Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: Fc1cccc(Br)n1
Product: Fc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 29.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoro-pyridine (66 mg, 0.37 mmol) and 2-but-3-ynyl-benzo[d]thiazole (70 mg, 0.37 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 31 mg (0.11 mmol, 29%) of 2-(4-(6-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.
Reaction SMILES: [F-].[K+].[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:30])[C:17]3[C:18](=[C:20]([CH2:28][CH3:29])[N:21]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:31]#[C:32][Si](C)(C)C)=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:30])[C:17]3[C:18](=[C:20]([CH2:28][CH3:29])[N:21]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:31]#[CH:32])=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCN(C)C)nc3c(=O)[nH]2)c1
Yield: 111.6 %

Procedure:
Potassium fluoride (72.5 mg, 1.25 mmol) was added to a stirred solution of 5-(2-butoxy-5-trimethylsilylethynyl-3-pyridinyl)-2-[2-(dimethylamino)-ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 45) (300 mg, 0.625 mmol) in N,N-dimethylformamide (10 mL) and water (2 mL) at room temperature. After 2 h the reaction mixture was poured into brine and extracted with ethyl acetate (2×100 mL) The organics were dried (MgSO4) and concentrated to give the product (285 mg) as a pale brown oil.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[C:27]([CH3:29])[CH3:28])[CH2:25][OH:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCC(O)=O.[Br:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47](O)=[O:48]>>[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[C:27]([CH3:28])[CH3:29])[CH2:25][O:26][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][Br:39])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)=C(C)C
Agent: O=C(O)CCCCCBr
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)CCCCCCCBr)=C(C)C

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-octadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (from Preparation 26) and 6-bromohexanoic acid with 8-bromooctanoic acid, the desired product was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.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+:12]([C:9]1[CH:10]=[CH:11][C:2]([CH2:17][CH:16]=[CH2:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])([O-:14])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])cc1C(=O)OC

Procedure:
A mixture of Methyl 2-bromo-5-nitrobenzoate (0.60 g, 2.3 mmol), allyl tri-n-butyltin (0.92 g, 2.8 mmol), lithium chloride (0.29 g, 6.9 mmol), and palladium tetrakis (0.13 g, 0.12 mmol) was heated to reflux for 16 hours in toluene. TLC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, and separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][NH:18]C(=O)OCC[Si](C)(C)C)=[O:15])[CH2:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1.ClC1C=CC(C(NC(C(C)C)CC(N2CC[C@@](C3C=CC(Cl)=CC=3)(O)C(C)(C)C2)=O)=O)=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[NH2:18][CH2:17][C@H:16]([CH:28]([CH3:30])[CH3:29])[C:14]([N:11]1[CH2:12][CH2:13][C@@:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:33])[C:9]([CH3:31])([CH3:32])[CH2:10]1)=[O:15]
Reactant: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: CC(C)C(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@H](CN)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl(S)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)-3-methylbutylcarbamate (110 mg, 0.221 mmol) in THF (1 mL) was added 1 equivalent of 1 M-tetra-N-butylammonium fluoride (0.221 mL, 0.221 mmol). The resulting mixture was stirred at room temperature for 1.5 hrs. After this time, the reaction was analyzed by LC/MS, which showed that the reaction was very slow. An additional 4 equiv. of TBAF (0.88 ml) was added and the mixture was stirred at room temperature for an additional 24 hour. After this time, the reaction mixture was added to EtOAc, washed with water and brine, dried over Na2SO4 and evaporated to give an oily residue. The oily residue was purified by Combiflash chromatography (24 g silica gel) with elution by 6:4 EtOAc-hexane to give the title compound (85.3 mg). MS (ESI+)=353.13 (M+H)+
Reaction SMILES: [OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]#[N:19])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:29].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]([NH2:19])=[O:29])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: CC1(C)Oc2ccc3nc(C#N)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)Oc2ccc3nc(C(N)=O)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (±)-trans-2-hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile (400 mg, 1.07 mmol) in t-butanol (40 mL), potassium hydroxide (800 mg, 14.3 mmol) was added at room temperature and the resulting mixture was stirred at 90° C. for 2 hour. Upon the completion of the reaction, aqueous sodium chloride solution was added to the reaction solution, and it was extracted with ethyl acetate and the resulting organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane-ethyl acetate to obtain the aimed product (yield: 54%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[O:21]1[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=2)[CH2:23][CH2:22]1.[CH3:43][C:44]([CH3:46])=[O:45]>O1CCCC1>[OH:45][C:44]([C:34]1[S:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[N:31][C:30]=1[CH2:29][CH2:28][O:27][CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)([CH3:46])[CH3:43]
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)cs1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)c(C(C)(C)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of diisopropylamine (9.5 mL, 67.2 mmol) in tetrahydrofuran (100 ml) was added butyllithium (42 mL, 1.6M in hexanes, 67.2 mmol) drop wise at −78° C. and stirred for 30 min. Thus obtained lithium diisopropylamide solution was immediately added by cannulation to a solution of Example 3C (7.36 g, 22.4 mmol) in tetrahydrofuran (100 ml) at −78° C. and stirred for 30 min at the same temperature. Then, dry acetone (8.2 ml, 112 mmol, Acros) was added slowly and the reaction mixture was removed from the cold bath and allowed to warm to room temperature with continued stirring overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.6 g (53%) of the title compound. MS (ESI+) m/z 387 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Br:15])[CH:8]=1)C.[OH-].[K+].CO>O>[Br:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)CCc1ccc(OC)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1Br

Procedure:
154 g (0.535 mol) of ethyl3-(3-bromo-4-methoxyphenyl)propanoate are mixed with 45 g (0.8 mol) of potassium hydroxide, 600 ml of methanol and 300 ml of water. The mixture is heated at reflux for 3 hours, and the methanol is then evaporated off. The solution obtained is washed with ether; the aqueous phase is acidified and extracted with ether. The organic phase is dried (Na2SO4), and the solvents are evaporated off: white solid (132.7 g; 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.F[B-](F)(F)F.C(P(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.O.C(=O)(O)[O-].[Na+].CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:32]3[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.29 g, 4.35 mmol) in tetrahydrofuran (12 mL) and water (6 mL). Add potassium carbonate (1.32 g, 9.56 mmol) then 4-hydroxymethylbenzeneboronic acid (0.924 g, 6.08 mmol) and degas with nitrogen for 15 min. Add tri-n-butylphosphine tetrafluoroborate (50 mg, 0.174 mmol) and tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.0869 mmol) and reflux for 20 hr. Cool to room temperature then dilute with saturated aq. sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 3:97 methanol (with 2 M ammonia): DCM), to give a yellow oil. Dissolve the oil in methanol and add ammonium chloride then sonicate the mixture for 10 min. Evaporate the solution to give 3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow semisolid (0.565 g, 35%). MS (ES): m/z=371 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][C:7]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=2)[N:20]=1)[CH:2]([CH3:4])[CH3:3].Cl[CH2:30][C:31](=O)[CH3:32]>C(O)C>[CH2:1]([O:5][C:6]1[C:7]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=3)[N:20]=2)=[CH:8][C:9]([C:12]2[S:14][CH:30]=[C:31]([CH3:32])[N:13]=2)=[CH:10][N:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CCCc1c2nc(-c3cc(C(N)=S)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Solvent: CCO
Product: CCCc1c2nc(-c3cc(-c4nc(C)cs4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 78 %

Procedure:
6-Isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]-pyrimidin-5-yl)-3-pyridinecarbothioamide (Example 37) (77 mg, 0.19 mmol) and chloroacetone (36 mg, 0.38 mmol) were heated to reflux for 14 h in ethanol (5 mL). The reaction mixture was cooled and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 3% methanol:dichloromethane) gave 65 mg of product.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]2[O:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:25]=1[CH3:26])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[C:13]3[C:25]([CH3:26])=[C:9]([NH2:8])[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=3[O:16][CH:15]=2)=[CH:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc(-c2coc3c(C)c(C)c(NCc4ccccc4)c(C)c23)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1ccc(-c2coc3c(C)c(C)c(N)c(C)c23)cc1
Yield: 85 %

Procedure:
Using N-benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 281, the title compound was synthesized in the same manner as in Reference Example 30. Yield 85%. Melting point: 68-69° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5](C)([C:11](OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Li+].O>CS(C)=O>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(Cc1ccccc1Br)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Cc1ccccc1Br
Temperature: 180 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of diethyl 2-(2-bromobenzyl)-2-methylmalonate (108 g, 310 mmole) in dimethylsulfoxide (350 ml) were added 26.4 g of lithium chloride (620 mmole) and 5.6 ml of water (310 mmole). After stirring at 180° C. for 8 hours, the product was extracted with n-hexane and concentrated to give 84.1 g of ethyl 3-(2-bromophenyl)-2-methylpropionate as a yellow oil (yield, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN1CCCC1=O>[CH2:10]([NH:16][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCNc1cc(C#N)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and hexylamine (1.15 ml, 8.7 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 4 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.26 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC(OC)=CC=1.BrCC1[C:42]2[C:37](=[CH:38][CH:39]=[C:40](C3C=CC=CC=3OC)[CH:41]=2)[NH:36]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>COC1C=CC(S)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccc(SCC2=CC(C)(C)Nc3ccc(-c4ccccc4OC)cc32)cc1
Agent: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-4-(4-methoxyphenylsulfanylmethyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 70 μL of 4-methoxy benzenethiol reacted to give 9 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[S:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:12]([C:3]1[S:4][C:5]2[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1csc2c(Br)cccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1sc2c(Br)cccc2c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
7.6 g (39.46 mmol) of 3-methyl-7-bromobenzothiophene (dried beforehand under vacuum over phosphorus pentoxide) and 70 ml of dichloromethane are placed in a 250 ml three-necked flask equipped with a thermometer. The mixture is cooled to 0° C. by an ice bath, 2.89 g (36.8 mmol) of acetyl chloride are added and then the reaction mixture is stirred for 5 minutes at 0 °C. 5 g of aluminium chloride are then added in small portions, the temperature being controlled so that it does not exceed 70° C., and stirring is continued at 0° C. for 45 minutes. The reaction mixture is poured onto crushed ice and extraction is carried out with ethyl acetate (3×150 ml). The organic phases are combined, washed with a saturated sodium bicarbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and then concentrated. The residue is purified by chromatography on a silica column (elution solvent: 5% ethyl acetate in petroleum ether). 8.55 g (Yield: 95%) of 2-acetyl-3-methyl-7-bromobenzothiophene are obtained in the form of a white solid. M.p.=105-107° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[N:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25](N(OC)C)=[O:26])=[N:17]1>C1COCC1>[C:25]([C:18]1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[CH:21][N:16]([C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[CH:10][C:5]=2[F:4])[N:17]=1)(=[O:26])[CH3:1]
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 72.3 %

Procedure:
MeMgBr (1 M solution in THF, 2.8 mL, 2.8 mmol) was added dropwise at −78° C. to a solution of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (351 mg, 0.94 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (223 mg, 72% yield) as a pale yellow solid: mp 159-161° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.93 (3H, s), 6.56 (1H, dd, J=1.5, 2.3 Hz), 7.64 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.79 (4H, m), 7.99 (1H, d, J=2.6 Hz). Anal. Calcd for C16H13FN4O3: C, 58.54; H, 3.99; N, 17.07. Found: C, 58.42; H, 4.01; N, 16.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:22]([O:24]CC)=[O:23].[OH-].[Li+].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
Combined ethyl 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (2.4 g, 6.62 mmol) and dioxane (50 mL) and added 1.0 M aq. lithium hydroxide (29.8 mL, 29.8 mmol) and the mixture was stirred at 20° C. for 2 days. The reaction was acidified with 1 N aq. HCl (30 mL) and extracted with chloroform (100 mL then 2×50 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the title compound (2.195 g, 99% yield) as an off-white solid. MS m/z 335 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 (quin, J=6.6 Hz, 2H) 3.21 (s, 3H) 3.30 (q, J=6.7 Hz, 2H) 3.36 (t, J=6.3 Hz, 2H) 4.10 (s, 3H) 7.74 (dd, J=8.5, 0.6 Hz, 1H) 7.94 (s, 1H) 8.35 (dd, J=8.5, 2.4 Hz, 1H) 8.72 (t, J=5.6 Hz, 1H) 8.94 (dd, J=2.4, 0.6 Hz, 1H) 12.64 (br. s., 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[C:11]([C:12]=2[CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]([O:17]C)=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.B(Br)(Br)Br.C(Cl)Cl.O.C(OCC)(=O)C>C(Cl)Cl>[CH:1]1([C:4]2[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]3[C:11]([C:12]=2[CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C1CC1)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(O)cc12
Yield: 78 %

Procedure:
A solution of 400 mg (1.2 mmol) of 2-cyclopropyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide and 2 mL of 1M BBr3/methylene chloride in 130 mL of methylene chloride was stirred for 1 hour with an ice-water bath and 3 hours at room temperature. The mixture was poured into water, 200 mL of ethyl acetate added, the organic layer separated, washed with brine and dried (Na2SO4). After concentrating at reduced pressure, the residue was crystallized from ethyl acetate to give 300 mg (79% yield) of 2-cyclopropyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 174-175° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[C:34]1([CH:41]=[CH:40][CH:39]=[C:37](O)[CH:36]=1)[OH:35].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:37]2[CH:39]=[CH:40][CH:41]=[C:34]([OH:35])[CH:36]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:28])=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(O)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 40.8 %

Procedure:
A mixture of 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate (0.045 g, 0.091 mmol), resorcinol (0.020 g, 0.183 mmol) and K2CO3 (0.063 g, 0.457 mmol) in MeCN (2 ml) was heated in a microwave reactor at 120° C. for 10 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 0-50% EtOAc in DCM as eluent to give the title compound (0.016 g, 41%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.48 (m, 2H), 7.46-7.41 (m, 3H), 7.13 (t, 1H), 6.46-6.41 (m, 2H), 6.39-6.36 (m, 1H), 5.75 (t, 1H), 5.14 (s, 1H), 3.86 (t, 2H), 3.11-3.04 (m, 2H), 1.86-1.78 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): 159.9, 157.1, 135.4, 131.8, 130.4, 129.8, 128.8, 125.3, 108.5, 107.1, 106.9, 102.3, 66.1, 61.8, 42.5, 28.9, 27.8; Mass Spectrum: M+H+ 431.