Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[CH:26]=1)[NH2:23])(=[O:18])[CH3:17]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:23][C:22]2[CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[CH:26]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[CH:21]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(N)cc(NC(C)=O)c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)Nc1cc(NC(C)=O)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
To a refluxing mixture of 0.96 g. (0.0045 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 35 ml. of methanol was added a solution of 1 g. (0.0045 mol) of 3,5-bis-acetamidoaniline (prepared as above) in 15 ml. of methanol. After three hours at reflux, the reaction mixture was cooled and filtered to yield 5-acetyl-4-hydroxy-3-[1-(3,5-bis-acetamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 265°-267° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][Si](C)(C)C)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: COC(C)(C)C
Product: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.7 %

Procedure:
To a solution of 5-(4-Chloro-phenyl)-7-trifluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (13.3 g, 34 mmol) in THF (60 mL) and MeOH (150 mL) at 0° C. was added K2CO3 (467 mg, 10 mol %) and the mixture was stirred at 0° C. for 6 h, diluted with TBME and ice water, separated, washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (heptane/EtOAc 100:0–90:10), triturated in heptane, filtered and dried to give the title compound(5.0 g, 45%) as an orange crystalline solid. MS (ISP) 322.2 [(M+H)+] and 324.2 [(M+2+H)+]; mp 102–103° C.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].S.Cl[CH:7]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]1=[O:17]>O.O1CCCC1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:7](=[S:2])[C:8]1=[O:17]
Reactant: O=C1Oc2ccccc2NC1Cl
Reactant: [S-2]
Agent: S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1oc2ccccc2[nH]c1=S

Procedure:
A solution of 3.6 g of sodium sulfide hydrate in 15 ml of water saturated with hydrogen sulfide was added dropwise to a solution of 5.45 g of 3-chloro-4H-1,4-benzoxazin-2-one in 30 ml of tetrahydrofuran at -150° C. The mixture was stirred one hour to 0° C. The tetrahydrofuran was evaporated and the precipitated filtered and recrystallized from toluene to provide the solid product 4H-1,4-benzoxazin-2-one-3-thione, m.p. 215°-220° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:23]1([PH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([P:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CCCCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCCCCCP(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
In a manner similar to Example 1, docosene (obtained from Aldrich) and diphenylphosphine were reacted under nitrogen at 250° C. for 27 hours. Removal of unreacted olefin and diphenylphosphine by vacuum distillation gave docosyldiphenylphosphine. The yield was 96% based on recovered olefin. The conversion was 57% based on recovered olefin.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])/[CH:4]=[CH:5]/[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:7]=1
Reactant: COC(=O)/C=C/c1nc(C(=O)OC)ccc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1nc(C(=O)OC)ccc1OC
Yield: 72.1 %

Procedure:
Under the conditions of example 1 C, a solution of 11 g of 3-(3-methoxy-6-methoxycarbonyl-2-pyridyl)-(2E)-2-propenoic acid methyl ester in 600 ml of methanol is hydrogenated in the presence of 2.2 g of 10% palladium catalyst on activated carbon, worked up, and the crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 8 g of 3-(3-methoxy-6-methoxycarbonyl-2-pyridyl)-propionic acid methyl ester of melting point 98°-100° C. is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)[C:24]=1[F:36])=[O:22])[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@@H:29]([OH:30])[CH2:33][OH:32])[C:24]=1[F:36])=[O:22])[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]
Reactant: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccc(C#N)c3)=C3Nc4ccccc4N3)c2F)O1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C(=O)C(C(=O)c2cccc([C@@H](O)CO)c2F)=C2Nc3ccccc3N2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A 140 mg portion of 3-(2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorophenyl}-3-oxopropanoyl)benzonitrile was dissolved in 5 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 hours. The solvent was evaporated to carry out an azeotropic treatment using Tol. The thus formed residue was purified by a silica gel column chromatography, and the foamy substance obtained from a chloroform-methanol (10:0-9:1) eluate was recrystallized from ethyl acetate hexane to obtain 105 mg (82%) of 3-(2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1R)-1,2-dihydroxyethyl]-2-fluorophenyl}-3-oxopropanoyl)benzonitrile (Example 4-11).
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[S:3]([CH3:6])(=[O:5])=[O:4].[C:13]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[N:24]([C:44](Cl)=[O:45])[C@@:25]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)([CH3:36])[C@@:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:27]=2)=[C:19]([O:47][CH2:48][CH3:49])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[N:24]([C:44]([N:10]3[CH2:9][CH2:8][CH:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH2:12][CH2:11]3)=[O:45])[C@@:25]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)([CH3:36])[C@@:26]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[N:27]=2)=[C:19]([O:47][CH2:48][CH3:49])[CH:18]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 8, N-Methyl-N-piperidin-4-yl-methanesulfonamide from above was reacted with (4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O4S [(M+H)+] 714.2642, observed 714.2636.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C:14]1([CH3:18])[CH2:17][O:16][CH2:15]1>ClCCl.N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C:14]2([CH3:18])[CH2:17][O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 20 °C

Procedure:
4-Toluenesulfonyl chloride (20 g, 105 mmol) was dissolved in a mixture of dichloromethane (DCM) (50 ml) and pyridine (50 ml) and cooled in an ice bath. 3-(hydroxymethyl)-3-methyloxetane (100 mmol, 9.9 mL) was added dropwise. The temperature was increased to 20° C. overnight. The solution was diluted with DCM (100 mL) and extracted with water. The organic phase was dried over magnesium sulfate and filtered. The volatile solvents were removed by evaporation. The remaining material was concentrated several times with toluene to remove the residual pyridine and then with chloroform to remove the residual toluene. Yield: 22 g of a white crystalline solid (92%). TLC: Rf(petroleum ether/ethyl acetate, 1:1) 0.56.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1.Cl>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: OC(c1cccnc1)c1cccs1
Agent: Cl
Solvent: CC(=O)O
Product: c1cncc(Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
To a solution of 2-(3-pyridylhydroxymethyl)thiophene (8.82 g, 46.2 mmol), prepared as in step 1, in acetic acid (50 mL) was added tin(H)chloride dihydrate (22.9 g, 101 mmol) and HCl gas was bubbled through the reaction mixture for about 10 min. The reaction mixture was stirred for 1.5 hours at ambient temperature, and the liquid was decanted, concentrated in vacuo to a volume of about 10 mL, and poured into H2O. The aqueous solution was made basic by the slow addition of saturated aqueous NaHCO3 and extracted with ethyl acetate/ether. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (5% methanol/CHCl3) gave 2-(3-pyridylmethyl)thiophene (2.63 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:20]([C:28]#[N:29])=[C:19]([S:30][CH3:31])[N:18]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:28]([C:20]1[C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[N:22][C:17]([NH:16][C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])=[N:18][C:19]=1[S:30][CH3:31])#[N:29]
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: O=C(O)Cc1ccccc1I
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CSc1nc(NC(=O)Cc2ccccc2I)nc(-c2ccco2)c1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To a stirred solution of 338 mg (1.29 mmol) 2-iodophenylacetic acid in 5 ml dichloromethane were added dropwise 0.19 ml (2.58 mmol) thionyl chloride and one drop of N,N-dimethylformamide and the mixtured stirred at 50° C. for 2 hours. The reaction mixture was then concentrated in vacuo, protecting from moisture as much as possible, and the residue redissolved in 5 ml dichloromethane. 65 mg (0.43 mmol) 2-Amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and 0.48 ml (6.0 mmol) pyridine were added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo. Chromatography (dichloromethane then 5% methanol in dichloromethane) followed by trituration in ether afforded 32 mg (24%) N-(5-Cyano-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-yl)-2-(2-iodo-phenyl)-acetamide as a white crystalline solid. EI-MS m/e (%): 476 (M+, 68).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])C.[OH-].[Na+]>>[CH3:25][C:5]([CH3:26])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:16])=[O:17])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O

Procedure:
Ethyl-10-(4-chlorobenzenesulphonamido)-2,2-dimethyldecanoate (1.4 g, 0.003 mol) was treated with sodium hydroxide by the method described in Example 5(iii) to give the title compound which was recrystallised from ether/pet. ether (0.59 g, m.p. 78°-9° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:39](=[O:41])[CH3:40])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Solvent: c1ccncc1
Product: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 74.5 %

Procedure:
To a solution of 5.75 g (10.7 mmol) crude 5b in 50 ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 5c was obtained in 74.5% yield (4.62 g, 7.97 mmol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Clc1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 82 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 (with conversion to the HCl salt as outlined for Example 2), this product was prepared in 82% yield from 6-chloro-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. of free-base: 140°-141° C.; For HCl salt: M.P. 232°-233° C.; LC-MS: 312 (MH+); anal. RP18-HPLC RT: 5.68 min.).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([O:28][CH3:29])[CH:21]=1.CN1CCCC1=O>O>[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=3[N:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: CCC(CC)c1ccc(OC)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(OC)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 55.3 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (120 mg, 0.450 mmol), 4-chloro-2-methoxy-6-methylaniline (231 mg, 1.35 mmol) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 130° C. for 2 days under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (100 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: C=C(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
Prepared from 6.0 g of 4-hydroxybenzophenone and 4.4 ml of methacryloyl chloride in 70 ml of pyridine. Recrystallized from ethyl acetate-ethanol-water; M.P.~69.5°-70.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>ClCCl>[Cl:31][C:14]1[N:13]([CH2:12][C:11]2[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=3)=[CH:9][CH:10]=2)[C:17]2[N:18]=[C:19]([S:24][CH3:25])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=2[C:15]=1[CH3:26]
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1nc2c(c(C)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Yield: 57.9 %

Procedure:
In anhydrous dichloromethane (3 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (88 mg) and, under ice-cooling and stirring, N-chlorosuccinimide (28 mg) was added. After 2 hours of stirring, the solvent was distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; chloroform) to provide the title compound (55 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[Na+:10].C1(=O)[NH:15]C(=O)CC1>>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[Na+:10].[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH4+:15]
Reactant: O=C1CCC(=O)N1
Agent: N[C@@H](CC(=O)O)C(=O)[O-]
Agent: [Na+]
Product: [NH4+]

Procedure:
FIG. 9. Infrared spectrum of the 2:1 copolymer of monosodium aspartate and succinimide, produced via thermal polymerization of monosodium aspartate and monoammonium aspartate at 200° C. for 3 hours. The amide peaks in the region of 1600 cm−1 became more prominent with increasing relative amounts of monosodium aspartate monomer. The imide peak at ˜1716 cm−1 tended to become accentuated with longer reaction times, as aspartic acid residues were driven more toward the succinimide form. Again, the carboxylate peak at ˜1400 cm−1 is prominent and the monomeric peaks in the fingerprint region (<1000 cm−1) are absent.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[C@@H:24]([NH:31]C(OC(C)(C)C)=O)[C@H:23]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[F:46])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[C@@H:24]([NH2:31])[C@H:23]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[F:46])[CH2:22][CH2:21]2)=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2nccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In a 50 mL round-bottomed flask was dissolved (5R,8S,9S)-9-(tert-butoxycarbonylamino)-8-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (38.1 mg, 0.060 mmol) in methylene chloride (1 mL) to give a colorless solution. trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1 h. LCMS showed complete conversion. Volatiles were removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (22 mg, 69%) as a white solid: MS (ESI)[M+H+]=536.2; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 8.11 (d, J=4.9 Hz, 1H), 7.42 (s, J=16.5 Hz, 1H), 7.17-6.95 (m, 4H), 6.24-5.97 (m, 2H), 4.69-4.34 (m, 4H), 3.31-2.81 (m, 3H), 2.37 (dd, J=23.5, 13.6 Hz, 4H), 2.17-1.67 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −137.10-−137.50 (m), −142.45 (d, J=20.6 Hz).
Reaction SMILES: [BH4-].[Na+].[N:3]([C@H:6]1[C@H:11]([O:12][S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:7]1)=[N+]=[N-]>CO>[NH2:3][C@H:6]1[C@H:11]([O:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N=[N+]=[N-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N)cc1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a cooled (0° C., ice/water bath) solution of CuSO4.5H2O (642 mg, 0.5 equiv) in methanol (30 mL) was added slowly NaBH4 (200 mg, 1.05 equiv). To the stirred black suspension was added a solution of (3R,4R)-benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate (2.21 g, 5.14 mmol) in methanol (20 mL). Additional NaBH4 (578 mg, 3 equiv) was introduced into the reaction in four portions over the course of 1 h. LC-MS showed the reaction was complete. The reaction mixture was filtered through a pad of Celite, and concentrated. The residue was diluted with CH2Cl2 (70 mL), washed with water (15 mL), satd aq NH4Cl solution (2×10 mL) and brine (15 mL), and dried over Na2SO4. Concentration afforded (3R,4R)-benzyl 3-amino-4-(tosyloxy)piperidine-1-carboxylate (1.34 g, 64%). LC-MS (3 min) tR=1.26 min., m/z 405 (M+1). The product was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH:15](Cl)(Cl)Cl.CO>CO.OS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: ClC(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2cc(O)ccc2c1

Procedure:
6-Hydroxy-2-naphthoic acid (5.0 g, 26.6 mmol) was dissolved in 125 mL of methanol and refluxed with 6 drops of conc. H2SO4 for 36 hours. TLC analysis (SiO2, 10:1 CHCl3 /MeOH) revealed only a trace of the acid left. The solution was cooled partially and concentrated to dryness on a rotary evaporator The solid residue was dissolved in 200 mL of ether and washed successively with 100 mL of saturated aq. NaHCO3 and brine. Drying over MgSO4 and evaporating the solvent left 4.6 g of (85.5%) slightly yellow solid which showed only one spot on TLC. The material is sufficiently pure for use in subsequent reactions but may be purified further by recrystallization from ether affording a white solid mp 169°-169.5° C.; 1H NMR delta 3.976 (s, 3H), 5.3 (br. s, 1H), 7.16-8.54 (m, 6H); IR (KBr) 3370, 1680, 1630, 1435, 1310, 1210 cm-1. ##STR27##