Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCCl>[CH3:27][S:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-(2-aminophenyl)piperidinecarboxylate (Preparation B) (1.93 g, 7.2 mmol) and 1,2-dichloroethane (50 mL). The solution was magnetically stirred under a N2 atmosphere, treated with pyridine (2.9 mL, 36 mmol) and methanesulfonyl chloride (Aldrich) (1.1 mL, 1.7 g, 14 mmol). The vessel was immersed in a 50° C. oil bath for 6 h then cooled to 25° C. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (200 mL) and 1 N HCl (100 mL). The organic layer was washed with satd NaHCO3 (75 mL), satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated to give a foam. The foam was purified by silica gel chromatography (3:/EtOAc:hexane) to provide the title compound as a white foam (2.1 g). MS (ESI, pos. ion) m/z: 355 (M+1); (ESI, neg. ion) m/z: 353 (M−1). Calc'd for C17H26N2O4S: 354.47.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCO.[Pd]>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH2:8])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCCCN1CCCC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccncc1NCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1.300 g (5.940 mmol) 3-bromo-4-nitro-pyridine-1-oxide and 0.980 g (7.430 mmol) 3-pyrrolidin-1-yl-propylamine was added to a suspension of 0.820 g (5.940 mmol) potassium carbonate in 20 mL DMF and the mixture was stirred for 3 hours at 90° C. The solvent was evaporated i. vac. and the residue purified by column chromatography (Alox (neutral, activity II-III), gradient dichloromethane/MeOH 100:0→95:5 v/v) (0.950 g, 60% of theory). 0.900 g (3.380 mmol) of the intermediate product was added to a suspension of 300 mg Pd/C in 10 mL EtOH and the mixture was hydrogenated for 4.5 hours at RT and 50 psi H2-pressure. The catalyst was removed by filtration and the filtrate evaporated i. vac. The product is present in admixture with the corresponding pyridine-N-oxide and was used in the next reaction step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][C:12]#[N:13].C(O)C.Cl>O>[F:1][C:2]1[C:3]2[S:11][C:12]([NH2:13])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: N#CSc1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1nc2cccc(F)c2s1
Yield: 29.7 %

Procedure:
A mixture of 1-fluoro-3-nitro-2-thiocyanatobenzene 2 (3.96 g, 0.02 mol), ethanol (30 mL), water (25 mL) and conc. hydrochloric acid (25 mL) was refluxed gently during the addition of hydrogen-reduced iron powder (8 g). After refluxing for 16 hr, the liquor was filtered hot, cooled, the residue filtered, dissolved in hot water, and neutralized with ammonia and then extracted with EtOAc to get the compound 7-fluorobenzo[d]thiazol-2-amine (1 g) as a colorless oil. LC-MS: m/z 169.2 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:18]=[CH:19][CH:20]=1.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:43]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:44]=[N-:45]
Reactant: OC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)methanol (1.63 g, 4.24 mmol) in toluene (10 mL) under an atmosphere of nitrogen, diphenylphosphoryl azide (1.10 mL, 5.10 mmol) and DBU (0.77 mL, 5.11 mmol) was added. The reaction mixture was stirred at 45° C. for 3 hours and then at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford impure title compound (1.11 g, 64%). This material was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].CO>[Fe].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(Br)ccc1F
Yield: 93.8 %

Procedure:
3.0 g of 5-bromo-2-fluoronitrobenzene, 3.8 g iron powder and 7.3 g ammonium chloride were heated at 80° C. for 2 hours in a solution mixture of 30 mL methanol and 30 mL water. The reaction mixture was filtered through Celite, the methanol was evaporated, and the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate and filtered through a column with a small amount of silica gel. The solvent was evaporated to give 2.43 g of the title compound (yellow oil).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Cl[CH2:23][C:24]#[N:25]>CN(C=O)C>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][C:24]#[N:25])=[O:15])(=[O:19])=[O:18]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: N#CCCl
Solvent: CN(C)C=O
Product: N#CCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
In a similar manner to Example 2, furosemide can be reacted with chloroacetonitrile in DMF to yield cyanomethyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]-benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7]2.CC1(C)C(C)(C)OB([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[CH:7]2
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncccc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester (9.00 g, 27.4 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (8.42 g, 38.3 mmol), Pd(PPh3)4 (0.63 g, 2 mol %), and Cs2CO3 (20.5 g, 62.9 mmol) in dioxane/H2O (4:1, 300 mL) were heated under nitrogen at 100° C. for 16 h. Solvents were evaporated in vacuo, water (100 mL) was added to the residue, and the mixture was extracted with EtOAc (3×75 mL). The EtOAc extract was dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:3) to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=6.87 (brs, 2H), 6.81 (dd, J=8.7, 4.8 Hz, 1H), 7.18 (dd, J=9.3, 9.0 Hz, 1H), 7.22 (dd, J=8.1, 4.2 Hz, 1H), 7.99 (dd, J=7.5, 2.1 Hz, 1H), 8.15 (dd, J=6.8, 1.8 Hz, 1H), 8.13 (t, J=1.2 Hz, 1H), 9.56 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C(OCC)(=O)C>[NH2:26]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccc(Cl)cc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccc(Cl)cc2C1=O)c1ccccc1
Yield: 57 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-5-chloro-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 57% of theory. M.p. 172°-173° C. (ethyl acetate)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: Cc1cccc2c1C(=CNc1ccc(OCCN3CCCCC3)cc1)C(=O)N2
Yield: 49.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (754 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (530 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
As described for Reference Example 21, 25 g of 2-chloro-4-nitrobenzoic acid is reacted with thionyl chloride (124 ml) to give the product (27.0 g) as a brown oil.
Reaction SMILES: [OH:1][C:2]1([C:7]#[CH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25](I)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]>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.CN(C=O)C.CCN(CC)CC>[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25]([C:8]#[C:7][C:2]2([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]2)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCNC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCNC4)c32)c1

Procedure:
Using Method C above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P)4Pd (15 mg) and Cul (3.0 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 5 h. (Yield 10 mg, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([CH2:12][CH2:13][CH2:14][C:15](CC([O-])=O)=[O:16])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[O:16])[CH2:14][C:13]([CH2:12][CH2:10][CH3:11])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccc(Br)cc1
Product: CCCC1=NN(c2ccc(Br)cc2)C(=O)C1

Procedure:
From the reaction of 4-bromophenylhydrazine and ethylbutyrylacetate, 2-(4-bromphenyl)-2,4-dihydro-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4-bromophenyl)-4-(2-ethylanilinomethylene)-2,4-dihydro-5-propyl-3H-pyrazol-3-one, Mp.: 126.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[NH3:14].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:14][CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)ccc21
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N NH3 in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:19])[CH3:18]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:19])[CH3:18])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1cc2c(cc1Br)CC=C2CCN
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc2c(cc1Br)CC=C2CCNC(C)=O

Procedure:
Starting with 2-(6-bromo-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and acetyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 83%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:9]=2[N:10]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:10][C:9]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2oc(-c3cccs3)nc2c1
Product: ClCc1ccc2oc(-c3cccs3)nc2c1
Reaction time: 3 h
Yield: 85 %

Procedure:
To 2-(2-thienyl)-5-benzoxazolylmethanol (600 mg) was added thionyl chloride (3 ml) at 0° C., stirred for 3 hours. The reaction mixture was concentrated, which was neutalized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 5-chloromethyl-2-(2-thienyl) benzoxazole (550 mg, 85%). The recrystalization from ethyl acetate-hexane gave colorless needles, mp 152-153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2[C:29]([O:31]C(C)(C)C)=[O:30])[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2[C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
Trifluoroacetic acid (2.63 mL, 34.29 mmol) was added to tert-butyl 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#94) (1.38 g, 3.43 mmol) in CH2Cl2 (25 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (1.180 g, 99%) as a white crystalline solid.
Reaction SMILES: C[O-].[CH3:3][O:4][C:5](=O)[CH:6]=[O:7].[CH:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH3:3][O:4][CH:5]1[NH:18][C:16](=[O:17])[N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: COC(=O)C=O
Reactant: NC(=O)NC1CCCCC1
Agent: C[O-]
Solvent: CC(=O)O
Solvent: CO
Product: COC1NC(=O)N(C2CCCCC2)C1=O
Yield: 31.4 %

Procedure:
750 mg of glyoxylic acid methyl ester methyl alcoholate and 920 mg of N-cyclohexylurea were refluxed in 50 ml of a mixture of acetic acid and methanol (4:1) for 1 hour. After cooling, the solvent was removed by distillation and the residue was purified by column chromatography on silica gel. The obtained crude product was recrystallized from benzene to give 420 mg of 5-methoxy-3-cyclohexylhydantoin (compound 20) in the form of colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:24])[C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH:20]([CH3:24])[O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (8.3 g) in dimethylformamide (65 ml) were added potassium carbonate (20.5 g) and 2-chloropropionyl chloride (6.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (7.78 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH2:13])=[O:6])#[N:2].C1C=CC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:34](O)=[O:35])[NH:31]2)=[CH:27][CH:26]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:34]([C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([Cl:24])[CH:33]=2)=[O:35])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1N
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-cyclohexanecarboxylic acid cyanomethyl-amide (6.4 g, 35.31 mmol) in DMF (70 ml), were added HOBT (5.25 g, 38.84 mmol), 6-chloro-2-indolecarboxylic acid (7.60 g, 38.84 mmol), N-methylmorpholine (19.4 ml, 176.45 mmol), and EDCI (7.45 g, 38.84 mmol) respectively at 0° C. The reaction was stirred at room temperature for 16 hours, then 1N HCl (500 ml) was added and the resulting cloudy solution was extracted with ethyl acetate (3×200 ml). The organic layer was filtered through a Celite pad, washed with 1N NaOH (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo yielding 6-chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide, (6.25 g, 49%).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH3:21])[C:4]1=[O:5])[CH3:2].C([O:24]CC)C>[Os](=O)(=O)(=O)=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]3[O:24][CH2:19]3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH3:21])[C:4]1=[O:5])[CH3:2]
Reactant: CCOCC
Reactant: C=CCCCCn1cnc2c1c(=O)n(CC)c(=O)n2CC
Agent: O=[Os](=O)(=O)=O
Product: CCn1c(=O)c2c(ncn2CCCCC2CO2)n(CC)c1=O

Procedure:
The same compound was also obtained by hydroxylation of 1,3-diethyl-7-(5-hexenyl)xanthine ##STR19## with osmium tetroxide: 0.73 g of 1,3-diethyl-7-(5-hexenyl)xanthine in 11 ml of diethyl ether was added dropwise with stirring in 5 minutes to 0.65 g of osmium tetroxide in 11 ml of diethyl ether at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]>O=[Mn]=O.C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(CO)cnc1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Yield: 40.5 %

Procedure:
To a solution of 0.15 g. of 1-methyl-2-nitro-5-hydroxymethylimidazole in 20 ml. of benzene, 0.33 g. of MnO2 is added and the reaction mixture is heated on the steambath for two hours. After filtration and evaporation to dryness under vacuum, the crude product is crystallized from ethyl acetate and 0.060 g. (40.5%) of 1-methyl-2-nitro-5-imidazolaldehyde is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reaction time: 1 h

Procedure:
The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55 ml of dry DMF at room temperature and treated with sodium hydride, 60% dispersion (1.21 g, 31.75 mmol) added in portions. After stirring for 1 hr, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reaction stirred for 2 days. The reaction was poured into diethyl ether and washed once with saturated sodium bicarbonate solution and once with water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed over silica gel eluting with 10% acetone in dichloromethane solution to give the desired N-9 alkylation product as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([CH3:7])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#CCC(N)=S
Reactant: CCCCCC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCc1cc(C)c(C#N)c(S)n1
Temperature: 50 °C
Yield: 64.2 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (1.4 g, 14 mmol) and 2,4-nonanedione (2.0 g, 13 mmol) in anhydrous EtOH (40 mL) was added triethylamine (0.5 mL) and the reaction was heated at 50° C. for 1 h and then was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-pentyl-2-mercapto-4-methyl-nicotinonitrile as a yellow solid (1.84 g, 62.1%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]>CN(C)C(=O)C>[CH3:34][N:33]([CH3:35])[C:32]([O:31][C@H:29]1[CH2:28][N:27]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])[C@H:26]([CH2:25][CH2:24][O:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:30]1)=[O:36]
Reactant: Oc1c(F)cccc1CCc1ccccc1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1c(F)cccc1CCc1ccccc1
Yield: 81.2 %

Procedure:
520 mg of 6-fluoro-2-(2-phenylethyl)phenol (prepared as described in Preparation 10) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 300 mg of potassium t-butoxide and 820 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 984 mg (yield 81 %) of the title compound as an oily substance.