Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[N:12]=[N:13][C:14]([N:17]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]2)=[CH:15][CH:16]=1>O>[Cl:10][C:11]1[N:12]=[N:13][C:14]([N:17]2[C:21]([CH3:22])=[C:20]([N+:6]([O-:9])=[O:7])[C:19]([CH3:23])=[N:18]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a mixture of 230 ml of concentrated sulphuric acid and 230 ml of 100% nitric acid, 26 g of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine are added portionwise, under stirring at a temperature between 0° C. and 5° C., then the mixture is stirred at room temperature for 2 hours, poured into 1 liter of water and set aside overnight in the refrigerator. The separated crystals are filtered, washed with water and dried. Yield: 26.7 g (84.5%); m.p. 164°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([OH:17])=O)[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[NH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:17])[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cc2ccc(Cl)cc2n2nnnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NOC1CCCCO1)c1cc2ccc(Cl)cc2n2nnnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of carboxytetrazole (5, 0.05 g, 0.2 mmol) in CH2Cl2 (5 mL) at 0° C. under N2 was added DMF (4-drops) followed by (COCl)2 (IM CH2Cl2, 0.15 mL, 0.3 mmol) and the reaction was stirred for 1 h. The reaction solvent was removed and the resulting residue of acid chloride was dried under high vacuum. The acid chloride was then suspended in CH2Cl2 (5 mL), cooled to 0° C., to it was added pyridine (0.033 mL, 0.4 mmol) followed by H2N-OTHP (0.035 g, 0.3 mmol), and stirred at room temperature for 24 h. The CH2Cl2 solution was washed with water, dried and solvent was evaporated. The resulting residue was filtered through a pad of silica gel to obtain the requisite oxamic acid ester 6. 1H NMR (CDCl3): δ 11.58 (s, 1H), 8.92 (s, 1H), 8.74 (d, 1H, J=1.8 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.77 (dd, 1H, J=1.8 Hz and 8.7 Hz), 5.26 (m, 1H), 4.15 (m, 1H), 3.76 (m, 1H), 2.10-1.50 (m, 6H); LCMS (ret. time): 21.46 min.; MS (m/z): 347 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.CCCCC>[CH2:33]([O:32][C:30](=[O:31])[N:8]([C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine (57 gm 170 mmol) was dissolved in tetrahydrofuran (750 mL) and stirred under N2. Cooled in an ice/salt bath to −5° C. To this solution was added drop wise over a period of ˜30 minutes, a solution of potassium t-butoxide (21.2 gm, 189 mmol) in tetrahydrofuran (200 mL), maintaining the temperature between −5° and 0° C. to give a deep red reaction mixture. Stirred at this temperature for 15 minutes before the drop wise addition of a solution of ethyl chloroformate (21.4 gm, 198 mmol) in tetrahydrofuran (100 mL), keeping the temperature below 5° C. The cooling bath was removed and the reaction mixture was allowed to reach ambient temperature over 1 hour to give a light brown hazy solution. Evaporation of the solvent was followed by partition of the residue between saturated brine (50 mL) and t-butyl methyl ether (300 mL). The organic phase was washed with water (50 mL) followed by saturated brine (50 mL), dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was dissolved in n-pentane (250 mL) and stored at ambient temperature overnight. The n-pentane solution was decanted from a dark brown tar which had precipitated out. Evaporation of the solvent gave ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate as a pale brown viscous oil (63 gm, 91% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Oc1ccc2cc(C3(O)CCNCC3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1ccc2cc(C3(O)CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A mixture of 0.172 gm (0.82 mMol) 1-(4-indolyloxy)-3-chloropropane, 0.200 gm (0.82 mMol) 4-hydroxy-4-(6-hydroxynaphth-2-yl)piperidine, and 0.17 gm (1.2 mMol) potassium carbonate in 6 mL acetonitrile were stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to radial chromatography (silica, 2 mm plate), eluting with 2% methanol in dichloromethane containing a trace of ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.085 gm (25%) 1-(4-indolyloxy)-3-[4-hydroxy-4-(6-hydroxynaphth-2-yl)piperidine-1-yl]propane as a foam. The oxalate salt was prepared to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C.N1CCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:29]([N:31]3[CH2:32][CH:33]([OH:41])[CH2:35]3)=[O:30])=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: OC1CNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12)N1CC(O)C1
Yield: 98 %

Procedure:
To a DCM (1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (39 mg, 0.24 mmol) at ambient temperature in one portion while stirring. After 1 hour stirring, azetidin-3-ol hydrochloride (35 mg, 0.32 mmol) [purchased from Oakwood] was added in one portion, followed by addition of DIEA (83 μL, 0.48 mmol). The reaction mixture was briefly sonicated to help break up the solid particles from azetidine material. After 30 minute stirring at ambient temperature, the reaction was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a pale-yellowish solid (65 mg, 99% yield). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(R)-phenyl ethyl amine (0.03 mL, 0.23 mmol) in dichloromethane(0.3 mL)was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 14 mg of the thiazolo derivative.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
5-(4-Chloro-phenyl)-N-piperazin-1-yl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxamide trifluoroacetate (1:1) (200 mg, 378 μmol, example 13b) was combined with acetonitrile (10 mL) to give a yellow solution. To this solution 2-bromoethyl acetate (760 mg, 500 μl, 4.55 mmol) and K2CO3 (157 mg, 1.13 mmol) were added successively. The reaction mixture was heated to 60° C., stirred for 20 h, filtered through a Celite® pad after cooling to ambient temperature and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 50% methanol in ethyl acetate) to give the title compound (107 mg, 57%) as white solid; LC-MS (UV peak area/ESI) 97.8%, 501.1510 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:5][C:4]=1[CH2:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[CH2:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.27 g of ethyl 2-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}benzyl)butanoate was dissolved in 10 ml ethanol, and 1 ml of 5 N sodium hydroxide was added. After stirring the reaction solution at room temperature for 24 hours, water was added thereto and the aqueous layer was extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 2-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}benzyl)butanoic acid as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]([CH3:11])([CH:9]=[CH2:10])[CH2:6][CH2:5][CH:4]1[C:12]([CH3:14])=[CH2:13])[CH3:2].[H][H]>[Pd]>[CH2:9]([C:7]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:12]([CH3:13])[CH3:14])[CH:3]([CH2:1][CH3:2])[O:8]1)[CH3:10]
Reactant: C=CC1(C)CCC(C(=C)C)C(CC)O1
Reactant: [H][H]
Agent: [Pd]
Product: CCC1OC(C)(CC)CCC1C(C)C
Temperature: 90 °C
Reaction time: 0.58 h
Yield: 63.5 %

Procedure:
The hydrogenation was carried out in a hydrogenation autoclave. 202 g of 6-ethyl-5-isopropenyl-2-methyl-2-vinyltetrahydropyran (from stage 1) were filled along with 8 g of Pd/active charcoal (Pd content: 5%) in the autoclave in the autoclave and hydrogenated at 30 bar hydrogen pressure. The reaction took place exothermically from 20° C. to approximately 50° C., after which heating to 90° C. was carried out. The H2 absorption was complete after 35 minutes. 107% of theoretical H2 was absorbed. The catalyst was filtered off and this was then rinsed with ethanol. The material obtained in this way was distilled via a 120 cm column. 131 g of 2,6-diethyl-5-isopropyl-2-methyl-tetrahydropyran (purity >97%) were obtained (73% of theoretical yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])=[CH:43][CH:42]=2)[C:36]([N:55]=[O:56])=[C:35]([NH2:57])[N:34]=1.Cl>C1COCC1>[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:52])([F:53])[F:51])=[CH:45][CH:46]=2)[C:36]([N:55]=[O:56])=[C:35]([NH:57][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC(=O)Nc1nc(N)nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c1N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Under an argon atmosphere 4-(tert-butoxycarbonylamino)-butyric acid (1.58 g, 8 mmol) is dissolved in 20 mL dry THF and cooled to 0° C. Diisopropyl ethylamine (1.18 g, 9 mmol) is added, the mixture cooled to −20° C., and chloroformic acid isobutylester (1.15 g, 8 mmol) added. The mixture is stirred at this temperature for 5 min, and nitroso-pyrimidine 38 (Example 21, 2.64 g, 7 mmol) dissolved in 20 mL dry THF is added via a syringe. The reaction mixture is allowed to warm to room temperature, heated to 55° C. and stirred at this temperature over night. After cooling to room temperature, the mixture is poured into 100 mL of 1 N HCl and the product extracted with ethyl acetate (300 mL). The combined organic phases are washed with water and brine, subsequently dried over MgSO4 and the solvent evaporated. The residue is adsorbed on SiO2 and purified by flash column chromatography (cyclohexane/ethyl acetate 1:2 to 1:10) to yield the title compound as a blue solid (1.96 g, 3.53 mmol, 50.4%). From the crude material, an analytical sample is recrystallized from ethyl acetate.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Cl.[Cl:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>C(O)C>[ClH:11].[NH:17]1[CH2:16][CH2:15][N:14]=[C:13]1[CH2:12][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1
Reactant: Sc1nnc(S)s1
Reactant: ClCC1=NCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(SCC2=NCCN2)s1
Yield: 52.2 %

Procedure:
In 30 ml of ethanol was suspended 2.25 g of 2,5-dimercapto-1,3,4-thiadiazole, and 30 ml of 1N-sodium hydroxide solution was added to the suspension under ice-cooling and stirring. To the mixture was further added 2.33 g of 2-(chloromethyl)imidazoline hydrochloride, and the mixture was stirred at room temperature for 90 minutes and concentrated under reduced pressure. The concentrate was adjusted to pH 4.8 and washed with ethyl acetate. The aqueous layer was concentrated and subjected to a column chromatography on XAD-II (300 ml), being washed with water and eluted with 10% aqueous ethanol. The eluate was evaporated to dryness under reduced pressure. To the residue were added 50 ml of ethanol and 5 ml of conc hydrochloric acid, and the resultant was stirred. The precipitating crystals were collected by filtration and washed with ethanol to give 2.10 g of 2-(2-imidazolin-2-yl)methylthio-5-mercapto-1,3,4-thiadiazole hydrochloride as colorless crystals (mp 204°-209° C. decomp.).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc2cc(OC3CCCCO3)ccc2c1
Reaction time: 2 h

Procedure:
To a solution of 2 drops of 6N hydrochloric acid in 17 g. of dihydropyran is added 14.4 g. of β-naphthol under ice cooling. The resulting solution is stirred at 5° to 10° for 2 hours and then 5 g. of anhydrous sodium carbonate is added. After stirring at room temperature for 15 minutes, the resulting solids are filtered off and the filtrate is concentrated under reduced pressure to yield crude 2-tetrahydropyranyloxynaphthalene, suitable for use in the next step (2).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]([CH3:20])=[C:16]([CH3:19])[N+:17]=2[O-])[CH:10]=[CH:11][CH:12]=1>>[ClH:3].[Cl:3][CH2:19][C:16]1[N:17]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[O:14][C:15]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(-c2oc(C)c(C)[n+]2[O-])c1
Product: COc1cccc(-c2nc(CCl)c(C)o2)c1
Product: Cl
Reaction time: 22 h

Procedure:
The entire toluenic solution from Example 1 (420 ml) was admixed at 60° C. dropwise with 54.2 g (0.456 mol) of thionyl chloride and stirred at <60° C. for up to 22 h. Subsequently, the mixture was concentrated by distilling off 229 ml. The suspension was cooled to <20° C., and the product was isolated by filtration with suction, washed 3 times with 20 ml each time of toluene and dried at elevated temperature under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C(OC(=O)NC1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)(C)(C)C.[C:45]([O:49][C:50](=[O:65])[C:51]([O:54][C:55]1[CH:60]=[CH:59][C:58]([CH2:61][C:62]([OH:64])=O)=[CH:57][CH:56]=1)([CH3:53])[CH3:52])([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:49][C:50](=[O:65])[C:51]([CH3:52])([O:54][C:55]1[CH:56]=[CH:57][C:58]([CH2:61][C:62](=[O:64])[N:2]([CH3:1])[C:3]2[C:4]([CH3:19])=[N:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)=[CH:59][CH:60]=1)[CH3:53])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: CNc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)OC(C)(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N(C)C(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 124C], methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-amine (prepared from [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (example 125B] by N-methylation followed by Boc-cleavage in analogy to the procedures described in examples 5E] and 5F]) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-[4-({methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
4-Hydroxyindole (831 mg, 6.24 mmol) was dissolved in DMF (8.0 mL), and the solution was added with imidazole (510 mg, 7.49 mmol) and tert-butyldimethylsilyl chloride (1.03 g, 6.86 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=85/15) to obtain 4-(tert-butyldimethylsilyloxy)indole (1.53 g, 99%).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]#[N:19])[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]2[NH:19][C:18]([C:16]3[C:15]([OH:20])=[C:14]4[C:9]([CH:10]=[CH:11][CH:12]=[N:13]4)=[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][S:2]4(=[O:1])=[O:21])[N:17]=3)=[N:33][N:32]=2)=[CH:27][CH:28]=1
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Reactant: N#Cc1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Product: O=S1(=O)CCCCN1c1nc(-c2nnc(Cc3ccc(Cl)cc3)[nH]2)c(O)c2ncccc12

Procedure:
The title compound was prepared in a similar manner to that described in example 3 from 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carbonitrile (75 mg, 0.24 mmol) and 2-(4-chlorophenyl)acetic hydrazide (137 mg, 0.74 mmol) to give a white solid (49 mg, 43%). 1H NMR (CDCl3/CD3OD): δ 9.06 (d, J=3.6 Hz, 1 H), 8.62 (d, J=8.4 Hz, 1 H), 7.66 (dd, J=8.4, 4.0 Hz, 1 H), 7.28-7.21 (m, 4 H), 4.15 (s, 2 H), 3.89 (m, 1 H), 3.82 (m, 1 H), 3.63 (m, 1 H), 3.31 (m, 1 H), 2.41 (m, 3 H), 1.79 (m, 1 H); MS m/z 471 (M+1).
Reaction SMILES: C([S:9][CH:10]([CH2:21][S:22][CH3:23])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(CSC)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH2:21][S:22][CH3:23])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CSCC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: CSCC(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-benzoylthio-3-(methylthio)propanoyl]-L-proline for the 1-[3-acetylthio-2-(methylthiomethyl)propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercapto-3-(methylthio)propanoyl]-L-proline is obtained.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.C(N(CC)CC)C.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:14])[N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:12]2
Reactant: COCCN
Reactant: COC(=O)c1ccc(OC)cc1CBr
Solvent: CCN(CC)CC
Product: COCCN1Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A mixture of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.0 g, 3.9 mmol), triethylamine (391 mg, 3.9 mmol) and 2-methoxy-ethylamine (348 mg, 4.6 mmol) was heated under reflux for 2 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, Heptane:EtOAc 1:1 to EtOAc) to afford the title product (260 mg, 30%) as a light yellow solid. MS m/e=221.3 (M+).