Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>CS(C)=O.O.N>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Reactant: Nc1ccncc1
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccncc2)nc1NC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
A mixture of 0.64 g (3 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine and 0.62 g (6.6 mmol) of 4-aminopyridine in 5 mL of DMSO is stirred at room temperature for 15 minutes. The solution is diluted with water and basified with aqueous ammonia to give 0.41 g (44%) of the title compound: mp (EtOH) 219–221° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[CH2:9]([Cl:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(C)C>CCOCC>[Cl-:16].[C:10]1([CH2:9][N+:1]2[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccncc1C
Reactant: ClCc1ccccc1
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cc[n+](Cc2ccccc2)cc1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.3 %

Procedure:
A mixture of 3,4-lutidine (112 mL, 1.0 mole), benzyl chloride (115 mL, 1.0 mole) and isopropanol (500 mL) was refluxed under nitrogen for 5 hours and then was stirred at room temperature for 60 hours. The mixture was diluted with ether and the resulting white precipitate was filtered and dried to afford 178.3 g (76%) of N-(phenylmethyl)-3,4-dimethylpyridinium chloride.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:26])([F:27])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: NCCCc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1cccc(OC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.23 g, 1.0 mmol), 3-(3-trifluoromethoxy-phenyl)-propylamine (0.219 g, 1.0 mmol), and K2CO3 (0.25 g, 1.8 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-trifluoromethoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.153 g, 46%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.72 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.02-7.56 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 335 (M)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:17]1.C([Sn]([N:41]=[N+:42]=[N-:43])(CCCC)CCCC)CCC.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[N:41]=[N:42][NH:43][N:27]=2)[CH2:17]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCC#N)C3)c(C)o2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCc4nn[nH]n4)C3)c(C)o2)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
333 mg of (1R,3S)-4-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]butyronitrile are dissolved in 5 ml of xylene, and 919 mg of tributyltin azide are added. The mixture is stirred at 120° C. for 18 h and, after cooling, titurated with 0.5 ml of TFA. The solvent is removed under reduced pressure and the residue is purified by RP-HPLC. This gives (1R,3S)-5-{3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propyl}-2H-tetrazole as a colorless oil. C22H29N5O3 (411.51), MS (ESI): 412 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:19]([F:18])([F:29])[F:30])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 0 °C

Procedure:
One gram of 3-isopropylaniline and 0.8 gram of triethylamine were dissolved in 50 ml of THF, cooled to 0° C. and agitated. A solution prepared by dissolving 1.54 grams of 2-trifluoromethylbenzoyl chloride in 20 ml of THF were dropwisely added. After agitating for 30 minutes, the reaction mixture was filtered and THF in the filtrate was distilled off under reduced pressure. The residue was extracted by benzene, and rinsed with 3N-HCl, a saturated sodium bicarbonate solution and water successively in this order. The benzene layer was dried by adding anhydrous magnesium sulfate and then benzene was distilled off under reduced pressure to obtain the desired product. The yield was 1.98 grams (87%), and the product had a melting point of 87.5° to 88.5° C. and an IR absorption peak at 1655 cm-1 (c=b 0).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=2[O:2]1.[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20].[OH-:22].[K+]>C(Cl)CCl>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:21][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:11]4[O:22][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCCCCCCCN
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCNC(=O)c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2

Procedure:
m.p. 151°-152° C., 24.9 g., was prepared as in Example 1 using 3,4-methylenedioxybenzoyl chloride (prepared as in Example 6 using 30 g. of 3,4 -methylenedioxybenzoic acid) in 150 ml. of ethylene dichloride, 10.5 g. of 1,7-heptanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from ethanol using decolorizing charcoal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3c(Cl)cccc3Cl)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Dichlorobenzoyl chloride (1.52 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 24 h, then heated to 80° C. for 1 h. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19](O)[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:27]>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:27])[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 40 ml of N,N-dimethylaniline, and 35 g of 5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for one hour. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, removing a solvent, an oily product was obtained. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain an oily product. This was allowed to stand to cool and crystallized to obtain 31 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:26]([N:28]([CH2:39][CH3:40])[C:29]([S:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[NH2:38])=[S:30])[CH3:27]>CN(C)C=O.ClCCl>[CH2:39]([N:28]([CH2:26][CH3:27])[C:29]([S:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[NH:38][C:10]([C:3]1[N:4]=[C:5]([S:8][CH3:9])[N:6]=[CH:7][C:2]=1[Br:1])=[O:12])=[S:30])[CH3:40]
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Reactant: CCN(CC)C(=S)Sc1cnccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1nc(SC)ncc1Br
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A catalytic amount of N,N-dimethylformamide (2 drops) was added to a stirred suspension of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (2.07 g, 8.33 mmol) and a 2 M solution of oxalyl chloride (21 mL, 0.042 mol) in dichloromethane under nitrogen at r.t. Vigorous effervescence was observed. After 30 min everything had dissolved and the solvent was then evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL) and placed under nitrogen. Triethylamine (2.32 mL, 16.66 mmol) was added to this stirred solution at r.t. followed by 4-aminopyridin-3-yl diethylcarbamodithioate (2.01 g, 8.33 mmol). Everything quickly dissolved with a noticeable exotherm. After 3 h at r.t. tlc showed a new major product. The reaction was diluted with dichloromethane (20 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane 15:85 to 60:40) to yield 4-(5-bromo-2-(methylthio)pyrimidine-6-carboxamido)pyridin-3-yl diethylcarbamodithioate (1.99 g, 51%) as a pale yellow amorphous solid. 1H NMR: δ (CDCl3, 400 MHz) 1.30 (t, J=7 Hz, 3 H), 1.51 (t, J=7 Hz, 3 H), 2.60 (s, 3 H), 3.93-4.08 (m, 4 H), 8.57-8.62 (m, 2 H), 8.69 (d, J=6 Hz, 1 H), 8.85 (s, 1 H), 10.67 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:27]=[CH:26][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=3[CH:8]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=S1(=O)N=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCCCBr)cc21
Product: O=S1(=O)N=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCCCN3CCCCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole 1,1-dioxide and Piperidine were converted to yield 6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole 1,1-dioxide, MS: 467 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.Cl.[N:12]1([NH:21][CH2:22][CH2:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.O>[N:12]1([N:21]([CH2:22][CH2:23][CH3:24])[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: CCCNn1ccc2ccccc21
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCN(c1ncnc2[nH]cnc12)n1ccc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
To a solution of 6-chloropurine (5.0 g, 0.032 mole) in 50 ml 1-methyl-2-pyrrolidinone, was added 1 ml ethereal-HCl; followed by a solution of N-(1H-indol-1-yl)-N-propylamine (5.2 g, 0.030 mole) in 50 ml 1-methyl-2-pyrrolidinone. After stirring at 120° C. for six hours, the mixture was cooled, poured into 500 ml water and stirred for five minutes, pH adjusted to 10 with Na2CO3 ; then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solution was evaporated to an oil, about 8 g, which was eluted on a silica gel column with ethyl acetate via high pressure liquid chromatography. The desired fractions were combined, then evaporated to yield 2.2 g (25%) of N-(1H-indol-1-yl)-N-propyl-9H-purin-6-amine, m.p. 90°-5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13]I>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#N)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 54.9 %

Procedure:
To a solution of 3-bromophenylacetonitrile (12 g, 61.2 mmol) in tetrahydrofuran (150 ml) cooled down to 0° C., was added 60% sodium hydride in mineral oil (2.25 g, 56.3 mmol) portionwise over 10 minutes. The reaction mixture was stirred at 0° C. for 40 minutes. Methyl iodide (5.71 ml, 91.8 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for a further 1 hour. The reaction mixture was diluted with ethyl acetate (250 ml), washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion, 330 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless oil (7.06 g, 55% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=C=O)[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH2:22][N:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH3:1])[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27]
Reactant: Cc1c(Br)c(=O)c(C=C=O)c(C)n1Cc1c(F)cccc1F
Reactant: CNCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)c(=O)c(CN(C)CCc2ccccn2)c(C)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylaminoethyl)pyridine (680 mg, 5.00 mmol) was added to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone (430 mg, 1.16 mmol) in CH2Cl2 (15 mL). After 30 min., NaBH(OAc)3 (1.23 g, 5.80 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (15 mL) and the organic layer was separated and washed with sat. NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was used in the next step without any further purification. Crude yield 426 mg (75%). LRMS m/z 490.0 (M+−1), 492.0 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[I-:25].[Na+]>[Cu]I>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:25])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)c(F)c3)CC2)c(C)c1
Yield: 70.5 %

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (760 mg) described in Preparation Example 125, sodium iodide (581 mg) and copper(I) iodide (184 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (600 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7]1.[NH:16]1[CH2:21][CH:20]=[C:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]4=[N:7]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: O=c1n(CCCCCl)nc2ccccn12
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Product: O=c1n(CCCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{4-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared by reacting 2-(4-Chloro-butyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (225 mg, 1 mmol) and 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole (198 mg, 1 mmol) by adopting the procedure as outlined in Experimental 24. Yield: 87 mg (22%) compound was isolated as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27])[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:8][C:7]([S:18][C@@H:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[O:27])[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: CC(Cl)c1cccc(C(N)=O)c1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@H](C)c2cccc(C(N)=O)c2)nc2nc(N)sc12
Yield: 13 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 100 μmol) with 3-(1-chloroethyl)benzamide (20 mg, 100 μmol). Separation of the mixture by preparative HPLC gave a single diastereomer (6 mg, 13% yield) as an oil.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][N:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:9][NH2:10])[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:10][CH2:9][CH:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:18])[CH2:3][CH2:4]1)[C:11]1[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:23]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A mixture of 2-(4,4-difluoro-piperidin-1-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine (100 mg, 0.38 mmol), 2,3-dichlorobenzoic acid (51 mg, 0.28 mmol), HOBT (57 mg, 0.42 mmol), EDC.HCl (81 mg, 0.42 mmol) and DIPEA (108 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC directly to yield the title compound (43 mg, yield: 30%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1cc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c2cc1OC
Yield: 73.2 %

Procedure:
2.36 g (10.8 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.94 g (9.84 mmol) of 2-amino-4,5-dimethoxybenzoic acid were treated in the same way as in Example 1 to obtain 2.86 g of the above-identified compound (yield 73.3%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 3.79 (3H,s), 3.84 (3H,s), 6.62 (1H,s), 7.22 (1H,s), 7.74 (2H,d), 8.15 (2H,d), 11.36 (1H,br).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C[N:31]1CCOCC1>CO>[NH2:31][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][NH:29][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: CN1CCOCC1
Reactant: NCCc1ccccc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3ccc(N)cc3)cc2s1
Yield: 19.4 %

Procedure:
the title compound (25 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), phenethylamine (80 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 429.5 (M+1, 100%). Yield=19%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH:10]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])[CH3:11].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:16][CH2:15][C:14]([NH:13][CH:10]([CH3:12])[CH3:11])=[O:17])=[C:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=CC(=O)NC(C)C
Reactant: Nc1cc(Cl)ccc1S
Product: CC(C)NC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure H, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N-isopropyl-acrylamide, and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.