Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](=[O:43])([O:12][CH2:13][CH2:14][N:15]([C:17]([N:19]1[C:23]2[CH:24]=[C:25](OC)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[S:30]([CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=1)=[O:31])=[O:18])[CH3:16])[O:9][CH2:10][CH3:11].[O:44]1CCC[CH2:45]1>>[C:8](=[O:43])([O:12][CH2:13][CH2:14][N:15]([C:17]([N:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:44][CH3:45])=[CH:27][C:22]=2[N:21]=[C:20]1[S:30]([CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=1)=[O:31])=[O:18])[CH3:16])[O:9][CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)cc21
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 1 hr under ice-cooling, and ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Synthetic Example 14 was added thereto. A solution of triethylamine (0.418 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (15 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60° C. for 12 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a mixture of 3:2 of title compound and ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as pale yellow amorphous solid (0.92 g).
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[C:6]([CH3:36])=[C:7]([C:11]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]3[C:12]=2[CH2:13][CH2:14][C@H:15]3[O:21][C:22]2[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4]>O1CCCC1.O.CO>[C:3]([C:5]1[C:6]([CH3:36])=[C:7]([C:11]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]3[C:12]=2[CH2:13][CH2:14][C@H:15]3[O:21][C:22]2[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(C#N)c5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
LiOH×H2O (131 mg) is added to a solution of methyl 2-((3S)-6-((1R)-4-(3-cyano-2-methylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (119 mg) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The mixture is concentrated, cooled to 0° C., diluted with water and acidified with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 103 mg; LC (method 20): tR=6.30 min; Mass spectrum (ESI−): m/z=442 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:21])=[CH:10][CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(Oc2ccc(CBr)cc2)c1
Temperature: 0 °C

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 99 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: C([NH:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[N:13]=1)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:8][CH:9]1[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]1=[O:16]
Reactant: CN1C(=O)N=C(NCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1C(=O)NC(N)C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
To a solution of 5-benzylamino-3-methyl-imidazole-2,4-dione (Example 1.3, Part B) (400 mg, 1.84 mmol) in ethanol/ethyl acetate (50 mL, 1:1) was added 10% Pd/C catalyst (195 mg, 0.18 mmol). The flask was evacuated and filled with hydrogen three times and then stirred at room temperature for 23 h. After this period, the reaction mixture was filtered through celite and the filtrate was evaporated to give the product as a colourless solid (214 mg, 90%), mp 122-125° C. δH (300 MHz, CD3CN) 6.31 (br s, 1H, NH), 4.68 (d, J 1.5 Hz, 1H, CH), 2.87 (s, 3H, CH3). δH (300 MHz, D2O) 4.95 (s, 1H, CH), 2.96 (s, 3H, CH3). δC (75 MHz, D2O) 175.6, 158.5, 64.0 (CH), 24.3 (CH3).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.O1CCOCC1>[C:19]([O:23][C:24]([NH:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NC1C2CCC(C2)C1C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1C2CCC(C2)C1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
To a solution of 3-aminonorbornane-2-carboxylic acid (12.6 g.) in a mixture of water (100 ml.) and dioxane (100 ml.) were added triethylamine (12.2 g.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (16.2 g.). The mixture was stirred for 5 hours at ambient temperature and washed with ethyl acetate at pH 10 (each 250 ml., 2 times). The aqueous layer was adjusted to pH 2 with 10% aqueous hydrochloric acid. The acidified solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was pulverized with isopropyl ether to give 3-(N-tert-butoxycarbonylamino)norbornane-2-carboxylic acid (10.5 g.).
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1.[H-].[Na+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[C:13]1=[O:24])#[N:31]
Reactant: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cc(-c2ccccc2)cc(-c2ccccn2)c1=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5 ml of a dimethylformamide solution containing 0.26 g of 3-(2-pyridyl)-5-phenyl-2(1H)-pyridone was incorporated with 0.04 g of sodium hydride. After 15 minutes, the solution was further incorporated with 0.15 g of 2-fluorobenzonitrile and 00.10 g of cuprous iodide, and vigorously stirred at 100° C. for 2 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was distilled off under a vacuum. The residue was refined by silica gel chromatography (ethyl acetate/hexane=1:2), to obtain 0.03 g of the light yellow, powdery subject compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c2cc1OC
Yield: 70 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (66 mg, 0.3 mmol) using the procedure in Example 182 to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (113 mg, 0.21 mmol, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.08 (s, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.66-7.54 (m, 3H), 7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.28 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 535 (M+H)+.
Reaction SMILES: [N+](C1C=C(C=CC=1)C(NC1C=CC=CC=1OC1C=C([P:19](=[O:22])([OH:21])[OH:20])C=CC=1)=O)([O-])=O.C(OP([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[NH:51][C:52](=[O:62])[C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([N+:59]([O-:61])=[O:60])[CH:54]=2)[CH:39]=1)(=O)OCC)C>>[N+:59]([C:55]1[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=1)[C:52]([NH:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][C:40]1[CH:39]=[CH:38][C:43]([P:19](=[O:20])([OH:22])[OH:21])=[CH:42][CH:41]=1)=[O:62])([O-:61])=[O:60]
Reactant: CCOP(=O)(OCC)c1cccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: O=C(Nc1ccccc1Oc1cccc(P(=O)(O)O)c1)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1ccccc1Oc1ccc(P(=O)(O)O)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
{3-[2-(3-Nitrobenzoylamino)phenoxyl]phenyl}phosphonic acid (Compound 145) from {3-[2-(3-nitrobenzoylamino)phenoxy]phenyl}phosphonic acid diethyl ester (110 mg, 0.234 mmol) (yield: 64 mg white crystals (66%)). Mp: 120.4-122.4° C. LC/MS: m/e 415 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])[C:3]=1[F:19].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:27](Cl)(=[O:29])[CH3:28]>CC(O)C.CCCCCCC.O>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([O:15][CH3:16])=[C:13]([C:27](=[O:29])[CH3:28])[CH:14]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cc2cccc(Cl)c2F)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COc1cc(OC)c(C(C)=O)cc1Cc1cccc(Cl)c1F
Temperature: -10 °C
Yield: 85 %

Procedure:
The compound 5 DCM solution was transferred into a clean reactor and cooled to −13 to −7° C. Dichloromethane (3 volumes) was charged and then aluminum chloride (1.03 eq) was added to this solution while maintaining the temperature at not more than −7° C. Acetyl chloride (1.12 eq) was slowly charged to the mixture while maintaining the temperature at not more than −10° C. The reaction mixture was agitated at −13 to −7° C. and the progress of the acylation reaction was monitored by HPLC. After the acylation was completed the reaction mixture was transferred into 5 volumes of cold (2 to 8° C.) water while maintaining the temperature at not more than 25° C. The quenched mixture was allowed to warm to 19 to 25° C. and agitated till a biphasic mixture was formed. The organic phase was separated and washed with water (3 volumes). The organic phase was separated and concentrated by vacuum distillation. The solvent was exchanged to 2-propanol by coevaporation under vacuum. The slurry that formed was diluted with 2-propanol (1 volume) and then heated to reflux to form a solution. Heptane (2.92 volumes) was slowly charged to the hot solution and cooled to 0 to 5° C. to form a slurry. The product was isolated by filtration. The wet cake was washed with a mixture of 2-propanol and heptanes and dried at not more than 40° C. to yield approximately 85% of compound 8 as off-white to light pink solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.[Li+].[Cl-].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1cc(OCC2CC2)c(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(OCC2CC2)c(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of the title compound from step 1 (450 mg, 1.74 mmol) in DMF (5 mL) was added LiCl (370 mg, 8.72 mmol) and TsOH H2O (1.52 g, 8.72 mmol) at room temperature. The mixture was heated to 120° C. and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (380 mg, yield: 88.9%) as yellow solid which used directly for the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J=6.8 Hz, 2H), 1.36-1.22 (m, 1H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS: 244.0 (M+1)+; 246.0
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=1.O>C1COCC1>[CH3:27][O:26][C:24]([C:21]1[CH:20]=[N:19][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][N:22]=1)=[O:25]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.24 g, 6.55 mmol) in THF (12 mL) was added sodium hydride (55% dispersion in mineral oil, 0.31 g, 7.2 mmol) at 0° C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. Methyl 5-chloropyrazine-2-carboxylate (1.36 g, 7.86 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50, 1.00 g, 47%) which was obtained as a light yellow oil. MS: m/e=326.2 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:19]=1)[CH2:3][CH2:4][CH3:5]>O1CCOCC1.CO>[ClH:1].[ClH:1].[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:2][CH2:3][CH2:4][CH3:5])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:8]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4M HCl in dioxane (12 mL) was added to a solution of the product from step (v) (6.7 g) in MeOH (100 mL) and stirred at rt for 18 h. The solvent was evaporated under reduced pressure, the residue triturated with diethyl ether, filtered and dried. Yield 5.53 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1.[NH4+].[Cl-]>CS(C)=O>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:10][CH:11]=1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of pyrazole (19.4 g, 0.28 mol) in 100 mL anhydrous DMSO, which was at a temperature of 0° C., was added NaH (7.5 g, 0.3 mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6-chloronicotinate (35 g, 0.2 mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0° C. and poured into a saturated aqueous, 0° C. NH4Cl solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3 g, 93% yield) as an off-white solid.
Reaction SMILES: [C:1]1([P:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[CH2:12][C:11](=[O:13])[O:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:27]>>[C:21]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:12][C:11]([OH:10])=[O:13])[C:9]([OH:14])=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O
Reactant: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Product: O=C(O)CC(C(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by stirring 3-triphenylphosphoranylidene dihydro-2,5-furandione (5.0 g, 0.014 mole) for 48 hours in 100 ml water. The solid residue was isolated by filtration and air-dried to give essentially quantitative yields of a product as a white crystalline solid whose IR spectrum and elemental analysis corresponded to the structure ##STR9## Calc. for C22H19O4P: C, 69.84; H,5.06; P, 8.19. Found: C, 69.86; H, 5.16; P, 8.18.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH3:21][S-:22].[Na+].Cl>CN(C=O)C>[CH3:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]([S:22][CH3:21])[N:7]=1
Reactant: C[S-]
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc(SC)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.078 g, 0.267 mmol) was dissolved in DMF (3 mL). Sodium thiomethoxide (0.019 g, 0.267 mmol) was added and the reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was poured onto ice. The pH was adjusted to 7 with 1 N HCl. The title compound was isolated as a yellow solid by vacuum filtration (72.8 mg, 90%). [M+H] calc'd for C15H17N3O2S, 304. found, 304.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:24])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=1)[NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].[CH2:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([N:6]([CH2:36][CH:33]1[CH2:34][CH2:35][CH2:30][CH2:31][CH2:32]1)[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([OH:24])=[C:18]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:19]=1)[CH3:2]
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)C(NCc1cccnc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(Cc1cccnc1)CC1CCCCC1

Procedure:
Synthesized as in Example 2 from Example 2 (0.418 g, 1.05 mmol) and cyclohexyl carboxaldehyde (384 μL, 3.10 mmol). This gave 0.120 g (24%) of product.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O>C(O)C.ClCCl.[Pt](=O)=O>[NH2:1][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1c(O)cccc1O

Procedure:
2-Nitroresorcinol (4.995 g, 0.032 mol) was suspended in ethanol (90 ml). Platinum(IV) oxide (0.356 g) was added and the mixture was shaken under an atmosphere of hydrogen (pH2 100 psi). After 2.75 hours (pH2 90 psi) the reaction mixture was filtered through celite. The residue was washed with methanol (50 ml) and the combined filtrate and washings were evaporated in vacuo at 30° C. During the course of the evaporation the solution, which was originally pale yellow, darkened considerably. A brown solid was obtained which was suspended in dichloromethane (100 ml) and re-evaporated to dryness. Yield 3.83 g (0.031 mol, 95%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH2:16][N:17]([CH3:27])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F-].[Na+]>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:48]1([C:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[CH:15][CH2:16][N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Brc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)C(=CCN(C)S(=O)(=O)c1ccccc1)CN1CCC(c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN1CCCC1=O
Product: CN(CC=C(CN1CCC(c2ccccc2)CC1)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
To 250 mg (0.37 mmol) of N-[4-(4-phenylpiperidin-1-yl)-3-tributylstannylbut-2-en-1-yl]-N-methylbenzenesulfonamide from Example 21, Step B (isomeric higher Rf product) in 0.5 mL of N-methylpyrrolidinone under argon was added 75 mg (0.55 mmol) of potassium carbonate, 8 mg (2% cat) of dichlorobis(triphenylphosphine)-palladium (II) and 90 mg (0.55 mmol) of bromobenzene. The mixture was heated at 70° C. for 24 h, cooled, treated with aqueous sodium fluoride for 10 min, and partitioned between water and ether. The water layer was reextracted with ether and each organic layer was washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FCC eluting with 20-25% ethyl acetate/hexanes to give 120 mg of title product as an oil. 1H NMR (400 MHz, CDCl3): δ 1.55-1.6 (m, 2H), 2.75 (br d, J=11, 2H), 2.00 (br dt, J=2 and 14, 2H), 2.42 (m, 1H), 2.78 (s, 3H), 2.93 (br d, J=11, 2H), 3.33 (s, 2H), 4.05 (d, J=6.5, 2H), 5.78 (t, J=6.5, 1H), 7.1-7.4 (3 m, 5H), 7.5-7.65 (m, 3H), 7.84 (dd, J=1.5 and 7, 2H). Mass spectrum (ESI): m/z 461 (M+1, 100%).