Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[Cl:42])[N:35]([CH3:43])[C:34](=[O:44])[C:33]=1[C:45](O)=[O:46]>C(Cl)(Cl)Cl>[CH3:2][CH2:1][N:3]([C:45]([C:33]1[C:34](=[O:44])[N:35]([CH3:43])[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([Cl:42])[C:41]=2[C:32]=1[OH:31])=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCNc1ccccc1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 27.5 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
N-Ethyl aniline (5.2 gm) was taken in chloroform (100 ml) and stirred for 10 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (26.6 gm) at 25-30° C. and the reaction mixture was stirred for 15 minutes. 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (10 gm) was added to the resulting mass at 25-30° C. followed by heating to reflux (40-45° C.) and then stirred for 3 hours at reflux. Chloroform was distilled out from the reaction mass under vacuum at below 55° C. The resulting residue was cooled to 25-30° C., followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. and the resulting mixture was stirred for 30 minutes at 25-30° C. The separated solid was filtered, washed with water and then dried to yield 12.95 gm of laquinimod (HPLC purity: 99.24%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:17]([CH3:16])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
Cyanuric chloride (7.30 g, 39.6 mmol) was dissolved in toluene (100 ml), cooled to -15° C., added with anhydrous sodium carbonate (4.19 g, 39.6 mmol), stirred for 10 minutes and gradually added dropwise with N-methylaniline (4.24 g, 39.2 mmol) dissolved in toluene (50 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (4: 1) as eluant, to obtain 6.13 g (yield: 60.6%) of 2,4-dichloro-6-(N-methyl-N-phenylamino)-1,3,5-triazine as colorless crystals having melting point of 131.5° C.-132.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][O:8][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=1
Reactant: COCCOCCl
Reactant: OCc1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCc1cc(Br)ccc1Cl
Yield: 88.1 %

Procedure:
To a solution of 100 g (4.52 mmol) of 5-bromo-2-chlorobenzyl alcohol in dry dichloromethane (20 ml) were added 675 mg (5.42 mmol) of 2-methoxyethoxymethyl chloride and 1.20 ml (6.89 mmol) of N,N-diisopropylethylamine in an atmosphere of argon, and the mixture was allowed to react at room temperature for 18 hours. To the reaction solution at 0° C. was a added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:5) yielded 1.23 g (3.98 mmol) of 4-bromo-1-chloro-2-(2-methoxyethoxymethoxymethyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[O:16]C)=[O:10])=[CH:5][CH:4]=1.O>ClCCl>[OH:16][C:15]1[CH:14]=[CH:13][S:12][C:11]=1[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(C(=O)c2sccc2OC)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sccc2O)cc1

Procedure:
993 mg of (4-methoxy-phenyl)-(3-methoxy-thiophen-2-yl)-methanone were dissolved in 20 ml of dry dichloromethane, and 7 ml of boron tribromide/dimethyl sulfide complex were added. The mixture was stirred at room temp. until the reaction was complete (TLC check). It was then poured into water and extracted several times with dichloromethane. The organic phase was dried and concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:4). The product with the molecular weight of 234.3 (C12H10O3S), MS (Cl): 235 (M+H+) was obtained.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=CN=[C:12]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@H](NC2[C:43]([N+:44]([O-])=O)=CN=C(Br)C=2)C)C=CC=CC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C.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]1([C@H:7]([N:9]2[C:10]3[C:15](=[N:44][CH:43]=[C:12]([C:19]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:20]=4[CH:21]=[CH:22][CH:23]=[N:24]5)[CH:11]=3)[NH:16][C:61]2=[O:62])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](Nc1cc(Br)ncc1[N+](=O)[O-])c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](Nc1cc(-c2cccc3ncccc23)ncc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1cccc2ncccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 85 °C
Yield: 77 %

Procedure:
((1R)-1-Phenylethyl)(5-nitro-2-(5-quinolyl)(4-pyridyl))amine. ((1R)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6g, 1.75 mmol)and 5-quinolineboronic acid (393 mg, 2.27 mmole) were dissolved in DMF (25 ml). Nitrogen gas was bubbled into solution for 2 min. Potassium carbonate (970 mg, 7.00 mmol) in water (5 mL) was then added followed by tetrakis(triphenylphosphine)palladium (0) (0.175 mmol). The solution was then heated to 85° C. under nitrogen for 1 h. The solution was condensed under reduced pressure and the crude product was diluted with ethyl acetate and filtered through a plug of silica-gel. The resultant filtrate was condensed under reduced pressure to afford the title compound (502 mg, 77%). MS (ESI) m/z 371 [M+1]+.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1>CC(O)C>[ClH:2].[ClH:1].[F:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(F)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(F)ccc1N1CCNCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (1.79 g, 10.03 mmol) and 4-fluoro-2-methylaniline (1.26 g, 10.07 mmol) were dissolved in 2-propanol (Volume: 10 mL) and stirred in a closed vial at 100° C. overnight. The reaction mixture was diluted with i-PrOH (10 mL) and cooled to 10° C. The resulting precipitate was filtered and purified using HPLC (10-80% ACN in water, TFA-buffered). The fractions were concentrated in vacuo, suspended in ether (3 mL) and treated with 4N HCl in dioxane (1 mL). The precipitate was filtered and dried in vacuum to afford 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (150 mg, 0.561 mmol, 5.60% yield). ESI-MS: m/z 195 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:17])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27]CC)=[O:26]>CN(C)C=O>[NH3:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([O:17][CH2:24][C:25]([OH:27])=[O:26])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(OCC(=O)O)CC2
Product: N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 19 (210 mg) in anhydrous N,N-dimethylformamide (3 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (40.4 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction mixture was stirred at 0° C. for 30 min. To the reaction mixture was added neat ethyl bromoacetate (0.105 mL) in one charge the reaction was then left stirring at 0° C. for 1 hour and then warmed to ambient temperature and left stirring under nitrogen atm. for 1 hour. The RM was cooled down to 0° C., sodium hydride (40.4 mg) as a 60% by weight suspension on mineral oil was then added in one charge. The reaction mixture was stirred at 0° C. for 30 min. To the reaction mixture was again added neat ethyl bromoacetate (0.105 mL) in one charge the reaction was gradually warmed to ambient temperature under nitrogen atm. overnight. The RM was concentrated under vacuum. The residue was purified by MDAP (Method B). The desired fractions were combined and concentrated under nitrogen blowdown to give the title compound (61 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[C:9](=[S:11])=[S:10].C(N(CC)CC)C.Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CS(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:9](=[S:11])[S:10][CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24])[O:3][C:4]=1[CH3:8]
Reactant: S=C=S
Reactant: Cc1nc(N)oc1C
Reactant: FC(F)=C(F)CCBr
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(NC(=S)SCCC(F)=C(F)F)oc1C
Yield: 34.7 %

Procedure:
In a manner similar to Example 9, Step (a), 2-amino-4,5-dimethyloxazole (3.0 grams, 0.027 mole), carbon disulfide (2.67 grams, 0.035 mole), triethylamine (3.44 grams, 0.34 mole), dimethyl sulfoxide (13.5 ml) and 4-bromo-1,1,2-trifluoro-1-butene (6.43 grams, 0.034 mole) were reacted to produce 2.78 grams of (3,4,4-trifluoro-3-butenyl) N-(4,5-dimethyl-2-oxazolyl)dithiocarbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>O.CO.C1COCC1.[Zn]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH3:3])=[O:15])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N)cc1
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Ammonium chloride (29.6 g, 55.4 mmol) in water (200 mL) and methanol (200 mL) was added to a solution of N-methyl-4-nitro-benzamide (10 g, 55.4 mmol) in THF (160 mL). Zinc powder (29 g, 44.4 mmol) was added portion wise and the mixture stirred for 15 minutes. The reaction mixture was filtered over celite, the filtrate was then concentrated and extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford 7.2 g (86%) of 4-amino-N-methyl-benzamide. 1H NMR: (DMSO-d6): δ 7.9 (s, 1H), 7.6 (d, 2H), 6.5 (d, 2H), 5.6 (s, 2H), 2.7 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].C(N(C(C)C)C(C)C)C.C[C:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>ClCCl.N1C=CC=CC=1>[C:54]1([S:57]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]3[CH:17]=[CH:16][N:15]4[N:18]=[CH:19][C:20]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:28]=6)=[CH:25][CH:26]=5)=[C:14]4[N:13]=3)[C:5]2=[O:40])(=[O:59])=[O:58])[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1CN(CCOS(=O)(=O)c2ccccc2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, step 6; 0.080 g, 0.142 mmol) in dichloromethane/pyridine (1:1, 10 mL total) was added N-ethyl-N-isopropylpropan-2-amine (0.0520 mL, 0.284 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.136 g, 0.711 mmol). The reaction was stirred overnight at ambient temperature to provide (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl benzenesulfonate. The crude material was directly in the next reaction (0.102 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:47]([CH2:51][CH3:52])[CH2:48][CH2:49][NH2:50])[CH3:46]>C(Cl)(Cl)Cl.O>[CH2:45]([N:47]([CH2:51][CH3:52])[CH2:48][CH2:49][NH:50][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:43])[CH3:46]
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (51 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (107 mg, yield 76%).
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].C(OCC)C.[ClH:28].O1CCOCC1>CO>[Cl-:28].[C:1]([C:3]1([CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:8][CH2:7][NH2+:6][CH2:5][CH2:4]1)#[N:2].[ClH:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: N#CC1(CC2CCOCC2)CC[NH2+]CC1
Product: [Cl-]
Reaction time: 8 h

Procedure:
In a round bottom flask was placed tert-butyl 4-cyano-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidine-1-carboxylate (8) (5 g, 16.21 mmol), diethyl ether (200 ml), and methanol (1 ml). To this was added commercially available HCl in dioxane (4M, 0.985 ml, 32.4 mmol.). The solution was stirred overnight. A fine white solid was formed in suspension and filtered with a medium frit to give 4-cyano-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidinium chloride (9) as an HCl salt in quantitative yield after washing with diethyl ether (3×50 ml). MS 209 (M+1)
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1
Reaction time: 12 h

Procedure:
To a solution of Example 29B (140 mg, 0.28 mmol.) in methanol (2 mL) was added hydrogen chloride in dioxane (0.5 mL, 2.000 mmol) and stirred for 12 hr. The solvent was removed under reduced pressure and the residue recrystallized from methanol:diethyl ether to provide the title compound as a hydrogen chloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.68-1.79 (m, 1H) 1.87-2.01 (m, 2H) 2.03-2.12 (m, 1H) 3.14-3.28 (m, 2H) 3.81 (s, 3H) 3.93-4.06 (m, 1H) 4.47 (d, J=6.44 Hz, 2H) 7.14 (d, J=9.16 Hz, 1H) 7.45-7.50 (m, 2H) 7.63 (d, J=2.71 Hz, 1H) 9.29 (d, J=4.41 Hz, 2H); MS (DCI) m/z 408 (M+H)+. Anal. calcd for C20H26ClN3O2S.2 HCl.1.0 H2O: C, 48.15; H, 6.06; N, 8.42. Found: C, 48.00; H, 6.04; N, 8.27.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C=O)CCC=CC1>O>[CH:2]1(/[CH:1]=[N:8]/[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: Cc1ccccc1
Agent: O=CC1CC=CCC1
Solvent: O
Product: C1=CCC(/C=N/Cc2ccccc2)CC1
Temperature: 112.5 °C

Procedure:
To a flask equipped with a Dean-Stark apparatus was added benzylamine (B) (97.3 g, 0.91 mol) and toluene (350 g). The mixture was warmed to 110-115° C. and 3-cyclohexene-1-carboxaldehyde (A) (100 g, 0.91 mol) was added over 1-1.5 h, while azeotropically removing water. After the addition was complete, toluene was distilled (approx. 100 mL) and then the reaction was cooled to 20-30° C. The resulting solution was approximately 40 w/w % (1) in toluene. The solution of (1) in toluene was carried forward without further isolation or purification. Typical assay: 99 area % purity (GC), retention time 15.3 min. 1H NMR (400 MHz, CDCl3) δ 7.78-7.75 (1H, m), 7.37-7.32 (2H, m), 7.30-7.26 (3H, m), 5.75-5.73 (2H, m), 4.62 (2H, s), 2.62-2.52 (1H, m), 2.31-2.23 (1H, m), 2.20-2.11 (3H, m), 2.00-1.93 (1H, m), 1.68-1.58 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1C=C(C2(C#N)CCC2)C=[CH:19][C:20]=1Cl.[Mg].C(Br)CC.Cl.CC[O:36]CC>O1CCCC1>[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:36])[CH2:15][CH2:20][CH3:19]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: [Mg]
Solvent: CCCBr
Solvent: C1CCOC1
Product: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (15 g) prepared in a similar manner to the 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile of Example 1 in dry ether (50 ml) was added to the product of the reaction between magnesium turnings (3.18 g) and propyl bromide (15.99 g) in dry ether (50 ml). The ether was replaced by tetrahydrofuran and the mixture heated with stirring under reflux for eighteen hours. The mixture was cooled and ice and then concentrated hydrochloric acid (52 ml) added. The resulting mixture was stirred under reflux for ten hours and extracted with ether. The ether extract yielded a residue from which 1-butyryl-1-(4-chlorophenyl)cyclobutane (b.p. 106°-108°/0.3 mm Hg) was distilled.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.[Cu]I>[C:24]1([C:30]#[C:31][C:2]2[N:7]=[N:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)nn1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)nn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloro-3-phenylsulfonylpyridazine (8.4 g) bis(triphenylphosphine)palladium(II) chloride (98%; 0.24 g), copper(I) iodide (95%; 63 mg), and triethylamine (9.2 ml) in N,N-dimethylformamide (84 ml) was added phenylacetylene (4.7 ml), and the mixture was stirred for 0.5 hour at 80° C. After being cooled to room temperature, water (168 ml) was added to the reaction mixture. The precipitate formed was collected, washed with water, and dried. Recrystallization of the crude product from a mixture of diisopropyl ether and acetone (2:1) gave 6-(2-phenylethynyl)-3-phenylsulfonylpyridazine (5.5 g). After the mother liquor was concentrated in vacuo, the residue was triturated with acetone. The precipitate was collected and dried to give a second crop of the pure material (2.0 g).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](Br)=[N:4][OH:5].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].[O-]CC.[Na+]>CCO>[NH2:10][C:9]1[O:5][N:4]=[C:3]([C:2]([F:8])([F:7])[F:1])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: ON=C(Br)C(F)(F)F
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1c(C(F)(F)F)noc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A solution of trifluoroacetohydroximoyl bromide etherate (17.6 g, 91.6 mmol) in 20 mL of EtOH was added to a solution of 2-cyano-acetamide (7.7 g, 91.6 mmol) and sodium ethoxide (6.2 g, 91.6 mmol) in ethanol (300 mL). After stirring at room temperature for 3 h, the solvent was removed. The residue was diluted with EtOAc and washed with water, brine, and dried over MgSO4. The organic phase was filtered and concentrated to give a brown oil. The product was purified by a flash chromatography on SiO2 eluting with hexanes:EtOAc (3:1) to give 7 as a light yellow solid (11 g, 40%); MS (ESI): 196 (M+H)+. Ref: J. Heterocyclic Chem. 1535 (1986).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)[CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[CH:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:28][CH2:29]3)[CH2:15][N:14]([C:5](=[O:7])[CH3:6])[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CCNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Acetic anhydride (35 □l, 0.37 mmol) was added to a solution of the amine of example 22 (120 mg, 0.30 mmol) and triethylamine in dichloromethane (5 ml) and stirred at room temperature for 2 hours. The dichloromethane was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound as a white solid (120 mg).