Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:36][CH2:37][C:38]1[C:39]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)=[N:40][CH:41]=[CH:42][CH:43]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:15][CH2:16]3)[CH2:37][C:38]3[C:39]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4cccnc4-c4cc(OC)c(OC)c(OC)c4)c4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
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.C1(P([C:25]2[CH:30]=[CH:29]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(O)CC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:29]2[CH2:30][CH2:25]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OC1CC1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CC3)c2n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
2,6-Dichloropurine (1 mmol), triphenylphosphine (1.3 mmol), tetrahydrofurane (5 ml) and cyclopropanol (5 mmol) were stirred at rt under nitrogen to give clear yellowish solution, which was then cooled to 0° C. and diisopropyldiazadicarboxylate (DIAD; 1.3 mmol) was added via syringe. The reaction mixture was then stirred at rt for 12 h. After evaporation of the solvents the product was extracted with diethylether and purified by column chromatography (silicagel, 1% MeOH in CHCl3). Crystallization from methanol gave the product in yield 35%, mp 121-124° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH3:12])=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].C(N)C1C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH3:12])[CH3:1]
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: COC(=O)CC#N
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C(C)c1ccc(F)cc1OC
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a round bottom flask fitted with a Dean-Stark trap was added a mixture of 19.54 g (116 mmol) of 4-fluoro-2-methoxyacetophenone, 15.29 mL (174 mmol) of methyl cyanoacetate, 1.42 mL (13 mmol) of benzylamine, and 6.6 mL of acetic acid in 170 mL of toluene and the mixture was warmed at reflux. The reaction was monitored by TLC (EtOAc-hexanes, 2:8). After 18 hours, the reaction was then cooled and concentrated in vacuo to afford a dark, orange oil. The crude oil was distilled (Kugelrohr) at 130° C. under vacuum to remove unreacted 4-fluoro-2-methoxyactophenone. The crude was then passed through a pad of silica gel using a 10% EtOAc in a 1:1 mixture of dichloromethane in hexanes to afford 27.64 g (95%) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester as a light orange oil which was a mixture of geometric isomers.
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C:6]1([CH3:26])[C@@H:8]([C:9]([O-:11])=[O:10])[C@@H:7]1[CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:5][C:6]1([CH3:26])[C@@H:8]([C:9]([OH:11])=[O:10])[C@@H:7]1[CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)[C@@H](C=C(c2ccccc2)c2ccccc2)[C@@H]1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)[C@@H](C=C(c2ccccc2)c2ccccc2)[C@@H]1C(=O)O

Procedure:
42.7 cc of a 2N methanolic sodium hydroxide solution were introduced into 100 cc of methanol and 10 cc of water, followed by 18.45 gm of ethyl dl-trans 3,3-dimethyl-2-(2',2'-diphenylvinyl)-cyclopropanecarboxylate were added thereto. The mixture was brought to reflux and maintained there for 1 hour and 30 minutes. The methanol was removed by distillation and water was added. Next the aqueous phase was extracted with ethyl ether to eliminate the neutral fraction and the combined ether extracts were washed with water and the wash water was combined with the principal aqueous phase. Then the entire aqueous phase was acidified with a dilute aqueous solution of hydrochloric acid which was then repeatedly extracted with methylene chloride; the methylene chloride solutions were combined, washed with water, dried and concentrated to dryness to obtain 7.95 gm of dl-trans 3,3-dimethyl-2-(2',2'-diphenylvinyl)-cyclopropanecarboxylic acid having a melting point of 115° C. A sample of this product crystallized from a mixture of isopropyl ether and petroleum ether, had a melting point of 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:24]=[CH:25][CH:26]=[N:27]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:12][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[CH3:11])[C:5]([NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Br)cc(C(=O)O)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dibromo-4-methylbenzoic acid (1 eq.) in DMF (0.4 M) was added HATU (1.3 eq.), cyclopropylamine (1.1 eq.) and Hunig's base (3 eq.). The resulting yellow mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in a mixture of ether and hexanes afforded the title compound as an off-white solid.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O:20][C:21](=O)[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]2[CH:32]=1)C>ClCCl.[Cl-].[NH4+]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:32]=[C:23]([CH2:22][C:21]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:20])[N:24]=2)[CH:27]=1
Reactant: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Reactant: C1COCCN1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cc1cn2cc(Br)ccc2n1)N1CCOCC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
Add 2M trimethylaluminum in toluene (1.94 mL, 3.88 mmol) to a solution of morpholine (0.34 g, 3.88 mmol) in dichloromethane (10 mL). Stir for 10 min and add a solution of (6-bromo-imidazo[1,2-a]pyridin-2-yl)-acetic acid ethyl ester (1.1 g, 3.88 mmol) in dichloromethane (12 mL). Heat at 40° C. for 1 h, carefully dilute with saturated aqueous ammonium chloride and extract into dichloromethane. Concentration followed by filtration gives the titled compound (0.55 g, 43%) as a white solid. TOF MS ES+ exact mass calculated for C13H14BrN3O2 (p+1): m/z=324.0348; Found: 324.0330. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (m, 1H), 7.77 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.29 (dd, J=10, 2.0 Hz, 1H), 3.81 (s, 2H), 3.55-3.4 (m, 8H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:14]I.OS(O)(=O)=O.[OH-].[Na+]>C(O)C.CCOC(C)=O.CCCCCC>[I:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Ic1ccc2[nH]c3ccccc3c2c1
Temperature: 65 °C
Yield: 140.1 %

Procedure:
To an ethanol solution (500 mL) of carbazole (2.50 g, 15.0 mmol), NaIO4 (0.80 g, 3.75 mmol) and I2 (1.89 g, 7.45 mmol) were sequentially added, and then an ethanol solution (100 mL) of H2SO4 (1.60 mL, 30.0 mmol) was added. The reaction solution was refluxed for one hour at 65° C. The loss of raw materials was confirmed by TLC (HexH:AcOEt=4:1), and an ethanol solution (100 mL) of NaOH (1.4 g) was added thereto to neutralize the system. Ethanol was removed, and then the reaction solution was extracted two times with chloroform. The extract was washed two times with water. The organic phase was dried over Na2SO4, and the solvent was removed. The residue was purified by column chromatography (HexH:AcOEt=4:1), and thus compound 1 (3.06 g, 70%) was obtained as a white powder. Thus, 3,6-diiodocarbazole (0.47 g, 7.5%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1OC)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36](OCC)(=[O:38])C>>[C:26]1([S:32]([NH:1][C:2]2[C:3]([O:38][CH3:36])=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:6])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCN(CC)CC
Product: COc1c(NS(=O)(=O)c2ccccc2)cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.9726 g, 4.00 mmol), triethylamine (0.56 mL, 4.02 mmol), and benzenesulfonyl chloride (0.51 mL, 4.00 mmol) in ethyl acetate (70 mL) was heated briefly to obtain a solution. The reaction was stirred overnight at room temperature under nitrogen. An additional equivalent of triethylamine and 1/2 equivalent of benzenesulfonyl chloride was added and the mixture heated to 50-60° C. After 7 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and washed with 1N HCl followed by saturated NaHCO3. The organic layer was filtered, dried with MgSO4, and stripped of solvent by rotary evaporator. Trituration of the residue in hexane/ethyl acetate (4:1) afforded the product (0.268 g); m.p. 190-194° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:22]([C:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[O:17][C:13]=1[CH2:11][CH3:12])(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Cl
Reactant: CCc1oc2ccccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo [b]furan-3-sulfonamide compound was prepared by the method of Example 41 with 4-chloro-3-methyl-5-amino-isoxazole (1.0 mmols, 0.13 g), NaH (2.5 mmols, 60 mg), 2-ethylbenzo[b]furan-3-sulfonyl chloride (1.2 mmols, 0.28 g) and THF (7 ml). Flash chromatography (20% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexane provided 97 mg (28%) of a white solid, m.p. 132-133.5° C.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>C(OCC)C>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CCC(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCC(C(=O)OC)c1ccccc1
Reaction time: 8 h

Procedure:
To 102 g. of 2-phenylbutyric acid dissolved in 1 liter of methanol was added 2 ml of thionyl chloride. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo to yield an oil which was dissolved in diethyl ether, washed successively with dilute sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo. Distillation yielded 101 g of the title compound as a water-white oil, b.p. 62°-65°/0.5 mm, having the following elemental analysis:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:35])=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH2:25][C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12].N[C@@H](C)CCN[CH2:42][C:43]1O[CH:45]=[CH:46][CH:47]=1.[C:49]([OH:52])(=O)[CH3:50].[Cl:53]CCl>>[ClH:53].[ClH:53].[NH2:20][C@@H:21]([CH3:31])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1.[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:35])=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH2:25][C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([O:52][CH2:49][C:50]2[CH:45]=[CH:46][CH:47]=[CH:43][CH:42]=2)=[C:16]2[C:32](=[O:33])[N:20]3[C@@H:21]([CH3:31])[CH2:22][CH2:23][N:24]([CH2:25][C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[C@@H:19]3[CH2:18][N:17]2[CH:34]=1)=[O:12]
Reactant: ClCCl
Reactant: CC(=O)O
Agent: C[C@H](N)CCNCc1ccco1
Agent: C[C@H]1CCN(Cc2ccco2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Product: C[C@H]1CCN(Cc2ccco2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Product: Cl
Yield: 70 %

Procedure:
[(3S)-3-Aminobutyl](2-furanylmethyl)amine dihydrochloride was prepared in a similar manner as described in example Z-32, NMR (400 MHz, CDCl3/CD3OD) δ 1.27 (d, J=6.4 Hz, 3H), 1.96-2.05 (m, 1H), 2.1.4-2.19 (m, 1H), 3.00-3.04 (m, 2H), 3.38-3.39 (m, 1H), 4.11-4.18 (m, 2H), 6.34 (m, 1H), 6.59 (m, 1H), 7.40 (m, 1H), 8.18 (br, <1H), 9.41 (br, <1H), b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (36 mg, 0.076 mmol) and free based [(3S)-3-aminobutyl](2-furanylmethyl)amine (70 mg, 0.42 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1-(2-furanylmethyl)-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (32 mg, 70%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (20 mg, 76%), as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.8 Hz, 3H), 1.45-1.49 (m, 1H), 2,042.13 (m, 1H), 2.77-2.82 (m, 1H), 2.94-3.01 (m, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.89 (d, J=16.0 Hz, 1H), 4.27-4.31 (m, 1H), 4.39-4.41 (m, 1H), 4:49-4.53 (m, 1H), 4.58-4.66 (m, 1H), 4.98-5.03 (m, 1H), 6.24 (m, 1H), 6.36 (m, 1H), 6.75-6.82 (m, 2H), 7.31-7.39 (m, 1H), 7.40 (m, 1H), 8.26 (s, 1H), 10.47 (m, 1H), 12.50 (br, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[S:18][C:19]([CH2:21][OH:22])=[CH:20][C:14]=2[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[S:18][C:19]([CH:21]=[O:22])=[CH:20][C:14]=2[CH2:13]1
Reactant: CN1CCc2sc(CO)cc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCc2sc(C=O)cc2C1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
DMSO (1.7 ml, 24 mmol) in 5 ml CH2Cl2 was cooled to −50-60° C. Oxalyl chloride (1 ml, 11 mmol) in 20 ml DCM was then added within 5 minutes at 50° C. The mixture was kept at −50° C. for 5 minutes and then 1.67 gram (9 mmol) of (5-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl)-methanol in 20 ml DCM was added at 50° C. and the mixture was stirred for another 15 minutes at 50° C. Triethylamine (7 ml) was then added at −50° C. and after 5 minutes the bath was removed and the mixture is naturally warmed up to 23° C. It was washed with 100 ml water and extracted with 100 ml ethyl acetate. The combined organic layers were dried over magnesium sulfate. Filter. Concentrate and flash column chromatograph using 0-15% methanol in ethyl acetate yielded 736 mg (45% yield) product.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21](Cl)=[O:22])=[C:14]2[N:13]=[N:12]1>C1COCC1.O>[CH2:1]([O:8][NH:9][C:21]([C:20]1[N:19]=[CH:18][N:15]2[C:16](=[O:17])[N:11]([CH3:10])[N:12]=[N:13][C:14]=12)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: Cn1nnc2c(C(=O)Cl)ncn2c1=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
O-benzylhydroxylamine (195 μL, 1.68 mmol, 2 eq.) was added to a solution of crude 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (200 mg, 0.84 mmol; see Arrowsmith et al., J. Med. Chem., 2002, Vol. 45, No. 25, p. 5458) in THF (6 mL) and a precipitate formed instantly. The resulting suspension was stirred for 1 hour and 30 minutes and was then poured into ice. The suspension was diluted with water and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give 158 mg of the pure title compound as an off-white solid (63% yield). δH (DMSO-d6): 11.9 (1H, s), 8.85 (1H, s), 7.42-7.50 (2H, m), 7.36-7.42 (3H, m), 4.96 (2H, s), 3.88 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C(B(CC)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.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>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCB(CC)c1cccnc1
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (31) (4 g, 11.6 mmol), diethyl 3-pyridylborane (2.04 g, 13.9 mmol), potassium carbonate (4.8 g, 34.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in a mixture of water (20 ml) and dimethoxyethane is stirred at 80° C. in a nitrogen atmosphere overnight. After cooling the resulting suspension is poured into water and the crude product is filtered off, washed with water and dried. Purification is achieved by column-chromatography on silica gel using a mixture of ethyl acetete and methanol (9:1) as the eluent. Yield 2.46 g (72%) of the title compound. Mp.191-193° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[NH:17][CH2:16][CH2:15]S3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[NH:17][CH2:16][CH2:15][S:32]3(=[O:35])=[O:33])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])[O-]
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)SCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1
Reaction time: 1 h

Procedure:
To a solution of 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane (2.5 g) in methylene chloride (80 ml) was added 80% m-chloroperbenzoic acid (3.8 g) at 0° C. After one hour, a saturated aqueous solution (50 ml) of sodium sulfite was added to the solution. The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (2.37 g).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+:10].Br[CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:13]([O:15]CC)=[O:14]>CO>[OH-:2].[Na+:10].[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:24])([F:26])[F:25])[C:13]([OH:15])=[O:14])[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(Br)CCCCCC(F)(F)F
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(CCCCCC(F)(F)F)n1cnc([N+](=O)[O-])c1
Product: [OH-]

Procedure:
4-Nitroimidazole (43 mmoles, 4.86 g) was reacted with sodium hydride(43 moles, 1.72 g) and then ethyl 2-bromo-8,8,8-trifluorooctanoate (43 moles, 13.2 g) as in Example 1. The ester was hydrolyzed in 10 ml methanol and 30 ml 2N NaOH to yield a quantitative yield of 2-(4-nitro-1H-imidazol-1-yl)-8,8,8-trifluorooctanoic acid. (NMR)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)C.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].C(OOC(C)(C)C)(=O)C.C([O-])(=O)CCCCCC(C)(C)C>C(C(C)=O)C>[CH:1]([CH:19]=[CH:18][C:17]([OH:21])=[O:20])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(=O)OOC(C)(C)C
Agent: CC(C)(C)CCCCCC(=O)[O-]
Solvent: CCC(C)=O
Solvent: CCc1ccccc1
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 446.8 %

Procedure:
Into a polymerization reactor equipped with an agitator and a reflux condenser were charged 580 grams of styrene, 3.0 grams of terpenolene and 200 ml of ethylbenzene. Then 80 grams of high cis-polybutadiene from Goodyear Tire & Rubber Company (Budene 1208) was dissolved in the mixture. After the rubber had dissolved, a solution of 40 grams of acrylic acid in 60 ml of methyl ethyl ketone (335 ml) was introduced into the mixture. The temperature of the reaction mixture was raised to 85° C. and maintained at this level during the ensuing polymerization. Polymerization was initiated by introducing into the system a mixture of 0.2 ml of tert-butyl peracetate and 0.2 ml of tert-butyl per-neo-decanoate. One hour later, continuous addition of a solution of 40 grams of acrylic acid and 60 ml of methyl ethyl ketone was initiated and this addition was continued over a four hour period. At one hour and again at four hours after the start of the continuous addition of the acrylic acid solution, additional 0.2 ml portions of tert-butyl peracetate were introduced into the polymerization mixture. Polymerization was terminated 5.5 hours after initiation and the resultant polymer was recovered and dried, first in air and then in a vacuum oven, to yield 432 grams of rubber-modified styrene-acrylic acid graft copolymer. In order to produce enough copolymer for the compounding and ensuing test work this polymerization procedure was repeated four more times and the products from the five runs were combined and mixed in a Waring blender. The resultant polymer contained about 84.2 weight percent styrene and about 15.8 weight percent acrylic acid. Its rubber content was approximately 18.5 percent based on the weight of the resin phase.