Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[CH2:45]([NH2:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([NH:52][C:15](=[O:17])[C:14]1[CH:19]=[CH:20][N:21]=[C:12]([N:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH:5]3[CH2:23][CH2:24]3)[C:8]2=[O:22])[CH:13]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccccc1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 31 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with benzylamine, N-benzyl-2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 31% yield: mp 121-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36 (d, J=5.4 Hz, 1H), 7.40 (d, J=5.1 Hz, 1H), 7.32-7.24 (m, 5H), 6.73 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.14 (d, J=6.9 Hz, 2H), 1.00-0.87 (m, 1H), 0.57-0.51 (m, 2H), 0.24-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 156.9, 153.2, 148.2, 142.9, 137.7, 128.8, 128.0, 127.7, 115.9, 108.8, 48.6, 44.2, 41.6, 41.5, 31.0, 9.0, 3.4; MS (ES+) m/z 351.3 (M+1).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)=[CH2:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][S:24]([O:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH:1]=[CH2:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
15.1 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethanol, 8.2 mL of pyridine, and 0.41 g of 4-dimethylaminopyridine were dissolved in 50 mL of dichloromethane. A dichloromethane (6 mL) solution containing 6.3 mL of methanesulfonyl chloride was added dropwise to the above solution on ice for 30 minutes. The solution was heated to room temperature, then stirred for 6 hours, and was left over night. The reaction solution was poured into 10% hydrochloric acid, and the organic layer was fractioned. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel/toluene) and recrystallization (hexane/toluene) 3 times, to thereby obtain 9.8 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate in the form of colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]1[S:45][C:44]([C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[F:53])=[N:43][C:42]=1[C:54](O)=[O:55])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:54]([C:42]3[N:43]=[C:44]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:45][C:41]=3[NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[O:55])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (86.6 mg, 0.189 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (89.5 mg, 0.251 mmol), and HATU (221.8 mg, 0.5833 mmol) was added DMF (2.0 mL) followed by DIPEA (164.3 mg, 1.271 mmol). The reaction mixture was stirred at 45° C. for 14 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark semi-oil (110.3 mg, 73%). LCMS calc. for C36H42F5N6O7S (M+H)+: m/z=797.3. found 797.3.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O-])=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:56][C:57]1C=CC(CN)=C[CH:58]=1>C(Cl)Cl>[Cl:56][C:57]1[CH:58]=[C:44]([CH:43]=[CH:42][CH:41]=1)[CH2:45][NH:46][C:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:15])[N:5]([CH2:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])[CH:6]=[N:7]2)=[CH:12][CH:11]=1)=[O:17]
Reactant: NCc1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C([O-])c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(Cl)c1)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
3-(2-flourobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboylate (65 mg, 0.218 mmol was dissolved in DCM (10 mL) followed by the addition of DIEA (0.1 mL), HATU (100 mg) and 4-chlorobenzylamine (34 mg, 0.239 mmol). The mixture was stirred at RT overnight. The residue was semi-purified by flash chromatography and then further purified by rotary prep TLC using DCM-Ether (1:1) to give the desired product in 65% yield with HPLC purity of ≧95%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)[CH3:2].P(Cl)(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[ClH:27].[CH3:2][C:1]1[C:22]2[CH:21]=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[O:16][C:15]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(Oc2cccc(OC)c2)c(NC(C)=O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)N=C(C)c1ccc(OC)cc1O2
Product: Cl
Yield: 93.6 %

Procedure:
A mixture of 8.3 g of ethyl 3-acetylamino-4-(3-methoxyphenoxy)-benzoate and 15.4 g of phosphorus oxychloride and 50 ml of dried toluene was refluxed for 3 hours. The mixture was then cooled and the precipitating crystal was filtered and washed with ethyl acetate to give 8.2 g of ethyl 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate hydrochloride. The product was neutralized with ammonia water and extracted with ethyl acetate. After concentrating the extract, ethanol was added to the residue and the precipitating crystal was recrystallized from ethanol to give 6.9 g of ethyl 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate as a colorless acicular crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9](O)=O)[CH:7]=1.[C@@H]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31]3[S:32][C:33](CC)=[CH:34][CH:35]=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][CH2:9][C:33]2[S:32][C:31]([C:30]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=3)=[CH:35][CH:34]=2)[CH:7]=1
Reactant: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Reactant: O=C(O)Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1CCc1ccc(-c2ccccc2)s1

Procedure:
The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCc2cc(C#CCn3ccnc3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: O=C1CCc2cc(C=CCn3ccnc3)ccc2N1
Reaction time: 0.25 h

Procedure:
A suspension of 75 mg of 5% palladium on barium sulfate catalyst in 8 ml of pyridine was stirred under hydrogen for 15 minutes. A solution of 502 mg of 6-[3-(imidazol-1-yl)prop-1-yn-1-yl]-3,4-dihydrocarbostyril in 3 ml of pyridine was added and the mixture stirred under hydrogen until the theoretical volume of hydrogen had been absorbed. The reaction mixture was filtered and the solvent removed from the filtrate under reduced pressure to give a residue which was recrystallized from a mixture of methanol and ethyl acetate to give 6-[3-(imidazol-1-yl)prop-1-en-1-yl]-3,4-dihydrocarbostyril, m.p. 158°-160° C.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH:2]1[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O=S1(=O)C2C=CC=CC=2N=CC1C(O)=O>CN(C=O)C.C(OC(=O)C)C>[CH2:26]([NH:33][C:11]([CH:2]1[CH:3]=[N:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1]1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1C=Nc2ccccc2S1
Agent: O=C(O)C1C=Nc2ccccc2S1(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C1C=Nc2ccccc2S1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A solution of 1,4-benzothiazine-2-carboxlic acid (70 mg, 0.36 mmol) and 1,1′-carbonyldiimidazole (70 mg, 0.43 mmole) in DMF ( 5 mL) is stirred at 80° C. for 30 mins. It is then treated with benzylamine (0.05 mL, 0.43 mmol) and heated at 80° C. for 1 h. The reaction mixture is cooled to room temperature, taken up with ethylacetate, and extracted with water (3×10 mL). The organic layer is dried over sodium sulfate and concentrated. The solid is filtered and washed with ethylacetate to give N-benzyl-1,4-benzothiazine-2-carboxamide (35 mg, 35% yield) as a white solid (compound 1), m.p. 160-162° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1>C(O)C>[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[N:42]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)n1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 23.8 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 150 mg of the racemic title compound. The racemic title compound (150 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (54 mg) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (51 mg).
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3(=O)=[O:34])[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1.[Cl:36]C1C=C(N2CCNCC2)C2OCCOC=2C=1.[Cl:53]CCCCN1C(=O)C2C=CC=CC=2S1=O>>[ClH:36].[ClH:53].[Cl:1][C:4]1[CH:5]=[C:6]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3=[O:34])[CH2:18][CH2:19]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: Clc1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Reactant: O=C1c2ccccc2S(=O)N1CCCCCl
Agent: Cl
Product: O=C1c2ccccc2S(=O)N1CCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1
Yield: 41 %

Procedure:
The title compound was obtained analogous to the method described for 2-(4-(4-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)-butyl)-1,2-benzisothiazole-3(2H)-one-1,1-dioxide, dihydrochloride (Example 3) using 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (intermediate 2a) (2.50 g, 8.54 mmol) and 2-(4-chlorobutyl)-1,2-benzisothiazole-3(2H)-one-1-oxide (Intermediate 19c) (2.20 g, 8.54 mmol). Yield: 1.90 g (41%) of the title compound, m.p. 258°-60° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[CH:16]N(C)C)[N+:8]=1[CH2:20][CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:33]([N+:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[S:37][C:36]=1[CH3:44])[CH3:34].C(N(CC)CC)C>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[N:8]([CH2:20][CH3:21])[C:9]([CH:16]=[CH:44][C:36]2[S:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:35]=2[CH2:33][CH3:34])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: CC[N+]1=C(Cl)c2ccccc2C1=CN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(Cl)c2ccccc2c1C=Cc1sc2ccccc2[n+]1CC

Procedure:
3-chloro-1-dimethylaminomethylene-2-ethyl-1H-isoindolium perchlorate (0.5 g) and 3-ethyl-2-methylbenzothiazolium p-toluene sulfonate (0.5 g) were dissolved in acetonitrile and triethylamine added. After 30 minutes at room temperature the product was precipitated by the addition of ether and purified by chromatography on silica gel. After recrystalization from ethanol, the purified product melted at 244° C. CH3CN λ max 553 nm.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].[OH-].[Na+:28]>O.ClC1C=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O-:10])=[O:9])([OH:16])(=[O:4])=[O:3].[Na+:28]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
273.6 g of 3-(chlorosulfonyl)benzoic acid containing 28.6% water (corresponding to 195.3 g (0.89 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 50 g of water and 500 g of chlorobenzene and heated in a water separator. A total of 106 ml of water are expelled. After cooling the reaction mixture to 100° C., 108 g (0.89 mol) of 33% strength sodium hydroxide solution are added dropwise over 30 minutes. Subsequently a further 90 ml of water are expelled. After cooling, the precipitated product is filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 190.4 g of sodium 3-sulfobenzoate are obtained, the purity determined by titration being 97.3%; this corresponds to a yield of 93.3%.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:11]([N:15]=[N:16][C:17]([C:24]#[N:25])([CH3:23])[CH2:18][CH2:19][C:20](Cl)=[O:21])([CH3:14])([CH3:13])[CH3:12].O>CCOCC>[C:11]([N:15]=[N:16][C:17]([C:24]#[N:25])([CH3:23])[CH2:18][CH2:19][C:20]([O:4][CH2:1][CH:2]=[CH2:3])=[O:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reactant: C=CCO
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CCOC(=O)CCC(C)(C#N)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.32 g (0.040 m) of allyl alcohol and 10 ml of pyridine in 50 ml of ether cooled to 10° C. in a 250 ml 4 neck round bottom flask was added a solution of 10 g (0.0435 m) of 4-t-butylazo-4-cyanovaleryl chloride* in 10 ml ether. The acid chloride solution was added dropwise holding the reaction temperature below 20° C. After the addition was complete, the reaction was stirred an additional 2 hours at room temperature and poured into 100 ml water. The ether layer was separated, washed with 20 ml portions of 10% HCl, 10%, NaHCO3 and water. The ether solution was dried over anhydrous sodium sulfate, filtered and the ether evaporated off. The crude produce weighed 8.95 g (89%). The infrared spectra indicated there was a small amount of unreacted acid chloride present in the product. The crude product was purified by column chromatography over alumina using pentane as the eluent. The acid chloride did not come off the column. The pentane was evaporated off to leave the pure product.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[O-].[Na+]>CO.[Cu]>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C(Br)C#N
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 2 h

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (15.1 parts), copper-containing catalyst in amount indicated in the table below and methanol (32 parts) is heated to reflux and ethyl bromocyanoacetate (19.2 parts) in methanol (14 parts) is then added at a uniform rate during 6 hours, and the acid-base balance ("pH" as indicated by a pH meter) is maintained at a predetermined value by the addition of a 13% solution of sodium methoxide in methanol. On completion of the ethyl bromocyanoacetate addition, heating at reflux temperature is continued for a further 2 hours, maintaining the desired acid-base balance as necessary. The resulting solution is evaporated under reduced pressure to remove the solvent and the product is isolated as described in Examples 2-6 above. The yield, strength and composition of the ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate obtained are given in the following table together with other reaction details:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34]Br)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1.C(OCC)(=O)C>C1OC1C.CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34][S:44][C:43]2[N:39]([CH3:38])[N:40]=[N:41][N:42]=2)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nnnc1S
Reactant: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: CC1CO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CSc1nnnn1C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 563 mg (1 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-bromo-2-butenoate in a mixture of 2 ml propylene oxide and 4 ml of dimethylformamide at 0° was added 128 mg (1.1 mmol) of 1-methyl-5-mercapto-1,2,3,4-tetrazole. After 1 hour at 0°, the solution was added to a large amount of ethyl acetate and washed thoroughly with brine. The ethyl acetate layer was dried and evaporated to provide the title product: nmr (CDCl3) δ 2.20 and 2.37 (s, 3, CH3), 3.83 and 3.86 (s, 3, N--CH3), 4.43 (s, 2, --CH2S--), 5.88 (d, 2, C4 --H), 5.50 (q, 1, C3 --H), 4.57 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=4)[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cc1ccc(CNc2ccc3cc(Nc4cccc(C(F)(F)F)c4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=398.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-(trifluoromethyl)aniline.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:37]([N:40]1[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]3[CH:41]1[CH2:49][C:50]([OH:52])=O)(=[O:39])=[O:38])[CH:31]=[CH:30]2.[NH:53]1[CH2:57][CH2:56][N:55]=[C:54]1[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][NH2:66])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH:55]1[CH2:56][CH2:57][N:53]=[C:54]1[C:58]1[CH:59]=[CH:60][C:61]([CH2:64][CH2:65][NH:66][C:50](=[O:52])[CH2:49][CH:41]2[N:40]([S:37]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=4)[CH:33]=3)(=[O:38])=[O:39])[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]23)=[CH:62][CH:63]=1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NCCc3ccc(C4=NCCN4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
HATU (563 mg, 1.48 mmol, 2.0 eq.) was added to a mixture of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S-2) (297 mg, 0.74 mmol, 1.0 eq.), 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine (A49) (140 mg, 0.74 mmol, 1.0 eq.), and DIPEA (0.39 ml, 2.22 mmol, 3.0 eq.) in THF (10 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM (30 ml) and washed with saturated ammonium chloride solution (15 ml), saturated sodium bicarbonate solution (15 ml), water (15 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product which was purified by column chromatography (neutral alumina; 1% MeOH/DCM) to afford the desired product as an off-white solid. Yield: 35% (140 mg, 0.245 mmol); MS, Rt=3.3 min; m/z=572.5 [MH]+