Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)=O.CC(C)=O.C([Li])CCC.CCCCCC.[C:19]([NH:26][C@H:27]([CH:32]=O)[CH2:28][CH:29]([CH3:31])[CH3:30])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCOCC.CCCCCC.O>[C:22]([O:21][C:19]([NH:26][CH:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:32]=[CH2:1])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C=O
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(CC(C)C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred suspension of methyltriphenyl phosphonium bromide (10.97 g, 30.70 mmol) in anhydrous tetrahydrofuran (200 mL) at -78° C. (dry ice/acetone bath) under an argon atmosphere, was added n-butyl lithium, (19.8 mL of a 1.55 M hexane solution) dropwise over the course of 5 minutes. After 10 minutes, the -78° C. bath was replaced with a 0° C. bath for one-half hour, at which time the resulting orange solution was cooled again to -78° C. The solution was then added dropwise by cannula to a stirred -78° C. solution of Boc-leucinal (6.00 g, 27.91 mmol) in anhydrous tetrahydrofuran (30 mL) over the course of one-half hour. The mixture was then allowed to warm to room temperature during a 3 hour period after which water (150 mL) was added. Extraction with hexane (4×100 mL) provided a combined organic phase which was washed with brine (100 mL), dried (Na2SO4 ), and concentrated to give crude 3-t-butyloxycarbonylamino-5-methylhex-1-ene (6.5 g). Chromatography with ether/hexane (1/9) provided pure 3-t-butyloxycarbonylamino-5-methylhex-1-ene (3.71 g, 60%). Mass spectrum: EI, M+ -57=156; CI, (M+H)30 =214.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxy-5-trifluoromethylaniline (55 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (27 mg, 34%). 1H NMR (CDCl3): 9.65–9.64 (m, 1H), 8.75–8.70 (m, 2H), 7.46–7.41 (m, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H).
Reaction SMILES: C1(C([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38]4[C:42]([CH2:43][OH:44])=[C:41]([Cl:45])[N:40]=[C:39]4[CH2:46][CH2:47][CH2:48][CH3:49])=[CH:33][CH:32]=3)=[N:23][N:22]=[N:21]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+].O>CO.C(OCC)(=O)C>[CH2:46]([C:39]1[N:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:32][CH:33]=2)[C:42]([CH2:43][OH:44])=[C:41]([Cl:45])[N:40]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-[(2'-(Triphenylmethyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (920 g), and methanol (2.10 L) were charged to a 12-liter round-bottomed flask, equipped with mechanical stirrer, condenser with N2 inlet and thermometer. The slurry was cooled to ~10° C. and 3.4 N hydrochloric acid (700 ml) was added over 10 minutes. After stirring two hours at 10°-20°C., the thick slurry was diluted with methanol (500 ml) and warmed to 30° C. After one hour at 30° C., the reaction was neutralized to pH 13 with 10 N sodium hydroxide (420 ml). Solvent (largely methanol, 2.3 L) was distilled while 2.3 L D.I. water was added. Heating was discontinued and D.I. water (700 ml) and toluene (1.40 L) was added. After cooling to ~30° C., the organic phase was removed. The aqueous phase was reextracted with toluene (700 ml). Ethyl acetate (1.20 L) was added to the pot containing the aqueous phase. After stirring 10 minutes, acetic acid (130 ml) was added. The mixture was stirred one hour, then let stand overnight. Agitation was restarted and the slurry cooled to ~5° C. The product was isolated by vacuum filtration, reslurried with 1.50 L D.I. water and sucked semi-dry. The wet cake was charged to a 12 L round bottomed flask and reslurried 1/2 hour at ambient temperature with ethyl acetate (4.0 L). The product was isolated by vacuum filtration, washed with 200 ml ethyl acetate and dried in vacuo overnight at 50° C. Yield: 518 g, 88.5%. M.P.: 184°185° C. Purity by HPLC: 98.8%.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:9])(=[O:8])[CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:10][C:11]1([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH2:13][O:12]1>CN(C=O)C>[OH:12][C:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)([CH3:10])[CH2:13][N:4]1[CH2:5][CH2:6][CH2:7][S:3]1(=[O:9])=[O:8]
Reactant: O=S1(=O)CCCN1
Reactant: COc1cc2ncnc(N3CCC(C4(C)CO4)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(C(C)(O)CN4CCCS4(=O)=O)CC3)c2cc1OC
Reaction time: 4 h

Procedure:
Sodium hydride (1.25 g of a 50% dispersion in oil) was added at room temperature to a stirred solution of isothiazolidine-1,1-dioxide (2.42 g) in DMF (15 cm3). After stirring for 0.5 hours 2-methyl-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]oxirane (5.0 g) was added and the mixture was stirred for 4 hours at 100°. Volatile material was removed in vacuo, the residue was partitioned between chloroform (100 cm3) and water (50 cm3) and the chloroform layer was dried (MgSO4) and evaporated. The residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:ethyl acetate, 1:4, to give a solid which was recrystallised from ethyl acetate-methanol to give 2-{2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]prop-1-yl}isothiazolidine-1,1-dioxide, m.p. 173°-174° (4.15 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[C:3]=1[NH2:4].BrC1C2N=C(S)SC=2C=CC=1.[Cl:21][C:22]1[S:23]C2C=CC(Cl)=CC=2N=1>>[Br:1][C:2]1[C:3]2[N:4]=[C:22]([Cl:21])[S:23][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1c(Br)cccc1Br
Agent: Sc1nc2c(Br)cccc2s1
Product: Clc1nc2c(Br)cccc2s1
Temperature: 150 °C

Procedure:
The title compound was prepared from 2,6-dibromoaniline via 4-bromo-2-mercapto-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 150° C. for 16 h.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Reactant: OCCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCCOCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate (0.400 g), 4-benzyloxy-1-butanol (0.313 g) and triphenylphosphine (0.456 g) in tetrahydrofuran (6.7 mL) was added dropwise diisopropyl azodicarboxylate (40% toluene solution, 0.878 g), and the resulting mixture was stirred at room temperature for 75 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=6/1) to give the title compound (0.551 g).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][SH:22])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][S:22][Se:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11](=[O:12])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: CCOC(=O)CS
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Product: CCOC(=O)CS[Se]c1ccccc1C(=O)Nc1ccccc1

Procedure:
Prepared similar to example 1 from 2 g (7,3 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 1 g (8,3 mmol) of mercaptoacetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(C)n(C)ccc2=O)cc1
Yield: 86 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.4 mmol) was reacted with p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) in 10 mL of pyridine to afford PZBG-3b in 86% yield (0.35 g, 1.2 mmol). 1H NMR (500 MHz, CDCl3) δ=7.99 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 6.40 (d, J=7.2 Hz, 1H), 3.64 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ=170.71, 145.67, 145.54, 141.48, 134.07, 129.72, 128.96, 126.07, 117.53, 42.25, 22.00, 14.7. ESI-MS(+): m/z 294.05 [M+H]+, 315.97 [M+Na]+.
Reaction SMILES: BrCC1C(CBr)=NC2C(=CC=CC=2)N=1.C([O:17][C:18](=[O:37])[CH:19]([NH2:36])[CH2:20][C:21]1[C:30]([CH2:31][P:32]([OH:35])([OH:34])=[O:33])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)C.[OH-].[K+].C1OC1C>O>[NH2:36][CH:19]([CH2:20][C:21]1[C:30]([CH2:31][P:32]([OH:34])([OH:35])=[O:33])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[C:18]([OH:37])=[O:17]
Reactant: CCOC(=O)C(N)Cc1nc2ccccc2nc1CP(=O)(O)O
Agent: BrCc1nc2ccccc2nc1CBr
Agent: CC1CO1
Agent: [K+]
Solvent: O
Product: NC(Cc1nc2ccccc2nc1CP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude hydrobromide of α-amino-3-(phosphonomethyl)-2-quinoxalinepropanoic acid ethyl ester (1.4 mmole, 600 mg) was added to 1N aqueous potassium hydroxide (5.75 mL). The mixture was stirred overnight at room temperature, and then applied to an ion-exchange column (20 mL volume, Amberlite IRA 400) which had been prewashed with deionized water (40 mL). The column was washed to neutrality with deionized water, and the elution was continued with 0.5N hydrochloric acid. The acidic eluate was evaporated to dryness under reduced pressure, the residue was stripped with water (2×30 mL), benzene (2×30 mL), and dissolved in ethanol (10 mL). This solution was treated with propylene oxide (14.5 mmole, 1 mL), stirred for 30 minutes, the precipitate was collected by filtration, washed successively with cold ethanol and diethyl ether, and dried in vacuo at 85° C. The α-amino-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (300 mg) melted at 176° C. with decomposition; MS (pos. FAB) 312 (MH+ ); 1H NMR (D2O, 400 MHz): δ3.29 (dd, J1 =21 Hz, J2 =6 Hz, 2H, CH2 --P), 3.69 (m, 2H, CH2), 4.41 (m, 1H, CH), 7.56 (m, 2H, ArH), 7.71 and 7.81 (m, 2H, ArH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[CH3:11][O-:12].[Na+]>CO>[CH3:10][O:9][C:3]1[C:4]([CH3:8])=[N:5][CH:6]=[CH:7][C:2]=1[O:12][CH3:11]
Reactant: COc1c(Cl)ccnc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(C)c1OC

Procedure:
To a solution of 4-chloro-3-methoxy-2-methylpyridine (3.2 g) in methanol (5 ml) was added dropwise under ice-cooling a solution of 28% sodium methylate in methanol (20 ml) and the mixture, refluxed for 10 hours, and concentrated to dryness. To the residue, were added ice-water (10 ml) and then chloroform (100 ml) in this order, and the chloroform layer was separated, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, to give 3,4-dimethoxy-2-methylpyridine (2.95 g) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[O:12]=[C:4]1[CH:3]=[C:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A solution of 4-hydroxycoumarin (30.7 mmol, 4.98 g) and triethylamine (37.3 mmol, 5.2 mL) in THF (50 mL) is cooled to (0° C.). A THF solution (50 mL) of p-toluenesulfonyl chloride (33.5 mmol, 6.45 g) is added dropwise The mixture is stirred at 0° C. for 1.5 hrs., is filtered and the solid is washed with EtOAc. The filtrate is concentrated under reduced pressure and Et2O is added. The resulting precipitate is filtered, is washed with Et2O and is dried to afford the title compound (7.57 g, 79%); 1H NMR (CDCl3, 300 MHz) δ 7.91 (2H, m), 7.61 (2H, m), 7.34 (4H, m), 6.31 (1H, s), 1.55 (3H, s); MS (ESI, Pos.) calcd for C16H12O5S m/z [M+H]=317.0, found 317.0.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH2:11][OH:12])([CH3:5])[CH:3]=[CH2:4]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:5][C:2]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH:11]=[O:12])([CH3:1])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C)c1nc[nH]c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: C=CC(C)(C)c1nc[nH]c1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
Manganese dioxide (20 g, 0.23 mol) was added to a solution of [5-(1,1-dimethyl-allyl)-3H-imidazol-4-yl]-methanol (2.56 g, 0.02 mol) in acetone (300 ml) and the resulting mixture was stirred at room temperature for 5 h. The mixture was filtered through filter paper and the residue was washed with acetone. The filtrate and washings were combined and evaporated to afford 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carbaldehyde (1.82 g, 51%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000)).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[Al].[Li].[H-]>O1CCCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Al]
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4′-Bromo-biphenyl-4-carboxylic acid methyl ester, 7.8 g (27.9 mmol) in 150 mL of tetrahydrofuran was cooled to 0° C. via ice-water bath. Lithiumaluminum-hydride, 1.1 g (27.9 mmol) was added to the solution in one portion. The reaction mixture stirred at 0° C. for 1 h. The mixture was slowly quenched with 10 mL of isopropyl alcohol, then with 10 mL of water. The aqueous mixture was extracted with 3×50 mL portions of ethyl acetate. The organic layers were combined, washed with sat. aq. NaCl, and dried (MgSO4). The solution was concentrated to afford the desired product in 7.01 g (100%) as a white solid. The material was taken to the next step without further purification.
Reaction SMILES: [Mg].Cl[C:3]1[C:4]([CH3:14])=[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.II.CI.[C:19](=[O:21])=[O:20].[Cl-].[NH4+]>CI.C(OCC)C.O1CCCC1>[CH3:14][C:4]1[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]([OH:21])=[O:20]
Reactant: Cc1c(Cl)cccc1-n1cccc1
Reactant: O=C=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: Cc1c(C(=O)O)cccc1-n1cccc1
Temperature: 25 °C

Procedure:
A sample of 1.27 grams (0.052 mole) of magnesium metal was placed in a Morton Flask. The flask and contents were flame-dried under a nitrogen atmosphere. After the flask and contents were cooled, 10.0 grams (0.052 mole) of 1-(3-chloro-2-methylphenyl)pyrrole, a few crystals of iodine, and 20 ml of tetrahydrofuran were added; followed by three drops of methyl iodide. The reaction was commenced by the addition of an external Grignard Reagent of magnesium, methyl iodide and tetrahydrofuran. Once started, the reaction warmed the stirred reaction mixture to reflux. A precipitate appeared and was dissipated by the addition of 20 ml of tetrahydrofuran. The reaction mixture was heated under reflux for 22.5 hours. After this time the reaction mixture was cooled and crushed dry ice (CO2) was added until a thick slurry formed. An additional 20 ml of tetrahydrofuran was added and the thick slurry was reformed by the addition of more dry ice. The reaction mixture was stirred while being allowed to warm to ambient temperature. After the reaction mixture had warmed an aqueous solution saturated with ammonium chloride was added until a solid precipitate appeared. Upon complete addition the reaction mixture was stirred for 2.5 hours then 150 ml of diethyl ether was added. The mixture was filtered through a small amount of magnesium sulfate. The filtrate was concentrated under reduced pressure to a residual oil. The residual oil was dissolved in diethyl ether and extracted with three portions of 200 ml each of aqueous 2 N sodium hydroxide. The combined basic layers were washed with 200 ml of diethyl ether and acidified to pH=1 with concentrated hydrochloric acid. A solid precipitate formed. The mixture was cooled and extracted with four portions of 200 ml each of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 9.8 grams of 2-methyl-3-(pyrrol-1-yl)benzoic acid; mp 146°-148.5° C.
Reaction SMILES: N1CC[O:4]CC1.Cl[C:8]1(Cl)[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([CH2:19][N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14][C:8](=[O:4])[C:9]1=[O:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Reactant: C1COCCN1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Reaction time: 18 h

Procedure:
A mixture of morpholine (0.315 ml, 3.6 mmol) and 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.5 g) was stirred under nitrogen at 110° for 18 hours. The solution was diluted to 10 ml with chloroform and cooled to 0°. 20% H2SO4 (1 ml) was added and the solution stirred for 2 hours at 0°. The solution was extracted with chloroform (2×20 ml) and the extracts washed with 2N HCl (2×10 ml) and saturated brine (5 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to yield 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,3-dione. NMR (CDCl3): δ1.25 (t,3H); 2.6 (m,2H); 3.6 (m, 2H); 4.2 (q, 2H); 7.3 (m, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([N:21]2[CH2:27][CH2:26][CH2:25][CH:22]2[CH:23]=[O:24])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5 g (0.0394 mol) of oxalyl chloride in 50 ml of CH2Cl2 at -60° is added dropwise 7 g (0.0833 mol) of DMSO. The solution is stirred 30 minutes at -60° and then 10 g (0.039 mol) of N-tosylprolinol is added over five minutes at 60° and 15 ml of triethylamine is added. The solution is warmed to 25° and stirred one hour. The solution is then washed with H2O, dried over MgSO4 and the solvents removed. The residual oil, 10 g, is purified using a silica gel column and CHCl3 :MeOH (90:10) as the eluates. An oil is obtained which solidifies, 9.5 g (96%), mp 139°-140°.
Reaction SMILES: C[N:2](C)C.[Cl-].[NH4+].[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][O:14][CH2:15]2)=[CH:10][C:9]=1[C:18]#[N:19].ClC1C(C#N)=CC=C2C=1CCOC2.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][O:14][CH2:15]2)=[CH:10][C:9]=1[C:18]([NH2:2])=[NH:19]
Reactant: N#Cc1cc2c(cc1Cl)COCC2
Reactant: CN(C)C
Agent: N#Cc1ccc2c(c1Cl)CCOC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N=C(N)c1cc2c(cc1Cl)COCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of trimethyl amine in toluene (5 ml, 9.8 mmol) was added to a solution of ammonium chloride (0.6 g, 11.1 mmol) in toluene (3 mL) at 0 to 5° C. After the mixture was stirred at room temperature for 1 hour, a mixture (50 mg, 0.26 mmol) of 7-chloroisochromane-6-carbonitrile and 5-chloroisochromane-6-carbonitrile was added thereto. The reaction solution was stirred while heating under reflux overnight. After the reaction solution was cooled to room temperature, an aqueous solution of 2N sodium hydroxide was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a 1:0.5 mixture (44 mg, 81%) of the title compound and 5-chloroisochromane-6-carboxamidine.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.Cl>[ClH:1].[ClH:1].[C:14]1([CH2:13][N:20]2[CH2:25][CH2:24][C:23]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3]3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N=C(N)c1ccccc1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(Cc3ccccc3)CC2)Nc2ccccc21

Procedure:
A solution of 2-aminobenzamidine dihydrochloride (2.0 g, 9.6 mmol) and N-benzyl4-piperidone (2.1 ml, 11.5 mmol) in ethanol (40 ml) and HCl (1M in Et2O, 5 ml) was heated at 70° C. for 20 h. Evaporation and flash column chromatography on untreated alumina eluting with DCM/methanol (10:1) gave after trituration from ether a yellow solid, MS (+EI) 307 ([M+H]+), 1H NMR (d6 -DMSO) 9.99 (1H, s), 9.1 (1H, s), 8.5 (1H, s), 7.81 (1H, d), 7.53 (1H, s), 7.46 (1H, t), 7.2-7.4 (5H, m), 6.89 (1H, d), 6.79 (1H, dd), 3.52 (2H, s), 2.4-2.6 (4H, m), 1.91 (2H, m), 1.82 (2H, m).