Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+:2].[O-:3][P:4]([O:7][P:8]([O:11][P:12]([O-:15])([O-:14])=[O:13])([O-:10])=[O:9])([O-:6])=[O:5].[Na+:16].[Na+].[Na+].[Na+].[Na+].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)([O-])=O>>[O-:6][P:4]1([O:7][P:8]([O-:10])(=[O:9])[O:11][P:12]([O-:14])(=[O:13])[O:15]1)=[O:5].[Na+:16].[Na+:16].[Na+:16].[OH-:3].[K+:2]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=P1([O-])OP(=O)([O-])OP(=O)([O-])O1
Yield: 13.3 %

Procedure:
Example 4 illustrates that the addition of potassium hydroxide to sodium tripolyphosphate (wherein the level of the tripolyphosphate anion concentration was about equal to that which results by hydrolyzing 13.3% sodium trimetaphosphate with KOH) did not solubilize the sodium tripolyphosphate and a very heavy precipitate was observed.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:69][O:70][C:71]1[CH:72]=[C:73]([CH:75]=[CH:76][C:77]=1[O:78][CH3:79])[NH2:74]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:69][O:70][C:71]1[CH:72]=[C:73]([NH:74][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:15][C:14]5[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:13]=5[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:75]=[CH:76][C:77]=1[O:78][CH3:79]
Reactant: Cc1cccc2cc(-c3cnc4ccc(Cl)nn34)sc12
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5cccc(C)c5s4)n3n2)cc1OC
Temperature: 110 °C
Yield: 116.8 %

Procedure:
To a solution of 6-chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.167 mmol, 1.0 equiv), xantphos (19 mg, 0.0334 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0167 mmol, 0.1 equiv), and potassium carbonate (461 mg, 3.34 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (21 mg, 0.184 mmol, 1.1 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 40 mg, 0.195 mmol of the yellow solid, 58%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=[C:6]2[C:14]=1[CH:13]([CH2:15][OH:16])[C:12]1([OH:18])[O:17][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.C(O[C:25](=[O:27])[CH3:26])(=O)C>N1C=CC=CC=1>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=[C:6]2[C:14]=1[CH:13]([CH2:15][O:16][C:15](=[O:16])[CH3:13])[C:12]1([OH:18])[O:17][N:7]2[CH2:8][CH:9]2[CH:11]1[N:10]2[C:25](=[O:27])[CH3:26])(=[O:1])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2CO
Solvent: c1ccncc1
Product: CC(=O)OCC1c2c(OC(C)=O)cc(C=O)cc2N2CC3C(N3C(C)=O)C1(O)O2
Reaction time: 8 h

Procedure:
6,9-Dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (4 mg) was dissolved in pyridine (1 ml). To this solution was added acetic anhydride (50 μl) and the mixture was allowed to stand at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to yield 8-acetoxymethyl-11-acetyl-4-formyl-9-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl acetate (1.5 mg).
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[NH:1]([C:8]1[C:13]([CH2:14][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: c1c[nH]cn1
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Cn3ccnc3)c(Nc3ccccc3)n2)cc1
Yield: 25 %

Procedure:
Using an analogous method to that described in Example 105, but starting from 4-anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86) and imidazole, the product was obtained in 25% yield. NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.76 (br s, 1H), 5.20 (s, 2H), 6.75 (d, 2H), 6.89 (d, 1H), 7.08 (t, 1H), 7.20 (d, 1H), 7.32 (dd, 2H), 7.50 (d, 2H), 7.61 (d, 2H), 7.78 (s, 1H), 7.96 (s, 1H), 8.54 (s, 1H), 9.00 (s, 1H); MS (MH+): 460.4.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C=O)C.CCO.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[CH:8]=[N:7][C:6]=2[N:5]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:3]1=[O:4]
Reactant: CCOC(=O)CCCI
Reactant: Cn1c(=O)[nH]c2ncn(COC(=O)C(C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCn1c(=O)n(C)c(=O)c2c1ncn2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.6 %

Procedure:
A mixture of 1-methyl-7-(pivaloyloxymethyl)xanthine (350 mg, 1.25 mmes) sodium carbonate (265 mg, 2.50 mmoles) and ethyl 4-iodobutyrate (384 μl, 2.50 mmole) in 5.8 ml dry DMF was stirred under nitrogen at room temperature for 18 hours. Water was added and the reaction mixture extracted with chloroform. After drying, the extracts were stripped to leave a yellow oil which goes to chromotographed on four thick silica gel plates with 10% EtOH/CHCl3. The band was scraped off and eluted with 100 ml of 25% EtOH/CHCl3 to yield 609 mg of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([Cl:19])[CH:3]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:53]1([N:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54]1.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[C:8]([C:9]([N:59]3[C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[N:56]([CH:53]4[CH2:55][CH2:54]4)[CH2:57][CH2:58]3)=[O:11])=[CH:12][CH:13]=[CH:14][N:15]=2)=[C:4]([Cl:19])[CH:3]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)c(Br)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.14 mmol, 1.0 equiv) in anhydrous dichloromethane (1.5 mL) was added N-ethyldiisopropylamine (36 mg, 47 μL, 0.28 mmol, 2.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.3 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt. After 10 min, 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (29 mg, 0.17 mmol, 1.2 equiv; Example 125, Step 5) was added and stirring at rt continued over night. To the reaction was added a sat. solution of NaHCO3 (20 mL) and the solution extracted with dichloromethane (3×20 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 45 mg (63%) of the title compound as an off-white powder. MS (ISP): 520.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:20][C:21]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (210 mg, 1.13 mmol) and pyridine (137 mg, 1.73 mmol) in anhydrous CH2Cl2 (2 mL) was cooled to 0° C. under an atmosphere of N2, treated with a solution of triphosgene (402 mg, 1.35 mmol) in anhydrous CH2Cl2 (2 mL) and stirred at 0° C. for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 1 h. After this time, the mixture was diluted with 1 M hydrochloric acid (25 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure to provide tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate as a white solid (280 mg, 100%): 1H NMR (500 MHz, CDCl3) δ 10.76 (br s, 1H), 7.33 (dd, J=17.0, 9.0 Hz, 1H), 7.11 (dd, J=9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J=4.5 Hz, 4H), 3.32 (apparent t, J=4.5 Hz, 4H), 3.25 (apparent t, J=12.5 Hz, 1H), 3.14-2.88 (m, 2H), 1.94 (d, J=12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Li].[H-].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15](O)=[O:16])[CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.O.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:14][CH2:15][OH:16])[CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12
Reactant: COc1cc(CC(=O)O)cc2c1OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCO)cc2c1OCO2
Yield: 60.7 %

Procedure:
7.30 g (0.192 mol) of lithium alminium hydride was added to 270 ml of anhydrous tetrahydrofuran, and to this solution was added portionwise 33.68 g of 3-methoxy-4,5-methylenedioxyphenylacetic acid (2) with stirring under water-cooling. The mixture was stirred at room temperature for one hour, then added with 2.0 g (53 mmol) of lithium aluminium hydride and further stirred for one hour. The reaction mixture, while being cooled in an ice bath, was added portionwise with a solution of 9.3 ml of water and 10 ml of tetrahydrofuran and then further added portionwise with 9.3 ml of 15% sodium hydroxide aqueous solution. The resulting mixture was further added with 27.9 ml of water and then 500 ml of ethyl ether followed by stirring for 30 minutes. The deposited salt was filtered out and washed with ethyl ether. The filtrate and the ethyl ether used for washing were joined and concentrated under reduced pressure, and the residual oil was distilled in vacuo to obtain 19.09 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) as an oil. Boiling point: 140°-142° C./ 1 mmHg: yield 68.4%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH3-]C#N.[Na+]>CO>[Cl:2][C:3]1[C:4]([CH3:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: Cc1cc2[nH]c(=O)n(C3CCNCC3)c2cc1Cl
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-5-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D9) (˜0.2 mmol, 60 mg), Ti(iPrO)4 (2 eq., 0.400 mmol, 0.130 ml), tetrahydro-4H-pyran-4-one (2 eq., 0.400 mmol, 40 ul) were stirred together at room temperature for one hour; dry MeOH (2 ml) followed by NaBH3CN (2 eq., ˜30 mgs) were added and the mixture was stirred under argon at room temperature for 3 hours. The crude mixture was subsequently quenched with water (5 ml) and it was firstly purified by SCX followed by chromatography (methanol-NH3-dichloromethane) to yield 6-chloro-5-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 10 mg, 14%, M++H=350, which was converted into the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][OH:35])[CH2:33][O:32][CH2:31]1>C(#N)C>[OH:35][CH2:34][C:30]1([CH2:29][O:1][C:2]2[C:3]([O:20][CH3:21])=[C:4]([C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[CH2:12][CH2:13][C:14]4=[O:19])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:33][O:32][CH2:31]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (115 mg, 0.843 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (153 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 27.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 29 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 31 (29% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.22 and 2.25 (2s, 3H), 2.78 and 3.03 (2t, 2H), 3.54 and 4.17 (2t, 2H), 4.43 and 5.05 (2s, 2H), 6.27-6.75 (m, 2H), 6.85-7.03 (m, 3H), 7.45-7.63 (m, 3H), 7.90-8.01 (m, 2H), 8.08-8.12 (m, 1H), 8.52-8.59 (m, 2H); MS (ESI) m/z 430 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.O>CS(C)=O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:4](=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: CC1(C)CCCC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Reaction time: 1 h

Procedure:
3,3-Dimethylcyclohexanone (5.60 mL) was added to sodium bis(trimethylsilyl)amide (45.3 mL, 1M in tetrahydrofuran), and the reaction was stirred for 1 hour. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (11.1 g) in dimethylsulfoxide (30 mL) was added, and the reaction was stirred at 50° C. for 24 hours. The reaction was cooled, poured into water (300 mL), extracted three times with ether, and the combined extracts were washed three times with water, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 5-20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3F)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidin-4-yl)propanoate (300 mg) in methanol (2.0 mL) and THF (4.0 mL) were added water (2.0 mL) and lithium hydroxide monohydrate (123 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (30 mg) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](OCC)(OCC)OCC>C(O)C>[Cl:9][CH2:10][C:11]1[S:8][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][N:4]=2
Reactant: Nc1cccnc1S
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCO
Product: ClCc1nc2cccnc2s1

Procedure:
3-Amino-2-pyridinethiol (5.0 g, 39.6 mmol) and 2-chloro-1,1,1-triethoxyethane (8.57 g, 43.5 mmol) were combined in absolute ethanol (40 mL) and refluxed for 2 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography (ethyl acetate:hexanes, 1:4) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 4.93 (s, 2H) 7.47 (dd, J=8.14, 4.75 Hz, 1H) 8.26 (dd, J=8.31, 1.53 Hz, 1H) 8.62 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 186 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH:28]1([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[N:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([O:33][C:34]2[N:35]=[C:36]([C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]4[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[O:12][C:11]4=[O:27])[CH3:9])=[CH:6][CH:7]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC1(C)OB(c2cccc(OC3CCCC3)n2)OC1(C)C
Product: C[C@@H](c1ccc(-c2cccc(OC3CCCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-(cyclopentyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=2.23 min, m/z=515, 457; 1H NMR (CD3OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.56 (d, 3H), 1.70 (2H), 1.85 (4H), 2.05 (2H), 2.17 (s, 2H), 2.24 (m, 1H), 2.46 (2H), 3.05 (m, 1H), 5.47 (m, 1H), 5.58 (q, 1H), 6.70 (d, 1H), 7.00 (d, 2H), 7.25-7.40 (6H), 7.70 (t, 1H), 7.77 (d, 2H).
Reaction SMILES: N1C2C(=CC=C(C(O)=O)C=2)C=CC=1.NC1C=CC(C#N)=C(C(F)(F)F)C=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)=[O:37])=[CH:31][C:30]=1[C:48]([F:51])([F:50])[F:49])#[N:28].C(C1C=CC(NC(C2C=C3C(CCCN3)=CC=2)=O)=CC=1C(F)(F)F)#N.[Cl:77][C:78]1[CH:79]=[C:80]([S:84](Cl)(=[O:86])=[O:85])[CH:81]=[CH:82][CH:83]=1>>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[CH:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][N:45]3[S:84]([C:80]3[CH:81]=[CH:82][CH:83]=[C:78]([Cl:77])[CH:79]=3)(=[O:86])=[O:85])=[CH:40][CH:39]=2)=[O:37])=[CH:31][C:30]=1[C:48]([F:51])([F:49])[F:50])#[N:28]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc(NC(=O)c2ccc3cccnc3c2)cc1C(F)(F)F
Agent: N#Cc1ccc(N)cc1C(F)(F)F
Agent: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1C(F)(F)F
Agent: O=C(O)c1ccc2cccnc2c1
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1C(F)(F)F

Procedure:
In analogy to example 40, quinoline-7-carboxylic acid was reacted with 4-amino-2-trifluoromethyl-benzonitrile in step 2, and the resulting quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide was reduced to 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide in step 3. This was coupled with 3-chloro-benzenesulfonyl chloride in step 4, yielding 1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]([CH3:31])[CH2:17][S:18]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][S:18]([CH2:17][CH:16]([OH:15])[CH3:31])(=[O:20])=[O:19])=[CH:23][CH:24]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(O)CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(O)CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of methyl 4-(bromomethyl)benzoate was reacted with 1-mercaptopropan-2-ol via Procedure Q. 1 g of methyl 4-((2-hydroxypropylthio)methyl)benzoate was oxidized with 2 g of MCPBA in DCM at −78° C. to form crude methyl 4-((2-hydroxypropylsulfonyl)methyl)benzoate. The reaction was evaporated and purified by ISCO Combi-Flash to yield 567 mg of pure methyl 4-((2-hydroxypropylsulfonyl)methyl)benzoate which was subsequently hydrolyzed via Procedure M to give 328 mg of 4-((2-hydroxypropylsulfonyl)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((2-hydroxypropylsulfonyl)methyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-hydroxypropylsulfonyl)methyl)benzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=[O:34]>>[I:1][CH2:2][C:3]1[N:4]=[C:33]([C:32]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=2)[O:34][C:7]=1[CH3:8]
Reactant: COc1ccc(C=O)cc1OC
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: COc1ccc(-c2nc(CI)c(C)o2)cc1OC

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3,4-dimethoxybenzaldehyde gave 4-iodomethyl-5-methyl-2-(3,4-dimethoxyphenyl)oxazole.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.OO>CO>[CH3:7][C:4]1[S:3][C:2]([S:1][S:1][C:2]2[S:3][C:4]([CH3:7])=[N:5][N:6]=2)=[N:6][N:5]=1
Reactant: Cc1nnc(S)s1
Agent: OO
Solvent: CO
Product: Cc1nnc(SSc2nnc(C)s2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Within a flask having a capacity of 1000 ml, 2-mercapto-5-methyl-1,3,4-thiadiazole of 150 mmol is solved in methanol of 450 ml. Into the solution thus prepared, 34.5% hydrogen peroxide of 39 ml is dropped slowly. The solution was stirred for one hour at room temperature. Thereafter, by decompression and heating, precipitate was created. The solution was filtered and washed. By the subsequent drying in a decompressing atmosphere, crude crystal was obtained. By recrystallization using ethanol, 5,5'-dithiobis (5-methyl-1,3,4-thiadiazole) (hereinafter referred to as "active material ε") was obtained.