Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1.[Cl-].[NH4+].[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:10][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1
Reactant: Sc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1cncc(Sc2ccccc2)c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
In a volume of 268 μl of thiophenol was dissolved in 8 ml of dimethylformamide, added with 62.6 mg of sodium hydride at room temperature, and stirred for 1 hour. The reaction system was added with 618 mg of 3,5-dibromopyridine, heated to 130° C., and stirred under the same condition for 6.5 hours. The reaction system was added with saturated aqueous ammonium chloride, and extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (50:1 to 7:1)) to obtain 403 mg of the title compound.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.O>[C:13]([O:12][C:10]([N:1]1[CH:9]2[CH:4]([CH2:5][N:6]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CCC21
Yield: 77 %

Procedure:
To a solution of tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.63 g) in acetone (15 mL) was added K2CO3 (1.54 g) and 1-bromo-3-chloropropane (1.45 mL). The reaction mixture was heated to reflux overnight, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to give the title compound as pale yellow liquid (0.65 g, 77.00%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.Cl.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]([OH:27])=[O:26])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2CC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
To tert-butyl [2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]acetate (209 mg) was added a solution of 4 N hydrogen chloride in ethyl acetate (8.0 ml), and the mixture was stirred at room temperature for 5 hours to hydrolyze. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain [2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]acetic acid (129 mg, 43%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:4][C:3]([N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:5][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: CN(C(N)=S)c1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(N(C)c2ccccc2)nc1C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 1-methyl-1-phenyl-thiourea (5.03 g, 30.3 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.4 mL, 31.8 mmol) in ethanol (18 mL) was refluxed for 20 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a brown solid (7.39 g): MS: (+) m/z 277.0 (M+1).
Reaction SMILES: C(OC([CH:8]([NH2:44])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([N:22]2[CH2:26][C@@H:25]([CH:27]3[CH2:29][CH2:28]3)[C@H:24]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:23]2)=[O:21])[CH:13]=[CH:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C.C1(C)C=CC=CC=1>[NH2:44][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([N:22]2[CH2:26][C@@H:25]([CH:27]3[CH2:29][CH2:28]3)[C@H:24]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:23]2)=[O:21])[CH:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)C(N)CCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 0.1 g (0.16 mmol) of 1-(N-(3-t-butoxycarbonyl aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine in 2 mL of CH2C2 was added 0.3 mL of a 1M solution of TFA in dichloroethane and the reaction mixture was stirred at rt for 24 h. The reaction mixture was then diluted with toluene and concentrated. The residue was purified by chromatography (silica, CHCl3: MeOH: NH3, 90:10:1) to give 0.07 g of the title compound. Mass Spectrum (EI) m/e 503 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCCCO)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A suspension of 3.3 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid 3-hydroxypropyl ester in a mixture of 60 ml. of methylene chloride and 5 ml. of triethylamine is treated dropwise at 15°-20° C. with a solution of 2.4 ml. of methanesulfonyl chloride in 10 ml. of methylene chloride and the mixture is stirred at room temperature for 1 hour. After dilution with 60 ml. of methylene chloride, the suspension is removed by filtration and the filtrate washed successively with water, 0.5-N hydrochloric acid, 5% sodium bicarbonate solution and again with water. After drying over sodium sulfate and evaporation of the solution, there is obtained a solid crude product which is chromatographed on 100 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The uniform fractions yield 5-chloro-3-phenylisoindole-1-carboxylic acid 3-[(methylsulfonyl)oxy]propyl ester having a melting point of 155°-158° C. which can be used in the process without further purification. An analytical sample is obtained by recrystallization from ethanol, and there are obtained greenish crystals having a melting point of 159°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1.CN(C)C=O.C(N(CC)CC)C>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1cc[nH]c(=O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cc[nH]c(=O)c1
Yield: 54 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.26 g, 0.94 mmol) and 4-aminomethyl-1H-pyridin-2-one hydrochloride (0.15 g, 0.94 mmol) were coupled in tetrahydrofuran (5 mL) and N,N-dimethylformamide (3 mL) with triethylamine (0.28 g) at room temperature overnight. After the addition of water, the solid material is collected by Buchner filtration, washed with diethyl ether, water, and methanol, and dried under vacuum to give (4Z)-6-bromo-4-({[(2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (0.19 g, 54%) as a gray powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:26])[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:17]1([NH:26][C:14]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=2)=[O:15])[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2ncccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2ncccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.45 mmol) in EtOAc (8 mL) is added to a stirred solution of pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and K2CO3 (0.45 mmol) in EtOAc (4 mL) and H2O (8 mL) at rt, and the reaction mixture is stirred at rt for 30 min. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid pyrrolo[3,2-b]pyridin-1-ylamide (116 mg, 77%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.60 (d, H) 7.15-7.60 (m, 4H), 8.01 (m, H), 8.10-8.41 (m, 3H), 9.27 (s, 2H), 12.45 (br, N—H). IC50=18 nM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>CCOC(C)=O.[Pd]>[NH2:16][CH:12]1[CH2:11][N:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:14](=[O:15])[CH2:13]1
Reactant: COc1ccc(N2CC(NC(=O)OCc3ccccc3)CC2=O)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N2CC(N)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round-bottomed flask containing a mixture of benzyl 1-(3-fluoro-4-methoxyphenyl)-5-oxopyrrolidin-3-ylcarbamate (Step 1, 1.5 g, 4.2 mmol) and 200 mg of Pd/C in 100 mL of EtOAc was applied with a H2 balloon. The reaction was stirred at RT for 8 h, and filtered with the aid of Celite®. The filtrate was concentrated in vacuo to give the title compound as a white solid. MS (ESI pos. ion) m/z: 225.3 (M+H). Calc'd Exact Mass for C11H13FN2O2: 224.23.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][N:47]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1
Reactant: C#CCCC(=O)O
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-pentynoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C, Example 6) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (142 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:5](\[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][CH:18]=1)/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][NH:15][CH3:16])=[CH:8][CH:7]=1>C(O)C.C(OC(=O)C)C>[Cl:1][CH2:2][CH2:3]/[C:4](/[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[C:5](\[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)/[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][NH:15][CH3:16])=[CH:10][CH:11]=1
Reactant: CNCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(O)cc2)cc1

Procedure:
5.99 g of Z-4-chloro-1-(4-benzyloxyphenyl)-2-phenyl-1-[4-[2-(N-methylamino)ethoxy]phenyl]-1-butene is hydrogenated in ethanol-ethylacetate (1:1) using 10% Pd--C as a catalyst. The catalyst is filtered off and the solvents are evaporated. The residue is recrystallized from ethanol-water (1:1). The yield is 3.21 g (66%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:16]=[CH:17][N:18]([CH2:20][CH3:21])[CH3:19])[C:5]([CH3:15])=[N:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([N:16]=[CH:17][N:18]([CH2:20][CH3:21])[CH3:19])[C:5]([CH3:15])=[N:6][C:7]=2[O:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCN(C)C=Nc1cc(Br)c(OCCCC(C)C)nc1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C)C=Nc1cc(-c2ccc(Cl)cc2)c(OCCCC(C)C)nc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 126.3 %

Procedure:
In a 10 ml single-necked round-bottomed flask equipped with a condensor (equipment flame-dried), 160 mg of crude N′-[5-bromo-2-methyl-6-(4-methyl-pentyloxy)-pyridin-3-yl]-N-ethyl-N-methyl-formamidine and 77.2 mg p-chlorophenyl boronic acid are dissolved in 1.20 ml of dioxane. To this solution, 162 mg of K3PO4 in 0.60 ml of water is added at ambient temperature under Argon atmosphere. The resulting biphasic mixture is degassed under Argon atmosphere for 20 minutes, whereupon 3.0 mg of tricyclohexylphosphine and 2.6 mg of bis(benzylideneacetone)palladium are added. The resulting suspension is vigorously stirred at a temperature of 100° C. for 5 hours. After letting the reaction mixture reach ambient temperature, 5.0 ml of a saturated aqueous NH4Cl solution is added. The water phase is extracted with AcOEt. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo to get 220 mg of a yellow oil. Purification by flash chromatography over a silica gel cartridge (20 g; 60 ml) of a solid deposition with heptane/ethyl acetate 9:1, then 4:1, then 3:2 (v:v) gave 80 mg of the compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.ClCCl>[CH2:19]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(OCc2ccccc2)=C1O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
Ascorbic acid (10 g, 56.8 mmol) was dissolved in 60 ml of dimethylsulfoxide, followed by addition of cesium carbonate (9.25 g, 28.4 mmol). After 20 minutes, benzyl bromide (6.75 ml, 56.8 mmol) was added to the reaction mixture and heated to 50° C. for 18 hours. The reaction mixture was cooled down to the room temperature and diluted with 150 ml of dichloromethane to produce a solid. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel to give 7.2 g of the 3-O-benzyl ascorbic acid (yield 48%).
Reaction SMILES: CO[CH:3]1[O:8][CH:7]([CH3:9])[C:6](=[O:10])[CH:5]=[CH:4]1.ClCl.[OH-:13].[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[O:8][CH:3]=[CH:4][C:5](=[O:13])[C:6]=1[OH:10]
Reactant: [OH-]
Reactant: COC1C=CC(=O)C(C)O1
Agent: ClCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine (0.01 mole) at room temperature. The reaction mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform. The chloroform extract was concentrated to yield maltol which was recrystallized from methanol to give the pure product (56%), mp 159.5°-160.5° C.
Reaction SMILES: [C:1](=[O:47])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[OH:48][C:49]1([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:48][C:49]1([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:54][CH2:53][N:52]([C:1]([O:2][C@H:3]([CH2:18][C:19]2[CH:27]=[C:26]([CH3:28])[C:25]3[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])[N:24]=3)[CH:20]=2)[C:4](=[O:17])[N:5]2[CH2:6][CH2:7][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][CH2:10]2)=[O:47])[CH2:51][CH2:50]1
Reactant: O=c1[nH]c2ccccc2cc1C1(O)CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(O)(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3-(4-hydroxypiperidin-4-yl)quinolin-2(1H)-one (55 mg, 1.0 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (3:97:1 methanol/dichloromethane/triethylamine) to give 90 mg (52%) as a foam solid. Mass spec.: 771.48 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(C)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCc1ccccc1)CC(=O)O
Yield: 91.8 %

Procedure:
A mixture of ethyl 5-phenyl-3-methylpentanoate (0.30 g, 1.36 mmol), a 1N-aqueous sodium hydroxide solution (3 ml), methanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 1 with a 1N-aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.24 g of 5-phenyl-3-methylpentanoic acid.
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>>[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][O:22][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:23][CH:24]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenoxy]-ethanol (10) (200 mg, 0.62 mmol), methanesulfonyl chloride (0.05 ml, 0.62 mmol) and Et3N (0.09 ml, 0.62 mmol) was stirred at room temperature for 2 h. Then the reaction was quenched by addition of CH2Cl2 and water. The organic layer was then extracted with water and NaCl-solution, dried over Na2 SO4 and evaporated. The crude product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][N:9]=2)=[C:4]([CH3:20])[CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[CH:15])=[CH:10][N:9]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cnc(C#C[Si](C)(C)C)cn1
Solvent: CCOC(C)=O
Product: C#Cc1cnc(-c2ccc(Cl)cc2C)cn1

Procedure:
The product was prepared analogously to Example 1.1c from 700 mg (2.33 mmol) of 2-(4-chloro-2-methylphenyl)-5-trimethylsilanylethynylpyrazine (40 minutes at RT, DCM as solvent). Yield: 200 mg (38% of theoretical); C13H9ClN2 (M=228.677); calc.: molpeak (M+H)+:229/231 (Cl); found: molpeak (M+H)+:229/231 (Cl); Rf value: 0.2 (silica gel, PE/EtOAc 9:1).
Reaction SMILES: [CH:1](=[C:3]1[C:12](=[S:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[O:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH:1](=[C:3]1[C:12](=[S:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[O+:5]([O-:29])[CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CC=C1C(=S)c2cc(C)ccc2OC1c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC=C1C(=S)c2cc(C)ccc2[O+]([O-])C1c1ccccc1

Procedure:
A cooled solution of 0.28 g 3-ethylidene-6-methyl-thioflavanone and 0.2 g meta-chloroperbenzoic acid in 3 ml methylene chloride is stirred at 0° C. for 5 minutes. After filtration the organic phase is washed with saturated sodium bicarbonate aqueous solution, then with water, dried over magnesium sulfate and evaporated. The crude solid is crystallized in cyclohexane. Pure 3-ethylidene-6-methyl-thioflavanone-1-oxide is obtained as yellow crystals; m.p. 151°-160° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].CN(C=O)C.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.8 %

Procedure:
A 7 mL vial was charged with 1H-quinolin-2-one (0.62 g, 4.2 mmol), 4 mL dry DMF and NaH (60% in oil, 0.200 g, 5.1 mmol). The mixture was stirred under a N2 atmosphere at rt for 45 min, and thereafter 1-bromo-3-chloropropane (0.42 mL, 4.2 mmol) was added and the reaction was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (15 mL). The water phase was extracted with EtOAc (25 mL) and the combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; CH2Cl2) to yield the title compound (0.38 g, 41%), containing 15% of 1-(3-bromopropyl)-1H-quinolin-2-one. 1H NMR (CD3OD) δ 7.90 (d, J=9.4 Hz, 1H), 7.73-7.57 (m, 3H), 7.34-7.28 (m, 1H), 6.66 (d, J=9.4 Hz), 4.46 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.21-2.02 (m, 2H); 13C NMR (CD3OD) δ 163.2, 140.7, 138.8, 131.3, 129.3, 122.8, 121.4, 120.2, 114.4, 42.18, 40.2, 30.5.