Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 326(MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[NH:11][CH:12]=O)=O)C.C([O-])=O.[NH4+:17]>C(N)=O>[OH:3][C:4]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[N:11]=[CH:12][N:17]=1
Reactant: CCOC(=O)c1ccsc1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: NC=O
Product: Oc1ncnc2sccc12
Temperature: 150 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol) was dissolved in formamide (12 ml), to which ammonium formate (3.0 g, 48.2 mmol) was added and the mixture was stirred at 150° C. for 6 hours. The reaction mixture was allowed to stand overnight at room temperature and the crystals that formed were filtered to obtain 4-hydroxythieno[2,3-d]pyrimidine (1.7 g, 11.0 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:10]C)(=O)[CH2:2][CH2:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8].[NH2:12][NH2:13]>CO.O>[C:1]([NH:12][NH2:13])(=[O:10])[CH2:2][CH2:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8]
Reactant: NN
Reactant: CC=CC=CCCC(=O)OC
Solvent: CO
Solvent: O
Product: CC=CC=CCCC(=O)NN
Reaction time: 24 h

Procedure:
To a solution of methyl octa-4,6-dienoate (16) (6 g) in methanol (10 ml) was added hydrazine (3 ml) at room temperature. After 24 h, the solution was diluted with water (50 ml). The crystalline precipitate was isolated by filtration to afford octa-4,6-dienoic acid hydrazide (17) as colorless microcrystals, yield 5.7 g. Dextran (nominal MW 10 kDa, Pharmacia) was diafiltered through a YM10 membrane (MW cutoff 10 kDa, Millipore) using 3 changes of water. The solution that passed through the membrane was diafiltered through a YM3 (MW cutoff 3000 Da) membrane, using five changes of water. The material retained by the membrane was lyophilized. A stirred solution of the dextran 18 thus obtained (22.5 mg, 2.25 μmol, corresponding to 139 μmol of glucose) in H2O (2.2 ml) at 5° C. (ice bath) was equipped with a temperature-sensing pH electrode, and 0.1 M NaOH was added with a 100 μL microsyringe until the pH reached 10.5. To this solution was added BrCN (50 μL of a 5 M solution in acetonitrile). The pH of the solution was maintained between 10.5 and 10.8 by addition of 0.1 M NaOH with a microsyringe. After 6 min, the solution was adjusted to pH 8.5 by addition of pH 8.0 phosphate buffer (ca. 1 ml). To the reaction mixture was immediately added a solution of octa-4,6-dienoic acid hydrazide (3.5 mg, 25 μmol) in 0.5 ml dimethyl sulfoxide. The pH of the reaction mixture rose to 8.95, at a temperature of 9° C. The ice bath was removed and the stirred solution was allowed to reach 25° C. After 2.5 h, the pH was 8.18 and remained unchanged over 5 min. The solution of 20 was diafiltered through a YM-3 membrane using 5 changes of water (4 ml each).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:38]=[C:37](Cl)[N:36]=[C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([O:53][CH3:54])[C:47]([CH3:56])([CH3:55])[CH2:46]3)[N:34]=2)[N:3]=1.[CH2:57]([CH2:59][NH2:60])[OH:58]>>[OH:58][CH2:57][CH2:59][NH:60][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:38]=[C:37]([NH:60][CH2:59][CH2:57][OH:58])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([O:53][CH3:54])[C:47]([CH3:56])([CH3:55])[CH2:46]3)[N:34]=2)[N:3]=1
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)n2)CC1(C)C
Reactant: NCCO
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(c2ccc(-c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.45 mmol), phenylboronic acid (180 mg, 0.83 mmol), Pd(PPh3)4 (100 mg, 20 mol %) and aqueous Na2CO3 (0.83 mL of a 2M solution) in DME (3 mL) is placed in a microwave vial and heated at 110° C. for 15 min. The mixture is filtered, diluted with EtOAc and washed with 1N HCl. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: CO[C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].NC(N)=O.N1CC(=O)NC1=O>C(Cl)Cl>[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]2[C:3](=[O:4])[CH:5]3[CH:10]([OH:11])[CH2:9][CH2:8][CH2:7][N:6]3[C:32]2=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@@H]1NCCC[C@@H]1O
Agent: NC(N)=O
Agent: O=C1CNC(=O)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2C(=O)C3C(O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
To a suspension of compound 53B (0.20 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added i-Pr2EtN (0.178 mL, 1.00 mmol). After stirring at 0° C. for 20 min, compound 23E (0.095 g, 0.59 mmol) in CH2Cl2 (1 mL) solution was added, along with 4 Å molecular sieves (0.5 g), and the resulting mixture stirred at rt until urea formation was completed (˜2 h). The mixture was then stirred at rt until hydantoin formation was complete (˜15 h). The reaction mixture was loaded on a silica gel column, eluted with 40% EtOAc/hexane, and 5% MeOH in EtOAc/hexane (1:1) to afford 0.11 g of the title compound as an off-white powder. HPLC: 99% at 1.67-1.79 min; Conditions: Phenom. Luna C18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient (A=90% H2O—10% ACN—0.1% H3PO4 and B=10% H2O—90% ACN—0.1% H3PO4), Flow rate at 4 mL/min., UV detection at 220 nm). The compound was further loaded on a Chiral AD column, eluted with 25% isopropanol in hexane isocratic to afford 50 mg each of enantiomer 53a (isomer A; retention time=14.2 min; 100% e.e.) and enantiomer 53b (isomer B; retention time=20 min; 100% e.e.) of the title compound as white powders. Chiral HPLC Conditions: (CHIRALPAK® AD column 4.6×250 mm; 25% isopropanol in hexane over 30 min at flow rate 1.0 mL/min, UV detection at 220 nm); MS (ES) m/z 320 [M+1]+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1C(O)C>C(Cl)Cl>[C:5]([O:4][CH:1]([C:16]1[C:17]([Cl:22])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[Cl:14])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
Acetic anhydride (1.42 mL, 15 mmol) and pyridine (1.7 mL, 21 mmol) were added sequentially to a solution of compound A1 (2.2 g, 10.5 mmol) in 20 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 12 h and then evaporated to give a yellowish oil residue. The residue was purified by flash chromatography (eluting with 7→9% EtOAc in hexanes) to give compound A2 as a colorless oil (2.26 g; 9.0 mmol; 85.6% yield); 1H NMR (400 MHz, chloroform-D) δ ppm 1.88 (d, J=6.82 Hz, 3H) 2.31 (s, 3H) 6.62 (q, J=6.82 Hz, 1H) 7.25 (t, J=8.46 Hz, 1H) 7.49 (dd, J=8.84, 5.05 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1.C([O-])(=O)C.[K+].[H][H]>C(O)C.[Pd]>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:4]2[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[CH2:18][CH2:17]1)[CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(Cl)n2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)cn2)CC1

Procedure:
31.1 g of ethyl trans-4-chloro-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are dissolved in 350 ml of ethanol and, after adding 14.1 g of potassium acetate and 2.56 g of palladium/carbon (5% by weight), the mixture is hydrogenated at room temperature until 0.10-0.11 mol of hydrogen have been taken up. The mixture is suction filtered, back-washed with methylene chloride and evaporated in vacuo. Thereby, there are obtained 35.6 g of crude, partly crystalline ethyl trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate which is used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1>CO.O>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCN(C)C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Yield: 71.5 %

Procedure:
Sodium hydroxide (pallets, 0.35 g) was added To a stirring mixture of (R)-(+)-Methyl 3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]-5-[(1-methyl-2-oxo-pyrrolidin-3-yl) oxy]benzoate (1.1 g) (Intermediate 19) in MeOH:H2O (1:1) at room temperature. The reaction was monitored by TLC. After completion, methanol was evaporated from the reaction mixture and water was added. The aqueous layer was washed with EtOAc, acidified with dil. HCl (0.05 N) to obtain solid. The solid obtained was filtered, washed with water, dried under suction or vacuum to get pure white solid (0.76 g).
Reaction SMILES: [OH-].[Na+:2].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[N:24]=[C:23]([C:25]([O:27]C)=[O:26])[C:22]([C:29]([O:31]C)=[O:30])=[CH:21][CH:20]=4)=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1>O.C(O)C>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[N:24]=[C:23]([C:25]([O-:27])=[O:26])[C:22]([C:29]([O-:31])=[O:30])=[CH:21][CH:20]=4)=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:4][CH2:5][CH2:6]1.[Na+:2].[Na+:2]
Reactant: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (0.66 g) in water (3 ml) was added to a solution of dimethyl 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E231) (1.69 g, 4.12 mmol) in ethanol (20 ml) at room temperature. The mixture was vigorously stirred at room temperature for 4 h and the resulting precipitate filtered off to give the title compound as a colourless solid (E232); MS (ES+) m/e 383 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22](O)=[O:23])(=[O:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]([C:22](=[O:23])[CH:21]([CH3:25])[CH2:20][S:19][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCC1CCCO1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)CC1CCCO1

Procedure:
To a solution of N-tetrahydrofurfurylglycine tert-butyl ester (6.6 g, 0.0307 mol) and 3-acetylthio-2-methylpropionic acid (5.3 g, 0.0307 mol) in dry methylene chloride (150 ml) chilled in an ice bath was added dicyclohexylcarbodiimide (6.7 g, 0.0325 mol). The resulting mixture was stirred with cooling for 30 minutes and then overnight at room temperature. Precipitated dicyclohexylurea was filtered and washed with a small amount of methylene chloride. Concentration of the filtrate afforded crude product as a thick yellow oil which was used without further purification.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]O>>[CH3:9][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: CO
Reactant: O=C1CCCCCN1
Product: CN1CCCCCC1=O

Procedure:
Thus after 2 times recycle of the distillation residue, an overall caprolactam yield of 91.2 mol % had been achieved based on the initial amount of M5FV. In the first cyclization pass, where still some methanol was present, 5.1 mol % of the unwanted by-product N-methyl caprolactam was formed. The approximated caprolactam yield per pass was 61.2% in the first pass, 66.5% in the second pass (first recycle of distillation residue) and 66.4% in the third pass (second recycle of distillation residue). Thus, it was proven that after distillative caprolactam recovery the remaining distillation residue can be successfully recycled to the cyclization reactor resulting in a high overall caprolactam yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[CH2:12][C:13]1[O:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:13]2[O:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)=[CH:3]1
Reactant: O=Cc1ccc(CO)o1
Reactant: Cn1ccc2ccccc21
Product: Cn1cc(C(c2ccc(CO)o2)c2cn(C)c3ccccc23)c2ccccc21

Procedure:
The compound Bis(1-methylindol-3-yl)-(5-hydroxymethyl-2-furyl)methane was prepared following general procedure A, starting from N-methyl indole and 5-hydroxy methyl furfural. LC: Tr 2.25 min, MS: 371 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: O=C(CCI)CCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
To a solution of 36 g (0.17 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 300 mL of dry tetrahydrofuran was added 71 g (0.17 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 55.3 g (0.19 mole) of 1-iodo-5-phenyl-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 30 min, at 50° C. for 3 hr., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh MgSO4, and concentrated at reduced pressure to give 71.5 g of crude oil. This crude material was passed through HPLC to give 46.4 g. of purified material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:34]=[C:33]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)[CH:32]=[CH:31][N:30]=1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Reactant: Clc1ccnc(Cl)n1
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)c2cc(-c3cccnc3)ncc21
Yield: 50 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2,4-dichloropyrimidine were reacted. The product was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 60 mg (50%) of 3-(2-Chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 439.2 (M+1).
Reaction SMILES: O=C1C2C=C(C=O)C=CC=2C(=O)C2C1=CC=CC=2.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH2:32])C=CC=CC=1.C1(C)C=CC=CC=1>C(O)(=O)C>[N:32]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:19]=1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc2[nH]cnc2c1
Yield: 139.9 %

Procedure:
9,10-Dioxo-9,10-dihydro-anthracene-2-carbaldehyde (1.63 g, 6.9 mmol) and N-phenyl-1,2-phenylenediamine (1.27 g, 6.90 mmol) were introduced into a mixture of 80 mL of toluene and 10 mL of acetic acid, and the mixture was refluxed for 12 hours. Solvent was removed and ethanol was poured therein to crystallize it, and then the precipitate was filtered to obtain a benzoimidazole compound ([2-(1-phenyl-1H-benzoimidazole-2-yl)-anthraquinone], 1.14 g, 41%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:12]1[C:16]([NH2:17])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2>N1C=CC=CC=1>[S:12]1[C:16]([NH:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2ccccc2s1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (0.661 mL, 5.15 mmol) was added to a solution of compound 1-C (0.87 g, 4.69 mmol) in pyridine (10 mL) at 0° C. The ice bath was removed and the solution was stirred at ambient temperature for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between 2N HCl and dichloromethane. The organic layer was dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was pre-absorbed on silica gel and purified by flash column chromatography, eluting with a gradient of ethyl acetate (10-50%) in heptane, to afford compound 1-D as a colorless solid (1.19 g, 88%). 1H-NMR (CDCl3): δ 6.96 (s, 1H), 7.25-7.34 (m, 2H), 7.44-7.49 (m, 2H), 7.55-7.66 (m, 3H), 7.84-7.88 (m, 2H); MS: m/z 290.1 (MH+).
Reaction SMILES: [C:1](=[O:3])=O.[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.C(N=C=O)CCC.C(Cl)(Cl)=O.S(N=C=O)(N=C=O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]([S:10]([N:13]=[C:1]=[O:3])(=[O:12])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: O=C=O
Agent: CCCCN=C=O
Agent: O=C(Cl)Cl
Agent: O=C=NS(=O)(=O)N=C=O
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Into a dry, 500 ml, 3 neck round bottom flask, equipped with a dry-ice-cooled reflux condenser, stirrer, gas inlet tube and thermometer was charged 12 g of 1,1'-biphenyl-2-sulfonamide, 100 ml of xylene, 0.2 g of 1,4-diaza[2.2.2]bicyclooctane (DABCO) and 5 g of n-butyl isocyanate. The mixture was heated to 135° and then phosgene was passed into the system until the temperature dropped to 125°. Heating was continued to bring the mixture up to 135° and additional phosgene was added to lower the temperature to 120°. This cycling was repeated until the temperature of the refluxing mixture remained at 120° without further addition of phosgene. The mixture was then allowed to cool to room temperature, filtered and concentrated in vacuo. Any contact with moisture was scrupulously avoided due to the extreme reactivity of the sulfonyl isocyanate. The product thus obtained (yield 10.4 g) showed an absorption peak in the infrared spectrum at 2200 cm-1, consistent with a sulfonyl isocyanate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19])=[CH:13][CH:14]=1.[ClH:23].[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27]>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:18][OH:19])[CH2:20][OH:21])=[CH:11][CH:10]=1.[ClH:23].[C:24]([O-:30])(=[O:29])[CH2:25][C:26]([O-:28])=[O:27]
Reactant: O=C(O)CC(=O)O
Agent: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C([O-])CC(=O)[O-]
Temperature: 25 °C

Procedure:
In an alternative procedure, FTY720 free base (2.27 mmol) was dissolved in ethyl acetate (16 ml) at 88 to 90° C. Then a solution of malonic acid (1.14 mmol) in ethyl acetate (3 ml) was added at 75° C., whereupon the product started to crystallize out immediately after addition. The resulting suspension was cooled to room temperature. The product was collected by filtration and was washed with ethyl acetate (2 ml). After drying at 50° C. the product (788 mg) was obtained as white crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[CH2:7]([C:8]1[O:9][CH:15]=[C:13]([CH2:12][Cl:11])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)Cc1ccccc1
Product: ClCc1coc(Cc2ccccc2)n1
Yield: 33 %

Procedure:
In substantially the same manner as in Reference Example 31, phenylacetamide was allowed to react with 1,3-dichloroacetone to give 2-benzyl-4-chloromethyl oxazole. The yield was 33%. Recrystallization from hexane gave colorless prisms, mp 31-32° C.