Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21](I)=[C:20]([F:26])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1COCC1>[CH2:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([C:19]4[CH:18]=[CH:23][C:22]([F:24])=[CH:21][CH:20]=4)=[C:20]([F:26])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3cc(F)c(I)c(F)c3)CC2)CC1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3cc(F)c(-c4ccc(F)cc4)c(F)c3)CC2)CC1

Procedure:
17.5 g (0.1 mol) of p-bromochlorobenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This was dripped into a 30 ml THF solution of 13.6 g of zinc chloride to obtain an organozinc reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 49.2 g (0.1 mol) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,6-difluorophenyl iodide. After a conventional after treatment, purification was conducted by means of chromatography to obtain 27.2 g (yield 59.4%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl) -2,6,4'-trifluorobiphenyl was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29].CCCCCC>C1(C)C(C)=CC=CC=1>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([NH:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4])=[O:29]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: Nc1ccccc1C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of (3aR*,l0aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and isatoic anhydride (196 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from ethanol-hexane to give 345 mg (yield 58%) of the titled compound. This compound was in good agreement in
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([O:10][C:11]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])[CH3:9].[Br:34][C:35]1[C:40]([CH2:41]Br)=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]>O>[Br:34][C:35]1[C:40]([CH2:41][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=2)[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% oily, 1.02 g, 25.6 mmols) was added to a DMF (80 ml) solution of ethyl 2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (8.55 g, 23.3 mmols), with cooling with ice, then allowed to warm to room temperature, and stirred for 30 minutes. Next, a DMF (10 ml) solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (9.47 g, 25.6 mmols) was dropwise added thereto at room temperature, and stirred for 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) to obtain the entitled compound (15.0 g) as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)nc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: COCC1CN(c2ccc(C3CCC4(CC3)OCCO4)nc2)C(=O)O1
Yield: 149.1 %

Procedure:
A solution of 0.8 g of (RS)-3-[6-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-3-yl]-5-methoxymethyl-oxazolidin-2-one and 1.1 g of palladium-on-charcoal (10%) in 250 ml of methanol was hydrogenated at room temperature and normal pressure. After filtering off the catalyst the filtrate was concentrated. 1.2 g of (RS)-3-[6-(1,4-dioxa-spiro[4,5]decan-8-yl)-pyridin-3-yl]-5-methoxymethyl-oxazolidin-2-one were obtained. A sample was purified further on silica gel 60 with ethyl acetate as the eluent and boiled with diethyl ether. M.p.: 93°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:19])([C:13]1[O:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([CH3:12])([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH3:19])[NH:8]1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: Cc1ccc(C(C)(C)C/C=N/CC(=O)OC(C)(C)C)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C)(C)CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)o1
Yield: 45.9 %

Procedure:
In a manner similar to the method described in Example 100b, [[3-methyl-3-(5-methyl-furan-2-yl)-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 125a (1.7 g, 6 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.48 g, 4.8 mmol) prepared in Example 52a, AgF (0.9 g, 7 mmol), and triethylamine (1.7 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5.7 ml) in tert-butanol (10 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow solid (1.3 g, 46%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.CCCCCCCCCCCC.NC(N)=[O:25].C(=O)(O)[O-].[Na+].OO>O.ClCCl.S([O-])([O-])(=O)=O.[Mn+2]>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]2[O:25][CH:7]2[CH2:8]1
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2CC1
Agent: [Mn+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCCCCCCCC
Product: c1ccc2c(c1)CCC1OC21
Yield: 99 %

Procedure:
To a mechanically stirred solution of 1,2-dihydronaphthalene (0.01 mol), dodecane (0.00 mol), urea (0.208 mol), sodium bicarbonate (0.003 mol) and manganese sulphate (0.1 mmol) in 10.0 ml of water and 30 ml of dichloromethane at 25° C. is added 30% aqueous hydrogen peroxide (0.4 mol) in three equal portions over a period of 3 hours. After 4 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded 1,2-dihydronaphthalene oxide in 99% yield with selectivity 95%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CS(O[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O>>[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OCCCCOCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde (11) with 4-(benzyloxy)butyl methanesulfonate following the method used in Example 149 gave 3-(4-(benzyloxy)butoxy)benzaldehyde (137) as a clear oil. Yield (1.5 g, 80%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.46 (m, 2H), 7.33-7.38 (m, 5H), 7.28-7.31 (m, 1H), 7.14-7.18 (m, 1H), 4.53 (s, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.4 Hz, 2H), 1.88-1.98 (m, 2H), 1.80-1.87 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[CH3:27].[Li+].[OH-]>>[Cl:26][C:21]1[CH:20]=[C:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2])=[C:7]([CH3:27])[CH:8]=3)[N:15]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(F)c(Cl)c3)n2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(F)c(Cl)c3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-3-{4-[2-(3-chloro-4-fluoro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (2S)-3-{4-[2-(3-chloro-4-fluoro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH3:17])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(C)cc1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Product: COc1cc2nc(Cl)nc(N(C)c3ccc(C)cc3)c2cc1OC

Procedure:
The title compound was prepared from 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and N-methyl-p-tolylamine (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (8 mg, 8%). 1H NMR (CDCl3): 7.27 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.26 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H), 3.28 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[C:4]#[C:5][CH2:6][OH:7])[CH3:2].CCOCC.C1COCC1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2]
Reactant: CCC(O)(C#CCO)CC
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC(O)(/C=C/CO)CC
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A 3 liter, round-bottom flask equipped with a mechanical stirrer, dropping funnel, thermometer and nitrogen bubbler was charged with 168 g of crude 4-ethyl-2-hexyn-1,4-diol TES-ether and 1 liter of THF. After cooling to −70° C. with a dry ice-acetone bath, 200 mL (600 mmol) 65+wt. % solution of Red-Al® in toluene was added slowly to control vigorous gas evolution and foaming during addition of the first 50% of the reagent. Then, the mixture was warmed to 0° C. with an ice bath and stirred for 1 hour. TLC analysis indicated complete reaction. The mixture was cooled to −70° C. and carefully quenched by the addition of 240 mL of 30% ammonium hydroxide solution, while maintaining the internal temperature below −50° C. The mixture was concentrated under reduced pressure to remove the THF and the resulting slurry was diluted with 400 mL of diethyl ether. The solid was removed by filtration and washed twice with 200 mL of diethyl ether. The combined filtrate and washes were washed twice with 200 mL of water and twice with 200 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure, then under high vacuum to give 160 g of crude (E)-4-ethyl-2-hexen-1,4-diol TES-ether as a pale yellow viscous liquid. This material was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[CH:15][N:16]=[C:17]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[CH:18]=2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3ccc4cccnc4c3)c2)cc1
Temperature: 155 °C
Reaction time: 0.17 h

Procedure:
To an oven-dried, 50-mL, round-bottomed flask-were added 7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). The solution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was added in one portion. After stirring for 10 min, 2-chloro-4-(4-trifluoromethylphenyl) pyridine (Example 410 (c), 129 mg, 0.5 mmol) was added. The reaction mixture was heated in a 155° C. oil bath for 72 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude material was purified on a Biotage 40 S column (3:1 hexanes: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 156.5-158.5° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH:15]=O.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO>[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1CCN(CCC(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a solution of ethyl isonipecotate (3.00 g, 19.1 mmol) in THF (20 mL) and MeOH (20 mL) was added 3,3,3-trifluoropropionaldehyde (2.14 g, 19.1 mmol) and AcOH (1.09 mL, 19.1 mmol) followed by sodium cyanoborohydride (1.20 g, 19.1 mmol). The reaction was allowed to stir for 10 min., at which time the reaction was quenched with water (15 mL) then made basic with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated in vacuo to yield a white powder (3.3 g, 68%). Mass Spectrum: Calcd for C11H19NF3O2(M+H): 254. Found: 254.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[N:7]1([S:13](Cl)(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO.C(O)(C)C>[N:7]1([S:13]([N:3]2[CH2:2][CH2:1][NH:6][C:4]2=[O:5])(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: O=C1NCCN1
Solvent: CO
Solvent: CC(C)O
Product: O=C1NCCN1S(=O)(=O)N1CCCCC1
Reaction time: 3 h

Procedure:
To 17.4 of ethyleneurea is added with shaking 36 g of piperidinosulfonyl chloride (b.p. 130°/11 mm) and the mixture kept under nitrogen at 100° for 3 hrs. The mixture is cooled and the gummy material treated with methanol-isopropanol (1:1) to give a granular product of 1-piperidinosulfonyl-2-oxo-tetrahydroimidazole which melts at 201° on recrystallization from methanol.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH:29]1([CH:35]2[CH2:37][O:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O.C(OCC)(=O)C.CN(C)C=O>[CH:29]1([C:35](=[O:36])[CH2:37][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: C1CCC(C2CO2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(=O)n(CC(=O)C3CCCCC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-cyclohexyloxirane (0.98 g), potassium carbonate (0.71 g) and N,N-dimethylformamide (13 mL) was stirred at 80° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (8 mL), 4-methylmorpholine-N-oxide (0.34 g), tetrapropylammonium perruthenate (0.026 g) and molecular sieves 4A (0.15 g) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and silica gel column chromatography gave the title compound as a colorless solid (0.68 g, 52%).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:15].[CH3:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1SC>>[IH:15].[CH3:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[N:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC1=NCCN1C
Reactant: NC(c1ccccc1)c1ccccc1
Agent: I
Product: CN1CCNC1=NC(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 31.1 %

Procedure:
A mixture of 1.8 g of benzhydrylamine and 3.4 g of 1-methyl-2-methylmercapto-2-imidazoline.hydroiodide was allowed to stand at room temperature for 2 days. Chloroform was then distilled off to give 1.2 g of 1-methyl-2-benzhydryliminoimidazolidine.hydroiodide having a melting point of 254°-256° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([N:13](OC)[CH3:14])[N:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[C:4]1=[O:27])[CH3:2].[H][H]>CO.[Pd]>[NH2:24][C:19]1[CH:18]=[C:17]([N:5]2[CH2:6][C:7]3[CH:12]=[N:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:27])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: [H][H]
Reactant: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(N(C)OC)cc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(NC)cc21
Yield: 84.6 %

Procedure:
1-Ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (4.6 g, 12 mmol), Pd/C (0.5 g) and hydrogen (45 psi) were reacted in MeOH (100 mL) at 50° C. overnight to give 3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.2 g, 84%). 1H-NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1 H), 6.94 (dd, J=11.2, 8.8 Hz, 1 H), 6.67 (dd, J=8.0, 2.4 Hz, 1 H), 6.42 (m, 1 H), 6.33 (m, 1 H), 5.98 (s, 1 H), 5.14 (s, 2 H), 4.48 (s, 2 H), 3.74 (q, J=7.2 Hz, 2 H), 2.73 (d, J=5.2 Hz, 3 H), 1.15 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 316.2 [M+H]+.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:29])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:28][S:25]([C:24]1[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])[CH:4]=2)=[CH:16][C:17]([CH3:29])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:26])=[O:27]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Reactant: Oc1cccc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
5.00 g of 3-pentafluorosulfanylphenol, 6.98 g of methyl 4-bromo-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017) and 22.20 g of Cs2CO3 were stirred in 200 ml of anhydrous DMF at 100° C. for 2 h. The mixture was allowed to cool, and the reaction mixture was poured onto 1 of water and stirred at RT for 16 h. The product was then filtered off and dried under reduced pressure. 8.20 g of pale yellow crystals were obtained, mp 139° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[C:30]([N+:37]([O-])=O)[CH:29]=1>C1COCC1>[NH2:37][C:30]1[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][C:31]=1[NH:34][C:35](=[S:36])[NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:24][CH:23]=1
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=S)Nc2ccc(OC)cc2N)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
The aminoester 4-2 (350 mg, 1 mmole) in 20 ml of THF is mixed with 4-methoxy-2-nitrophenyl isothiocyanate (210 mg, 1 mmole), followed by agitating for 1 hour at ambient temperature, evaporating under reduced pressure, then adding SnCl2 (380 mg then 190 mg, 3 mmoles) in 10 ml of DMF and agitating for 4 hours at ambient temperature. After evaporating under reduced pressure and taking up in a water/NaHCO3/AcOEt mixture, decanting, drying the organic phase and evaporating under reduced pressure, 530 mg of crude product is obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc(C(=O)OC)cc2)CC1

Procedure:
4-(methoxycarbonyl)phenyl chloroformate (5.00 g, 23.3 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.00 g, 17.9 mmol) according to general procedure 1. Yield=5.54 g, 99%. m/z MH+=302.02. HPLC rt=10.8 min.