Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]([N:26]3[CH2:27][CH2:28][NH:23][CH2:24][C:25]3([CH3:30])[CH3:29])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
This intermediate was prepared from 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].[I-].[K+]>CO.O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1]
Reactant: ClCCCCBr
Reactant: Cc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccn(CCCCCl)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
A mixture of 2-hydroxy-4-methylpyridine (1.50 g, 13.75 mmol) and potassium carbonate (1.90 g, 13.75 mmol) in 13 ml of methanol were stirred at room temperature for 15 minutes and then 1-bromo-4-chlorobutane (3.54 g, 20.62 mmol) and a spatula tip of potassium iodide were added thereto. The reaction mixture was heated to reflux for 6 hours and then stirred at room temperature for 12 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with dichloromethane. Drying of the organic phase and removal of the desiccant by filtration was followed by concentration of the organic phase in vacuo. Flash chromatography of resulting residue on silica gel (eluent: CH2Cl2/CH3OH: 98:2) afforded 2.0 g of 1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one.
Reaction SMILES: C(SP([O-])(OCC)=S)C.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]#[N:45])=[CH:41][CH:42]=4)[N:37]([CH3:46])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1.[CH2:47](N)[CH2:48][NH2:49]>C(O)C.O>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]5[NH:49][CH2:48][CH2:47][N:45]=5)=[CH:41][CH:42]=4)[N:37]([CH3:46])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C#N)ccc23)cc1
Reactant: NCCN
Agent: CCOP([O-])(=S)SCC
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C4=NCCN4)ccc23)cc1
Reaction time: 14 h

Procedure:
Diethyldithiophosphate (1.3 ml, 7.7 mmol) was added to 3-{1-(1,3-benzodioxl-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole (the product of Example 51, 800 mg, 1.5 mmol) in a mixture of ethanol (10 ml) and water (5 drops). The reaction was heated at reflux with stirring for 14 h. After cooling the solvent was removed in vacuo and the residues purified by flash column chromatography (elution with 98% dichloromethane/2% methanol) to give a brown oil. This residue was dissolved in ethylenediamine and the reaction mixture heated at reflux for 3 h. After cooling the ethylenediamine was removed in vacuo. Hydrochloric acid (10 ml) was added and the resulting precipitate was filtered and washed with dichloromethane and methanol. Flash column chromatography (elution with 80% dichloromethane/20% methanol/5%NH3) gave the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing p-toluenesulfonyl chloride (60 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 57.5 mg of the product: MS m/z 489 (M)+.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[C:19]([O-])=[O:20]>C(#N)C>[O:20]=[C:19]1[C:9]2[C:8](=[CH:18][CH:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:7]=[C:2]2[S:3][CH:4]=[CH:5][N:6]12
Reactant: CCOC(=O)c1ccc(N)c(C(=O)[O-])c1
Reactant: Clc1nccs1
Solvent: CC#N
Product: CCOC(=O)c1ccc2nc3sccn3c(=O)c2c1
Temperature: 150 °C

Procedure:
A mixture consisting of 2.4 gm of 2-chloro-thiazole and 5.6 gm of ethyl 4-amino-isophthalate was heated for eight hours at 150° C on an oil bath. Thereafter, the resulting dark brown oil was refluxed with 10 ml of acetonitrile for one hour, the reaction mixture was then thoroughly cooled, and the crystals formed thereby were collected by suction filtration and recrystallized from a little methanol. The compound of the formula ##STR9##
Reaction SMILES: [OH:1][CH:2]([CH2:11][OH:12])[CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[C:13]1([CH2:26][O:27][C:28](C2CC(=O)N(O)C2=O)=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[C:13]1([CH2:26][O:27][C:28]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH2:11][OH:12])=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CSCC(O)CO)C(=O)O
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)C1CC(=O)N(O)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](CSCC(O)CO)C(=O)O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 63.8 %

Procedure:
S-(2,3-dihydroxypropyl)cysteine (2.45 g, 12.6 mmole) was dissolved in 9% sodium carbonate (20 ml). A solution of fluorenylmethoxycarbonyl-N-hydroxysuccinimide (3.45 g, 10.5 mmole) in acetonitrile (20 ml) was added and the mixture stirred for 2 h, then diluted with water (240 ml), and extracted with diethyl ether (25 ml×3). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and was then extracted with ethyl acetate (70 ml×3). The extract was washed with water (50 ml×2) and saturated sodium chloride solution (50 ml×2), dried over sodium sulfate and evaporated to dryness. Recrystallisation from ether and ethyl acetate at −20° C. yielded a colourless powder (2.8 g, 6.7 mmole, 63.8%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8](S(C)=O)=[N:7][C:6]=2[CH:13]=1.[NH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[C:30]([F:33])([F:32])[F:31])=[O:22])[CH2:17]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[C:30]([F:33])([F:31])[F:32])=[O:22])[CH2:17]3)=[N:7][C:6]=2[CH:13]=1
Reactant: CS(=O)c1nc2cc(F)c(F)cc2s1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3nc4cc(F)c(F)cc4s3)C2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of 30 mg (0.129 mmol) rac-5,6-difluoro-2-methanesulfinyl-benzothiazole and 70.3 mg (0.258 mmol) ((R)-3-Amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13) in 540 μL dimethyl sulfoxide was heated in a 100° C. oil-bath for 4 h. The solution was cooled to room temperature, diluted with water and basified with a saturated NaHCO3 solution. The mixture was stirred for 1 h. The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 27 mg (47.6%) of the title compound as a white solid. MS(m/e): 442.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(O)C>[C:34]1([CH3:44])[CH:35]=[CH:36][C:37]([S:40]([OH:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1.[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)CC1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1

Procedure:
100 mg of 4-(4-trifluoromethoxyphenoxy)piperidine, 64 mg of 1,4-cyclohexanedione and 0.02 ml of triethylamine were heated in 15 ml of ethanol and reacted at 50° C. to 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and ethyl acetate was added thereto to prepare an ethyl acetate solution, to which p-toluenesulfonic acid was added. After leaving at room temperature for 30 minutes, the precipitate was filtrated and washed with ethyl acetate. The obtained crystal was air-dried and 139 mg of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine p-toluenesulfonate was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH2:16])[CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:16][C:21](=[O:22])[CH2:20][CH2:19][Cl:18])[CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)=[O:22]
Reactant: Nc1ccc2c(=O)c3cc(N)ccc3[nH]c2c1
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)Nc1ccc2c(=O)c3cc(NC(=O)CCCl)ccc3[nH]c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2,6-Diamino-9(10H)-acridone (AR-ACO-8, 8.40 g, 37.3 mmol was suspended in 3-chloropropionyl chloride (100 mL), stirred at room temperature for 1 hr, at 90° C. for 1 hr, and at reflux for 6 hr. Allowed to stand at room temperature overnight and then chilled with ice-water. The product was collected and washed with acetone (2×30 mL) followed by toluene (3×30 mL), acetone again (4×30 mL), ethanol (2×30 mL), dry ether (2×30 mL) and finally hexane (2×30 mL). The product was dried over P2O5 under vacuum to yield a yellow solid AR-ACO-09 (12.96 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(Cl)Cl.C(=O)=O>CO>[C:19]([NH:18][C:4](=[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:2][CH3:1])=[O:22])(=[O:21])[CH3:20]
Reactant: COC(=O)[C@H](NC(C)=O)C(c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(C)=O)=C(c1ccccc1)c1ccccc1

Procedure:
(R)-2-Acetylamino-3,3-diphenylpropionic acid methyl ester, reaction time 6 h, conversion 100%. [α]D25-101.6 (c=1.02, CHCl3). ee 80.7% (SFC, 2× Chiralpak AD-H columns, 10% methanol, 3000 psi CO2, 35° C., flow rate 3 ml/minute, retention times R 5.2 minutes, S 10.1 minutes). Comparative examples have been disclosed by Boulton (Boulton, L. T., WO 2006127273).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:14]2)[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Clc1ccnc(N2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)ccn2)CC1

Procedure:
Stir 1-(4-chloro-pyridin-2-yl)-piperazine hydrochloride (2.2 mmol, 0.4 g), triethylamine (7.6 mmol, 1.1 mL) in 13 mL of CH2Cl2 and pivaloyl chloride (2.2 mmol, 0.3 mL) overnight at room temperature. Add CH2Cl2 and wash with saturated aq. sodium chloride and water. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 1-[4-(4-chloro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one. MS(ES): m/z=282 [M+H].
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(OC(C)C)(=O)C.O>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(=O)NNc1ccc(C)cc1
Temperature: 57.5 °C

Procedure:
104.8 g of 1-(4-methylphenyl)hydrazine hydrochloride are suspended in 525 ml of isopropyl acetate, a solution of 104.8 g of potassium carbonate in 300 ml of water is added and then the mixture is stirred until the solid has disappeared. 77.4 g of acetic anhydride are added while maintaining the temperature below 20° C. and then the mixture is left stirring at 20° C. A precipitate is observed to form, which precipitate disappears when the mixture is heated at approximately 55-60° C. The organic phase is washed twice with 200 ml of water and is then cooled at 0-5° C. overnight. The product formed is recovered by filtration and is then washed twice with 100 ml of MTBE.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16])[CH3:11].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:18]([NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[O:12][CH2:10][CH3:11])=[O:19])[CH2:3]2
Reactant: CCOc1ccccc1C(=O)N=C=O
Reactant: NC1CN2CCC1CC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCOc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-ethoxybenzoyl isocyanate (1.59 g, ca 7 mmol). The product (1.77 g) was converted to the 1:1 fumarate, mp 198°-199° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCCCCC(=O)O
Product: CCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and hexanoic acid
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C(O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19]/[C:12](=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([NH:1][C:31]([NH2:32])=[O:30])[CH:10]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(N)ccc32)c2ccccc2)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(NC(N)=O)ccc32)c2ccccc2)cc1

Procedure:
560 mg of 6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone, 236 mg of potassium cyanate and 3.8 ml of glacial acetic acid are dissolved in 20 ml of ethanol and refluxed for 1 hour. After this time the solvent is evaporated, the residue is taken up in methylene chloride, washed with water and dried over sodium sulphate. After evaporation, the product is dried in the desiccator.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:35])[N:29]=[C:30](SC)[NH:31][CH:32]=2)=[CH:22][N:21]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:30]3[NH:31][CH:32]=[C:27]([CH2:26][C:23]4[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=4)[C:28](=[O:35])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (0.216 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.108 mmol, 0.5 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.090 mmol; yield: 18%, HPLC-MS/UV: [M+H]+=448.34; rt: 10.25 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.88 (t, J=7.17, 2H), 3.51 (s, 2H), 3.55-3.67 (m, 2H), 3.95 (s, 3H), 5.11 (br.s., 1H), 6.87-7.05 (m, 5H), 7.14-7.21 (m, 2H), 7.23-7.30 (m, 1H), 7.65 (s, 1H), 8.39 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](=O)[CH3:13].Cl>C(O)(C)C.C(OCC)(=O)C>[CH3:12][CH:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: CC=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1Nc2cccnc2S(=O)(=O)N1

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.28 g of acetaldehyde in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, a crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The 3-methyl-2,3-dihydro-4H-pyrido[3,2- e] [1,2,4]thiadiazine 1,1-dioxide is recrystallized from a CH3OH/H2O (1/4) mixture.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 15b (0.14 g, 0.53 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 15c.
Reaction SMILES: ClC1C=CC(C2N(C3C=CC(OC)=CC=3)N=C(CCCO)C=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:35]=[C:34]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH:33]=2)=[CH:28][CH:27]=1.[Br:50]C1C(CCCO)=NN(C2C=CC(OC)=CC=2)C=1C1C=CC(Cl)=CC=1>>[Br:50][C:33]1[C:34]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[N:35][N:36]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:32]=1[C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=1
Reactant: COc1ccc(-n2nc(CCCO)c(Br)c2-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Agent: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Product: COc1ccc(-n2nc(CCC(=O)O)c(Br)c2-c2ccc(Cl)cc2)cc1

Procedure:
Substituting Compound 2 for the acid 12 in Example 37 afforded 4-bromo-5-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)pyrazole, as an off-white solid, 87%, mp=118.5°-120°. (compound No. 183) MS, m/e 420 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4]NC(=O)C.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4][Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1ccc([N+](=O)[O-])cc1CCl
Yield: 85 %

Procedure:
A solution of N-(2-methyl-5-nitrobenzyl)acetamide (3.12 g; 0.015 mol), phosphorus oxychloride (5.12 g; 0.032 mol) and dimethylformamide (2.19 g; 0.03 mol) in xylene (50 ml) is refluxed for one hour. The reaction mixture is then washed with water and the solvent evaporated. This treatment produces 2.36 g (i.e., 85% yield) of product having a melting point of 56° to 62° C.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:23]#[N:24])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O)C.O.[NH2:28]N>C(O)(=O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:11]([C:23]#[N:24])=[C:10]([CH2:25][CH3:26])[S:9][C:8]=2[C:6]2[NH:28][N:2]=[CH:4][N:5]=2)=[CH:14][CH:15]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CCc1sc(C(=O)N=CN(C)C)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCc1sc(-c2ncn[nH]2)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Temperature: 90 °C

Procedure:
Dissolve 3-(4-tert-butyl-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid dimethylaminomethyleneamide (261 mg, 0.71 mmol) in 2 mL of glacial acetic acid, add hydrazine monohydrate (50 μL, 1.03 mmol) and heat to 90° C. under nitrogen. After 90 minutes cool the reaction slightly, pour into 50 mL of ice-water and stir for twenty minutes. Filter off the resulting solid and rinse with 10 mL of water. Vacuum-dry overnight to give the title compound, 206 mg (86%). MS(ES+, m/e)=337 (M++1); HPLC=00%.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1>>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:15](=[O:16])[C:14]1[C:9]([Cl:8])=[CH:10][CH:11]=[N:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnccc1Cl
Reactant: CC(C)NC(C)C
Product: CC(C)N(C(=O)c1cnccc1Cl)C(C)C

Procedure:
substituting diisopropylamine and 4-chloronicotinic acid gave N,N-diisopropyl-4-chloronicotinamide; and