51-7.49 (dd, J=8.9, 1.9 Hz, 1H), 7.40-7.39 (m, 4H), 7.33-7.30 (dd, J=8.5, 4.3 Hz, 1H), 6.63 (d, J=76 Hz, 1H), 4.90 (t, J=5.9 Hz, 2H), 4.54 (s, 2H), 3.86 (t, J=5.9 Hz, 2H), 3.77-3.68 (m, 2H), 3.18-3.13 (m, 2H), 2.17-2.13 (m, 2H), 2.03-2.00 (m, 2H); ESI MS m/z 414 [M+H]+; HPLC (Method C)>99% (AUC), tR=12.9 min.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24]>>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(O)CCCCCl
Product: CCCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
According to Example 1 7-butyl-3-ethylxanthine was reacted with 1-chloro-5-hydroxy-5-methylhexane; after isolation the final product was recrystallized from a mixture of ethyl acetate and petroleum ether.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:14]([NH2:16])=[O:15])=[CH:5][CH:4]=1)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[OH:33])[C:26]([NH:28][NH2:29])=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[OH:33])[C:26]([NH:28][N:29]=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:14]([NH2:16])=[O:15])=[CH:5][CH:4]=1)=[O:27]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: CCC(CC)=C(C(N)=O)c1ccc(C=O)c2ccccc12
Product: CCC(CC)=C(C(N)=O)c1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12

Procedure:
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1-naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc(C2(O)CCCC2)c(Br)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1(c2ccc(C)cc2Br)CCCC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 81 %

Procedure:
To a stirring solution of 1-(2-bromo-4-methylphenyl)cyclopentanol (4.2 g, 16.5 mmol) in DCM (40 mL) at rt were successively added DIPEA (11 mL, 66 mmol) and MOMCl (2.5 mL, 33 mmol) over a 10 min period. The solution was stirred for 11 h at rt, and afterwards a NH4Cl-saturated aqueous solution (40 mL) was added. The aqueous phase was segregated, and the organic one was washed with water (30 mL), brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1-(methoxymethoxy)cyclopentyl)-4-methylbenzene (4.0 g, yield 81%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CCCCCC.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 100.8 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply 97.05 g of 2,3,4,5-tetrafluorobenzoic acid (2, 500 mmol) were suspended under argon and with stirring in 100 ml of n-hexane and 0.5 ml of N,N-dimethyl formamide. To this suspension 44 ml of thionyl chloride (d=1.64, 600 mmol) were added at room temperature, and the mixture was heated to reflux for 15 hours. The light yellowish solution was evaporated in a rotary evaporator at 50° C. reducing the pressure first to 200 torr until distillation ceased, then to 30 torr holding this pressure for 3 minutes to yield 107.1 g of the crude acid chloride 2a as a pale yellow liquid, which was kept under argon and directly used for step 3).