Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](C2(O)CCN(CCCC([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)CC2)=[CH:4][CH:3]=1.ClC1C=CC(C2(O)CCN(CCCC(C3C=CC=C(C4C=CC=CC=4)C=3)=O)CC2)=CC=1.C1(C(C2CC2)=O)CC1.C1(C2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1C(C(CCCN2CCC(O)(C3C=CC(Cl)=CC=3)CC2)=O)=CC=C(F)C=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:20]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=1.[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1-c1ccccc1
Agent: O=C(C1CC1)C1CC1
Agent: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1cccc(-c2ccccc2)c1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCCCCC
Yield: 12 %

Procedure:
This example describes the synthesis of both 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone (UCSF51) and 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone (UCSF52). The ortho and meta biphenyl analogs of halopeddol were prepared from the opening of the cyclopropyl ring of the corresponding biphenyl cyclopropyl ketone (875 mg of the ortho isomer and 500 mg of the meta isomer) by 4-(4 chlorophenyl)4-hydroxy pipeddine by refluxing the two reagents in xylene for 5 days. The reaction was worked up as described for the synthesis of para-biphenyl haloperidol. The products were separated by flash chromatography using a slow gradient from 100% CH2Cl2 to 100% ethyl acetate to 10% methanol in ethyl acetate as eluent. Pooling of the fractions containing product followed by evaporation of the solvent resulted in an orange liquid for the ortho isomer, and a tan solid for the meta. In ethyl acetate, the Rf 's are 0.17 for o-biphenyl haldol, UCSF51, and 0.26 for the meta derivative, UCSF52. Both products were recrystallized from hexane yielding approximately 200 mg (12% yield), and 350 mg (35% yield), of the ortho and meta isomers respectively. A melting point of 96°-97° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone, and a melting point of 99°-100° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone. Spectral data supported the assigned structures for both products.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=1[N:23]=[C:24]=[O:25]>O>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:24]([NH:23][C:16]1[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=1[CH3:14])=[O:25]
Reactant: Cc1cc(C)c(N=C=O)cc1C
Reactant: CC(C)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c(NC(=O)N(O)C(C)C)cc1C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
A solution of N-isopropylhydroxylamine hydrochloride (1.85 g, 16.5 mmol) in water (5 mL) was combined with diethyl ether (50 mL) then cooled in an ice bath. A solution of sodium hydroxide (0.72 g, 18 mmol) in water (10 mL) was added over a 10 minute period. The reaction mixture was stirred for 10 minutes then 2,4,5-trimethylphenyl isocyanate (2.42 g, 15 mmol) was added as a solid. The reaction mixture was stirred at ambient temperature for 18 hours. A white solid was isolated by filtration then recrystallized from hexanes/ethyl acetate to provide 2.4 g of the desired product as a white crystalline solid, m.p. 176.2°-176.8° C. Analysis: Calculated for C13H20N2O2 : %C, 66.07; %H, 8.53; %N, 11.85; Found: %C, 65.85; %H, 8.35; %N, 11.68.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[H-].[Na+].CI.[CH3:30]N(C=O)C>C1COCC1.CCOC(C)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]([CH3:30])[C:17](=[O:25])[CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(NC(=O)Cc3cccnc3)ccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CCn1c2ccccc2c2cc(N(C)C(=O)Cc3cccnc3)ccc21
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a suspension of N-(9-Ethyl-9H-carbazol-3-yl)-2-pyridin-3-yl-acetamide (329 mg, 0.899 mmol) in THF at 0° C. was added NaH (60% oil dispersion, 86 mg, 2.158 mmol), then the cooling bath removed. After stirring an additional 25 minutes methyl iodide (67 μl, 1.08 mmol) was added, and the reaction mixture stirred overnight. A portion of DMF (4 ml) was then added and stirring continued for several hours. The reaction mixture was then diluted with EtOAc and the organic layer washed with saturated aq. NaHCO3, H2O, and brine, dried (Na2SO4), and concentrated to afford the crude product as a brown oil. Chromatographic purification (silica, 10% MeOH/CH2Cl2) afforded the desired product (7 mg, 2.2% yield). MS m/z @ 344 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20](OC)=[O:21])[CH2:16][C@H:15]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2.[OH-].[Li+]>O1CCCC1.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:29][CH2:30]3)=[O:21])[CH2:16][C@H:15]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.9 %

Procedure:
(1S,2R,4R)—N1-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (200 mg) was dissolved in tetrahydrofuran (5 ml) and water (0.6 ml), and lithium hydroxide (12 mg) was added to stir the mixture at room temperature. After 3 hours, the reaction was stopped, the solvent was concentrated under reduced pressure, and the residue was then dissolved in N,N-dimethylformamide (10 ml), to which piperidine (65 mg), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg), 1-hydroxybenzotriazole (77 mg) and diisopropylethylamine (390 mg) were added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, dichloromethane was added to the residue, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The resultant organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:10) to obtain a product (132 mg) in a free form. This product was dissolved in methanol, to which 1N ethanol solution (230 μl) of hydrochloric acid was added. The mixture was dried to solid. Ether was added to the residue to solidify it. This solid was collected by filtration to obtain the title compound (127 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13](=O)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:42](N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CC1C=CC(OCCN2CCNCC2)=CC=1)C>>[CH2:1]([N:3]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH3:42])[CH2:18][CH2:19]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(OCC(=O)N2CCNCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: CCN(Cc1ccc(OCCN2CCNCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-oxo-2-piperazin-1-ylethoxy)benzamide according to an analogous synthetic method to Example 337, ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][4-(2-piperazin-1-ylethoxy)benzyl]amine (650 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{4-[2-(4-methylpiperazin-1-yl)ethoxy]benzyl}amine (490 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (70 mg).
Reaction SMILES: [O:1]([C:8]1[C:13]2[C:14]([NH2:17])=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c2ccnc(Oc3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2n[nH]c3ccnc(Oc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a stirred solution of the compound prepared in Example 434 (0.217 g,) in toluene (12 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (0.205 g). The mixture was evaporated in vacuo to remove water from imine formed. Sodium triacetoxyborohydride (0.244 g) was added, followed by acetic acid (0.4 mL). After stirring at room temperature for 1 hour, the reaction mixture was quenched with methanol slowly, to decompose excess borohydride, and then concentrated in vacuo. Ethyl acetate, was added to the residue and then washed with aqueous saturated sodium bicarbonate, dried, evaporated in vacuo to provide the title compound (0.262 g) with the following physical data.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([C@H:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:47])=[O:46])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:24])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:79](O)(=[O:82])[CH2:80][OH:81]>O1CCCC1>[OH:82][CH2:79][C:80]([N:17]1[CH2:18][CH2:19][CH:20]([C@H:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=4)(=[O:46])=[O:47])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:24])[CH2:21][CH2:22]1)=[O:81]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCNCC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)CO)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
Diisopropylethylamine (179 μl, 1.025 mmol) was added to a mixture of 2-((R)-1-(piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 2,2,2-trifluoroacetate (140 mg, 0.205 mmol), TBTU (131.7 mg, 0.14 mmol) and glycolic acid (15.6 mg, 0.205 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness and redissolved in ethyl acetate. The organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (60 mg, 47% yield). Also obtained was 20 mg (21% yield) of the detosylated compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:21]1[CH2:28][CH2:27][C@@H:26]([OH:29])[C@H:22]1[C:23]([OH:25])=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O>[C:7]([O:29][C@@H:26]1[CH2:27][CH2:28][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:22]1[C:23]([OH:25])=[O:24])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Pyridine (5 mL) and acetic anhydride (2 mL) were added to N-boc-cis-3-hydroxy-L-proline (400 mg, 1.73 mmol) and the reaction was stirred for 4 hours at room temperature. The reaction was diluted with water, acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (370 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[NH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCCNC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (Example 3, Step A) in 2 mL dichloromethane, triethylamine was added (165 μL), followed by tert-butyl 3-aminopropylcarbamate (76 mg). The reaction was stirred for 2 hours at room temperature. The reaction was diluted with EtOAc, washed with saturated NaHCO3 and brine and dried over Na2SO4. The crude product was purified by flash chromatography on silica using EtOAc:hexane (1:3) as mobile phase to give the titled compound. ESI+ MS: 644 [M+H]+.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH:14]=[CH:15]CCl.O.[CH3:19][CH2:20]OCC>C(O)C>[CH2:6]([O:5][C:3]1([O:4][CH2:19][CH3:20])[C:2](=[C:1]=[O:9])[CH:13]1[CH:14]=[CH2:15])[CH3:7]
Reactant: ClCC=CCCl
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOCC
Solvent: CCO
Solvent: O
Product: C=CC1C(=C=O)C1(OCC)OCC

Procedure:
To a solution of 18.4 g (2 equivalents) in 300 ml of anhydrous ethanol is added rapidly 164 g (1 equivalent) of diethyl malonate. 1,4-Dichloro-2-butene (98% mixture of cis and trans, Aldrich) (50 g, 1 equivalent) is slowly added to the warm, stirred suspension of the diethyl sodio malonate during 15 minutes after which the mixture is refluxed for 3 hours. Upon cooling, the mixture is poured into 1.2 liters of water and an oil isolated by ether extraction. The ether extract is dried over magnesium sulfate and distilled to give 1,1-bis-ethoxy-carbonyl-2-vinylcyclopropane, B.P. 108°-116° C./14 mm.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O.C(OCC)(=O)C>[CH3:32][N:33]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)=[O:3])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)CCCOc1ccc2c(c1)CCC(=O)N2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, and then 1.0 ml of ethyl chloroformate is added dropwise to this solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.1 ml of N-methylaniline, followed by additional 2-hour agitation. The reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from chloroform-petroleum ether to obtain 2.2 g of 6-[3-(N-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needlelike crystals, m.p. 129.5°-131.5° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].Br[CH2:7][C:8]1[C:25]2[C:24]3[C:15](=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[NH2:26][C:27]([CH3:32])([CH2:30]O)[CH2:28][OH:29]>CC(O)C.CCOCC>[CH3:1][S:2]([O:5][CH2:30][C:27]([NH:26][CH2:7][C:8]1[C:25]2[C:24]3[C:15](=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([CH3:32])[CH2:28][OH:29])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: BrCc1cccc2ccc3c4ccccc4ccc3c12
Reactant: CC(N)(CO)CO
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(CO)(COS(C)(=O)=O)NCc1cccc2ccc3c4ccccc4ccc3c12
Yield: 27.5 %

Procedure:
Using the procedure outlined in Example 3D except that the crude free base was treated with methanesulfonic acid, 4-bromomethylchrysene (10A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 27.5% yield of 2-[(4-chrysenylmethyl)amino]-2-methyl-1,3-propanediol methanesulfonate 0.4 H2O 0.1 i-PrOH, mp 192°-193.5° (C,H,N,S), (i-PrOH/Et2O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1SC1CC1.ClC1C=CC=[C:28]([C:32](OO)=O)[CH:27]=1.C(=O)([O-])O.[Na+].[S:41]([O-:44])([O-])=[O:42].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[S:41]([CH:32]1[CH2:28][CH2:27]1)(=[O:44])=[O:42]
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-[3-bromo-4-(cyclopropylsulfanyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (4.57 g) was dissolved in dichloromethane (91 mL), followed by ice-cooling. To this solution was added m-chloroperbenzoic acid (5.75 g) in 5 divided portions. It was warmed to room temperature, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and further added a 1 M aqueous sodium sulfite solution. The organic layer was separated and the aqueous layer was then extracted with dichloromethane. The organic layer was further washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain ethyl 2-[3-bromo-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (4.72 g) as an (E)/(Z)-mixture.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:35])(=[O:34])[CH2:25][CH2:24]3)[CH:10]=2)[CH2:6][O:5][CH2:4]1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:35])(=[O:34])[CH2:25][CH2:24]3)[CH:10]=2)[CH2:4][O:5][CH2:6]1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a stirred solution of methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran and water (4 mL, V/V=3/1) was added sodium hydroxide (40 mg, 1.0 mmol). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo to remove the organic solvent. The residual aqueous solution was acidified with an aqueous solution of citric acid (5 mL, 20%) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a sticky solid, which was purified by flash column chromatography (eluting with 5% methanol in dichloromethane) to afford 20 mg of the desire product as a solid. MS obsd. (ESI+) [(M+H)+] 483, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1 H), 8.01 (d, 1 H), 7.90 (m, 2 H), 7.61 (t, 1 H), 7.47 (t, 1 H), 7.32 (d, 1 H), 6.29 (s, 1 H), 5.76 (s, 2 H), 4.40 (m, 6 H), 3.78 (s, 2 H), 3.62 (s, 2 H), 3.17 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)SC)#[N:15].[CH3:22][NH2:23]>>[C:14]([NH:16][C:17]([NH:23][CH3:22])=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:15]
Reactant: COc1cccnc1CCCCN
Reactant: CN
Reactant: CSC(=NC#N)SC
Product: CNC(=NCCCCc1ncccc1OC)NC#N

Procedure:
Reaction of 2-(4-aminobutyl)-3-methoxypyridine with dimethyl N-cyanodithioimidocarbonate and treatment of the product with methylamine according to the general procedure of Example 1(iv)(v) gives N-cyano-N'-methyl-N"-[4-(3-methoxy-2-pyridyl)butyl]guanidine.
Reaction SMILES: ClC(Cl)(Cl)C(=N)OC.F[C:10](F)(F)[C:11]([OH:13])=[O:12].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1)([O-:18])=[O:17]>ClCCl.C(OCC)C>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]2[NH:25][C:10]([C:11]([OH:13])=[O:12])=[N:26][C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: COC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
Methyl 2,2,2-trichloroacetimidate (0.73 g, 4.09 mmol) and trifluoroacetic acid (0.63 mL, 8.17 mmol) were added to a suspension of 4-nitrophenylenediamine (0.50 g, 3.27 mmol) in a 2:3 mixture of dichloromethane/diethyl ether (40 mL). After stirring at RT for 3 h, the reaction mixture was filtered. The residue in the filter was washed with a 1:1 mixture of dichloromethane:ether. The filtrates were combined and shaken with 1.5N aqueous sodium hydroxide (40 mL). The organic layer was removed. A 1:1 mixture of methanol/ether (40 mL) was added, and the mixture was stirred at RT overnight. The precipitated yellow solid was collected by filtration, suspended in water and the mixture acidified with 6N aqueous HCl. The precipitate was collected by filtration and dried under vacuum overnight to give the title compound (0.331 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.20 (d, 1H), 7.79 (d, 1H). MS: m/z 208 (M+H).