Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@@H:18]2[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][C@@H:19]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14].C(N(CC)CC)C.Br[C:46]1[S:47][C:48]2[C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=1>CO>[C:33]([O:32][C:31]([NH:30][C@@H:19]1[C@H:18]([NH:17][C:15]([C:10]2[NH:11][C:12]([CH2:13][CH3:14])=[C:8]([Cl:7])[N:9]=2)=[O:16])[CH2:23][CH2:22][N:21]([C:46]2[S:47][C:48]3[C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=[CH:51][C:49]=3[N:50]=2)[CH2:20]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)C(F)(F)F)C[C@@H]2NC(=O)OC(C)(C)C)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(=O)OC(C)(C)C)C3)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Potassium carbonate (40 mg, 0.289 mmol) was added to a solution of tert-butyl [(3S,4R)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1-(trifluoroacetyl)piperidin-3-yl]carbamate obtained in Example (202c) (123 mg, 0.263 mmol) in methanol (5 mL), and the mixture was heated under reflux at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and then the filtrate was dissolved in dimethylformamide (2 mL). Triethylamine (145 μL, 1.04 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (82.1 mg, 0.287 mmol) were added at room temperature, and the mixture was stirred at 70° C. for three hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:3) to obtain 121 mg of the title compound (80%) as a colorless solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[Cl:36][CH2:37][C:38]1[C:39]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)=[N:40][CH:41]=[CH:42][CH:43]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:37][C:38]3[C:39]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4cccnc4-c4cc(OC)c(OC)c(OC)c4)c4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. Yellow syrup obtained was converted to a trihydrochloroide to give the title compound as yellow powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH:3]([OH:5])[CH3:4].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][CH:3]([O:5][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH:2]([CH3:1])[CH2:6][CH3:7]
Reactant: C/C=C/C(=O)O
Reactant: CCC(C)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)C(C)CC
Reaction time: 3.5 h
Yield: 66.6 %

Procedure:
3-Methyl-pentan-2-ol (400 g), crotonic acid (CH3CH═CHCOOH) (445.5 g), toluene (400 mL), and para-toluenesulfonic acid (PTSA) (4 g) were charged into to 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged for about 3.5 hours. The resulting reaction mixture was then cooled and washed sequentially with water, aqueous sodium hydroxide (NaOH) (10%), and brine. The aqueous and organic layers were split. The organic layer was fractional distilled to provide but-2-enoic acid 1,2-dimethyl-butyl ester (444 g) with a boiling point of 106° C. at 34 mmHg.
Reaction SMILES: Cl[CH:2]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH3:15])[C:3]([O:5]C)=O.[NH2:16][C:17](N)=[S:18].C([OH:22])C.Cl>C(OCC)(=O)C.O>[Cl:13][C:12]1[C:7]([CH:2]2[S:18][C:17](=[O:22])[NH:16][C:3]2=[O:5])=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: COC(=O)C(Cl)c1c(Cl)cccc1OC
Reactant: NC(N)=S
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(Cl)c1C1SC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl alpha-chloro-alpha-(6-chloro-2-methoxyphenyl)acetate (1.37 g, 5.5 mmoles), thiourea (0.84 g, 10.0 mmoles) and ethanol (10 ml) was refluxed for 16 hours. Concentrated hydrochloric acid (4 ml) was added to the mixture and refluxing continued for an additional 16 hours. An additional 2 ml of concentrated hydrochloric acid was added and the mixture refluxed for 16 more hours. The yellow solution was then cooled to room temperature and poured into 150 ml of water. The title product was isolated by extraction of the aqueous mixture with ethyl acetate (2×150 ml). The extract was washed with water (1×50 ml) and brine (1×50 ml), then dried (MgSO4) and concentrated in vacuo to a brown oil (0.91 g). Trituration of the oil in hexane (50 ml) gave a solid which was recrystallized from ethanol-water (1:1) as a white solid, 0.0719 g. M.P. 195°-197° C.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])\[CH3:5].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1([C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1)[CH3:5]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C(=C\CCl)c1cccc(C#N)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1

Procedure:
To a solution of 3-[(E)-3-chloro-1-methyl-1-propenyl]benzonitrile (Preparation 34, 13.1 g, 69.6 mmol) in dichloromethane (20 ml) was added rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To the mixture was added dropwise at room temperature over 8 h (via a syringe pump) a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml). The solvent was removed in vacuo and the crude residue was then partially purified by silica column chromatography eluting with dichloromethane:hexane (80:20). This material was then dissolved in dichloromethane (20 ml) containing rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To this mixture was added dropwise a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml) at room temperature over 8 h. The mixture was concentrated in vacuo and the residue purified by silica column chromatography eluting with hexane:dichloromethane (80:20) and then hexane:diethyl ether (80:20) to give the title compound as a colourless oil which solidified on standing (5.82 g, 30%).
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N)CC>CCOCC.[Cu](I)I>[Si:6]([C:5]#[C:4]/[CH:3]=[CH:2]\[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)C#C/C=C\Cl
Agent: I[Cu]I
Solvent: CCCN
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)C#C/C=C\C#C[Si](C)(C)C
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
Tetrakistriphenylphosphine (4.75 g, 4.10 mmol, 0.48 equiv) was added to a solution of (Z)-1-chloro-4-(tert-butyldimethylsilyl)-1-buten-3-yne (17.2 g, 85.7 mmol, 1 equiv) in ether (160 mL) at -78° C. The resulting suspension was deoxygenated by alternately evacuating the reaction vessel and flushing with argon (5×), then was warmed to 23° C. In another flask, copper iodide (2.45 g, 12.8 mmol, 0.15 equiv) was added to a solution of trimethylsilylacetylene (17.0 mL, 120 mmol, 1.40 equiv) and n-propyl amine (27.5 mL, 334 mmol, 3.90 equiv) in ether (100 mL) at -78° C. The solution was deoxygenated (as above, 5×), then was stirred in an ice bath for 10 min causing the light green solution to turn reddish brown. The reddish brown solution was cooled to -78° C. and the palladium-containing suspension prepared above was added over 5 min via a wide-bore cannula. The mixture was deoxygenated (as above, 5×), then was stirred in an ice bath for 3 h and at 23° C. for 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (200 mL) and hexanes (300 mL). The aqueous layer was separated and extracted further with hexanes (2×300 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was filtered, then was purified by distillation under reduced pressure (bp 70°-80° C., 0.5 mmHg) to provide (Z)-1-(tert-butyl-dimethylsilyl)-6-trimethylsilyl-3-hexen-1,5-diyne as a light brown oil (20.4 g, 90%). ##STR29##
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([N:8]1[N:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:35])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1nn(Cc2ccccc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)isoxazole (1.34 g, 6 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and Na2CO3 (1.59 g, 15 mmol) in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) was degassed and heated to reflux with stirring for 18 h. After that time, the mixture was cooled to rt and diluted with ethyl acetate (80 mL). The organic phase was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The resulting semi-solid was triturated with hexanes to give a yellow solid. The product was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate) followed by recrystallization from CHCl3/hexanes to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)phthalazin-1(2H)-one (0.39 g, 23%) as a white solid: mp 186-188° C.; 1H NMR (400 MHz, CDCl3) δ 8.55-8.53 (m, 1H), 7.83-7.76 (m, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.44-7.42 (m, 1H), 7.35-7.26 (m, 3H), 5.45 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:19].[OH-].[Na+]>>[CH2:13]([O:12][P:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:19])[CH:8]=1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CCOP(=O)(Cc1ccnc(C#N)c1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC

Procedure:
A mixture of 1.10 g of 2-cyano-4-(diethylphosphonomethyl)pyridine and 4.5 ml of concentrated sulfuric acid is heated at 90° for 5 minutes. The reaction mixture is poured onto ice and neutralized with 10% sodium hydroxide. The resulting precipitate is collected to afford 4-(diethylphosphonomethyl)-2-pyridinecarboxamide melting at 140°-142°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[Mg:12].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Br:24]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Mg:12][Br:13])=[CH:4][CH:3]=1.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Br:24])=[CH:4][CH:3]=1
Reactant: [Mg]
Reactant: Cc1ccc(CCCBr)cc1
Reactant: BrCCCCCCCCCCBr
Solvent: C1CCOC1
Product: Cc1ccc(CCCCCCCCCCCCCBr)cc1
Product: Cc1ccc(CCC[Mg]Br)cc1
Temperature: -10 °C

Procedure:
A solution of 3-(4-methylphenyl)propylmagnesium bromide is prepared by reacting 20 g. 3-(4-methylphenyl)propyl bromide with 2.5 g. of magnesium turnings in 50 ml. dry tetrahydrofuran. The solution of Grignard reagent is added dropwise to a stirred, cold (-10° C.) solution of 30 g. of 1,10-dibromodecane and 0.2 g. of lithium tetrachlorocuprate in 75 ml. dry tetrahydrofuran at a rate such that the reaction temperature does not exceed -5° C. After one addition hour of stirring at -10° C., the solvent is evaporated and the resultant liquid is fractionated in vacuo to yield 13-(4-methylphenyl)tridecyl bromide as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:13][C:12](=[O:14])[C:11](=[O:15])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[O:18][CH3:19])([CH3:17])[CH3:16])[CH3:26]
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(C)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)c(Cl)c1OC
Yield: 81.6 %

Procedure:
5.37 g (18.86 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated sulfuric acid and refluxed for five hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution after 50 ml of water is added. It is extracted twice with ethyl acetate. The combined organic extracts are washed with water and with brine. After drying, and after the dessicant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.81 g (81.6%) of the desired compound is isolated.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[NH:8][C:9]2=[O:13])=[CH:4][C:3]=1[Br:17].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC#N.CN(C=O)C>[Br:17][C:3]1[C:2]2[N:1]=[C:23]([C:22]3[CH:25]=[CH:26][C:19]([CH3:18])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=3)[NH:12][C:11]=2[C:10]2[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]([CH3:15])([CH3:16])[C:5]=2[CH:4]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2N
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(Br)cc4c(c3[nH]2)C(=O)NC(=O)C4(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 7,8-diamino-6-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (1.40 g, 4.70 mmol) in MeCN (47 mL) and DMF (3 mL) was added 4-methyl-3-nitro-benzaldehyde (814.2 mg, 4.93 mmol) and p-chloranil (1.21 g, 4.93 mmol). The reaction mixture was stirred at 60° C. for 8 h. The cooled mixture was diluted with MeCN (50 mL) and the suspension was filtered. The solid was dried to give the title compound (1.65 g, 79% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>CC(C)=O>[CH3:15][N:16]([C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1)[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNc1ccc2ccccc2c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1ccc2ccccc2c1)c1nc(=O)c2cccnc2s1

Procedure:
The reaction procedure of Example 102 was followed except that 336 mg g of 2-chloronicotinoyl chloride, 145 mg of ammonium thiocyanate, 300 mg of 2-(methylamino)naphthalene and 7 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and chloroform to obtain 321 mg of 2-[N-methyl-N-(2-naphthyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: OC[C:3]1[N:8]=[CH:7]C=[CH:5][N:4]=1.SCCC[NH2:13].[NH2:14][CH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CN>>[C:5]([NH:4][C:3]([NH:8][CH3:7])=[N:14][CH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][CH:23]=[CH:24][N:25]=1)#[N:13]
Reactant: NCCCSCc1ncccn1
Reactant: OCc1ncccn1
Reactant: NCCCS
Agent: CN
Product: CNC(=NCCCSCc1ncccn1)NC#N

Procedure:
Also, reacting 2-hydroxymethylpyrimidine with 3-mercaptopropylamine by the procedure of Example 1 and then reacting the resulting 2-[(3-aminopropyl)thiomethyl]-pyrimidine with dimethyl-N-cyanoimidodithiocarbonate and methylamine by the procedure of Example 3(d) gives N-cyano-N'-methyl-N"-[3-(2-pyrimidylmethylthio)propyl]guanidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:22][C:13]1[CH:14]=[C:15]([S:18](=[O:20])(=[O:19])[NH2:21])[CH:16]=[CH:17][C:12]=1[NH:11][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:9]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (4.56 g; 25.8 mmol) in DCM (80 ml) was treated dropwise over 30 minutes with a solution of 4-amino-3-methyl-benzenesulfonamide (4.00 g; 21.5 mmol) and DIEA (7.40 ml; 43.0 mmol) in anhydrous DMF (10 mL). At the end of addition the reaction mixture was concentrated under vacuum and the residue was taken up in EtOAc (200 mL). The organic phase was washed with water/brine (80 mL). A precipitate was formed, which was filtered and dried under vacuum to afford the crude product which was recrystallized from EtOH. The title product was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCON=C(C(=O)O)c1csc(N)n1
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36 g.), methanol (133 ml.), tetrahydrofuran (133 ml.) and 2 N aqueous solution of sodium hydroxide (133 ml.) was stirred at 30° C. for 5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution was adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, washed with water and acetone in turn, and dried to give 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25.4 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[Br:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([N:1]4[C:29](=[O:30])[C:23]5[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=5)[C:32]4=[O:31])[CH:3]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole (166 mg, 0.5 mmol) and 1,2,4-benzenetricarboxylic anhydride (100 mg, 0.5 mmol) the title compound was obtained (238 mg, 93%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.32(m, 3H), 8.10(d, 1H), 8.02(d, 1H), 7.77(d, 1H), 7.57(dd, 1H), 7.48(d, 1H). MS 490.9 m/z (M−H)−.
Reaction SMILES: [C:1]1([C:7](=[N:13][NH2:14])[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(OO)(=O)C>CN(C)C(=O)C.C(O)(=O)C>[C:1]1([C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N+:13]=[N-:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN=C(c1ccccc1)c1cccs1
Agent: CC(=O)OO
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=C(c1ccccc1)c1cccs1
Reaction time: 0.67 h

Procedure:
To a mixture of phenyl-2-thienyl ketone hydrazone (20.2 g; 0.1 mole), and pyridine (24.8 ml; 0.307 mole) in N,N-dimethylacetamide (100 ml) stirred and cooled to 15° was added peracetic acid (17.7 ml of a 38% w/w solution in glacial acetic acid; 0.1 mole) during 40 minutes, the temperature being maintained at +15° throughout.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cnn(-c2ccccn2)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4-bromo-1H-pyrazol-1-yl)pyridine (0.669 g, 3 mmol), 3-chlorophenylboronic acid (0.468 g, 3 mmol) and potassium carbonate (0.828 g, 6 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and H2O (4 mL) were degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degasing continued a further 15 min. The solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) to afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4(3-chlorophenyl)-1H-pyrazol-1-yl]pyridine. MP=110-111° C. 1H NMR (CD3Cl, 300 MHz) δ 8.83 (d, 1H), 8.42 (dd, 1H), 7.99 (s, 1H), 7.99 (d, 1H), 7.82 (ddd, 1H), 7.57 (t, 1H), 7.45 (dt, 1H), 7.32 (t, 1H), 7.25˜7.18 (m, 2H). MS (ESI) 255.9 (M++H).