Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: O=C1c2ccccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Yield: 88.1 %

Procedure:
A solution of 1.0 g (0.0028 mol) of (S)-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 50 ml of tetrahydrofuran was treated with 4.6 ml (0.034 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate/tetrahydrofuran 2:1 as the eluent. There were obtained 1.04 g (95%) of (S)-1-(4-dipropylaminomethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as a pale yellow oil; [α]D20 =-253.8° (MeOH, c=1%).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:30])[CH3:28].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([NH:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[O:30])[CH3:28])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(O)C(=O)OC(C)C
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 79 mg of 2-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid and 90 mg of isopropyl (2RS, 3S)-3-(L-alanyl)amino-2-hydroxy-5-methylhexanoate hydrochloride in 5ml of N,N-dimethylformamide were added 0.062 ml of diphenylphosphoryl azide and 0.110 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 5/1 by volume: Rf2 =0.70) to obtain 19 mg of isopropyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-alanyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: Oc1ccc(N2CCN(c3nc(O)c4c(n3)CCS4)CC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1.11 g (3.36 mmol) of 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in 5 mL of phosphorus oxychloride, then stirred for 4 hours at 120° C. Excess phosphorus oxychloride is then distilled off and the residue is combined with water. The precipitate formed is suction filtered, washed with plenty of water, and dried. 1.18 g of product III is obtained as a brown powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:40]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[NH2:42]>CN(C=O)C.O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[N:40]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)OC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(c3nc(OC(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.222 mmol) of the carboxylic acid from Example 21A in 0.89 ml of DMF and 1.78 ml of 1,4-dioxane were added, at 60° C., 108 mg (0.666 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 52.4 mg (0.333 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 22.6 mg (22% of theory)
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([O-])=[O:12].[O-]CC.[Na+].[Na]>C(O)C>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11](=[O:12])[C:10]([O:15][CH2:16][CH3:17])=[O:14])#[N:9]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1

Procedure:
A mixture of 117.1 g. (1.0 mol.) of phenylacetonitrile and 326 ml. (2.4 mol.) of ethyl oxalate was added to an ethanol solution of sodium ethoxide [prepared by dissolving 23.8 g. (1.08 g.-atom) of sodium in 500 ml. of absolute ethanol] and refluxed two hours. After cooling, diluting with 2500 ml. of water and extracting with ether, the solution was acidified with acetic acid. The solid was removed and washed with water to give ethyl 3-cyano-3-phenylpyruvate, m.p. 127°-129°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9](O)[CH2:10]O>[Ru]>[CH3:1][N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]=[CH:9]1
Reactant: CNc1ccccc1
Reactant: OCCO
Agent: [Ru]
Product: Cn1ccc2ccccc21
Yield: 51 %

Procedure:
In Tetrahedron Letters, Vol. 27, No. 3, pp. 377-380, 1986, Watanabe discloses the reaction of N-methylaniline with ethylene glycol in the presence of a homogeneous ruthenium catalyst to provide a 51% yield of 1-methylindole. He also reported that: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH:6]12.[H-].[Na+].Cl[CH2:18][C:19]([NH2:21])=[O:20].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:18][C:19]([NH2:21])=[O:20])[CH:6]12
Reactant: O=C1CC2Cc3c(Cl)cccc3C2N1
Reactant: NC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)CC2Cc3c(Cl)cccc3C21
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of 2.7 g of 5-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one in 80 ml of dimethylformamide is added 0.8 g of sodium hydride (60% dispersion in mineral oil). After the evolution of gas ceases, the mixture is heated at 50°-60° C. for 1 hour whereupon a solution of 1.8 g of monochloroacetamide in 30 ml of dimethylformamide is added dropwise, and the resulting mixture is stirred at the same temperature for 2 hours and then cooled. The reaction mixture is poured into ice-cold water, acidified with dilute hydrochloric acid and extracted with chloroform. The extract is dried over sodium sulfate, and the solvent is distilled off. The residue is crystallized with a mixture of acetone and ether. The crystalline product is collected by suction filtration and recrystallized from ether to give 1.4 g of [5-chloro-1,2,3,3a,4,8b-hexahydro-2-oxo-indeno[1,2-b]pyrrol-1-yl]acetamide, melting at 186°-188° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C:12]2=[O:17])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][CH:26]([CH3:32])/[CH:27]=[CH:28]/[C:29](Cl)=[O:30]>ClCCl>[CH3:25][CH:26]([CH3:32])/[CH:27]=[CH:28]/[C:29]([N:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:12](=[O:17])[CH2:13]1)=[O:30]
Reactant: O=C1CNCCN1c1ccnc2ccccc12
Reactant: CC(C)/C=C/C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)/C=C/C(=O)N1CCN(c2ccnc3ccccc23)C(=O)C1

Procedure:
1-(4-Quinolyl)piperazin-2-one (23 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (21 μl, 0.15 mmol) followed by a solution of (E)-4-methylpent-2-enoyl chloride in 0.5 ml dichloromethane. The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile). 14.4 mg of a solid residue were obtained (0.044 mmol, 44%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:15][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][N:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(=O)[nH]n3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To 6-(6-chloro-pyridin-3-yl)-4,5-dihydro-2H-pyridazin-3-one (3 g, 14.4 mmol) in DMSO (40 mL) was added 4-hydroxy-boc-piperidine (2.9 g, 14.4 mmol), followed by 1M KtOBu (19 mL). After overnight stirring at 100° C. open to air, the reaction was cooled, diluted with dichloromethane and washed several times with water/brine, dried over sodium sulfate, and concentrated under vacuum to obtain 4.9 g crude product (92%); MS m/z 373 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH2:17][Cl:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
To a solution of 2-amino-5-bromopyridine (100 mg, 0.454 mmol) in dichloromethane (6 ml) were added triethylamine (0.19 ml, 1.364 mmol, 3 equiv.) and 3-chloro-2,2-dimethyl-propionyl chloride (CAS 4300-97-4) (140 mg, 0.909 mmol, 2 equiv.) at 0-5° C. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 5:95 to 10:90. The desired N-(5-bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (154 mg, 74% yield) was obtained as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1
Reactant: Brc1cccc(C2OCCO2)n1
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccc(C2OCCO2)n1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (2.0M, 12.4 ml, 24.8 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (20 ml) solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (2.7 ml, 24.8 mmol) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (2.7 ml, 24.8 mmol) under ice cooling. The temperature of the reaction mixture was raised gradually to room temperature and then, stirring was conducted for 16 hours. After a saturated aqueous solution of ammonium chloride was added, the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with water and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (2.90 g, 9.89 mmol, 40%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[Cl:14][O-].[Na+].S(=O)(O)[O-].[Na+]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Reactant: [O-]Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 9 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A1 or A2) (184 g, 1.02 mol) in water (45 mL) and concentrated hydrochloric, acid (292 g, 3 mol) at 8-12° C. was added dropwise aqueous sodium hypochlorite solution, (8.4%, 1.02 kg, 1.15 mol) over 2 h so that with cooling the reaction mixture was maintained at 8-10° C. The mixture was then held at 10-12° C. for 1 h and the conversion was monitored by HPLC. When less than 5% of the starting material remained solid sodium bisulfite was added until a negative KI starch paper test was obtained. The mixture was cooled to 5° C., and the suspended product was isolated by filtration and washed with a minimum amount of cold water. The product was then dried to constant weight in vacuum-oven at 50° C. to afford the title compound (194 g); m.p. 189-190° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH3:44][N:45]=[C:46]=[O:47]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:46]([NH:45][CH3:44])=[O:47])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CN=C=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with methyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2929.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2cn[nH]c2n1
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ccc2c(I)n[nH]c2n1
Yield: 96.3 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyridine (0.40 g, 2.6 mmol)(Ark Pharm Cat. No. AK-32412) and N-iodosuccinimide (0.64 g, 2.9 mmol) in methylene chloride (6 mL) and acetonitrile (3 mL) was stirred at 70° C. for 3 h. After cooling it was concentrated and the residue was treated with water. The precipitate was collected by filtration to afford the desired product (0.70 g). LCMS (M+H)+=279.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
50.0 g (0.248 m) 5-chloro-2-mercaptobenzothiazole and 53.0 g (0.248 m) α-bromophenylacetic acid are dissolved in 1.5 l acetone and the solution is heated for 4 hours in the presence of 50 ml glacial acetic acid. The solution is concentrated to a smaller volume (about 200 ml) and the residual solid (90 g) is collected. The resulting salt is suspended in 1 l of water and the mixture is stirred at room temperature overnight. The collected solid is recrystallized from 2.5 l acetonitrile to give a total of 64 g (85% yield) of title compound melting at 190°-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH2:10](I)[CH3:11].C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:10][CH3:11])[C:4](=[O:9])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Br)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(C)cc(Br)cc1=O

Procedure:
4-bromo-1-ethyl-6-methylpyridin-2(1H)-one was prepared by alkylation of 4-bromo-6-methylpyridin-2(1H)-one with ethyl iodide using K2CO3 following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN1CCCC1=O>[CH2:12]([N:11]([C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CNCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(Cc1ccccc1)c1cc(C#N)ccn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and N-methyl-N-benzylamine (1.0 ml, 7.8 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 2.5 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.47 g, 72%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:8](=[O:22])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10](=[O:12])[CH2:11]/2)=[CH:2]1.C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33]>ClCCl>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:8](=[O:22])[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[C:10]([O:12][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])[CH2:11]/2)=[CH:2]1
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\c3ccoc3)C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)C/C(=C\c3ccoc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[1-furan-3-yl-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (50 mg) in dichloromethane (2 ml) is added triethylamine (118 μl), followed by trimethylacetyl chloride (105 μl) and the resulting suspension allowed to stir at room temperature for 3 hours. The crude reaction mixture is then purified by automated flash chromatography to give 2,2-dimethyl-propionic acid 4-[1-furan-3-yl-meth-(E)-ylidene]-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>ClCCl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate (2.0 g, 7.08 mmol, 1.00 equip), dichloromethane (20 mL), and CF3COOH (4 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to yield 1-(2,2,2-trifluoroethyl)piperidin-4-amine 2,2,2-trifluoroacetate as a yellow oil. (ES, m/z) 183 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(N(CC)CC)C.[C:34](Cl)(Cl)=[S:35]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[O:18][C:34](=[S:35])[NH:20][N:19]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: S=C(Cl)Cl
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NN)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2n[nH]c(=S)o2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 206.6 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carbohydrazide (reference example 26) (750 mg, 1.78 mmol) was dissolved in THF (25 ml) and triethylamine (0.57 ml, 3.91 mmol) added followed by thiophosgene (0.1 ml, 1.96 mmol). The solution was stirred at ambient temperature under argon for 3 hours, then the THF removed in vacuo, water (75 ml) added, and then acetic acid was added dropwise till the mixture was at pH 5. The mixture was extracted with ethyl acetate(3×200 ml) and the combined organic phases washed with water and saturated brine (100 ml of each), dried (MgSO4) and concentrated in vacuo to give the title compound as a gum (1.7 g) which was purified by MPLC (98:2 dichloromethane:methanol), to give a solid foam (230 mg 28%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (5.398 g, 24.15 mmol) was reacted with cyclohexanone (2.257 g, 23 mmol) in ethanol (60 ml) to give the product (4.871 g, 19.473 mmol, 85%) as a white solid, mp 148-151° C. 1H NMR (DMSO-d6) δ 1.74-1.83 (m, 4H), 2.57 (t, J=6.0 Hz, 2H), 2.68 (t, J=5.7 Hz, 2H), 7.06 (dd, J=1.8, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 10.84 (s, 1H); [ESI(−)], m/z 248/250 (M−H)−.