Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:25]12[CH:31]([CH2:32][CH2:33][NH2:34])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:34][CH2:33][CH2:32][CH:31]2[CH:25]3[CH2:30][CH2:29][CH:28]2[CH2:27][CH2:26]3)=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: NCCC1C2CCC1CC2
Reactant: CCSc1ncc(C(=O)O)s1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 mole of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 2-(bicyclo[2.2.1]hept-7-yl)ethylamine in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured into 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]-thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)[CH:17]=1)=[O:14]>>[CH3:35][C:34]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)[CH:17]=2)=[O:14])=[CH:32][C:33]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1cccnc1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4cccnc4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound can be synthesized from 3-ethynylpyridine and 3-Iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 3-ethynylpridine was prepared from 3-bromopyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][NH2:17]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)-benzene sulphonyl chloride (200 mg) in 1,4-dioxane (1 mL) was added methylamine (40% aqueous solution, 96 mg). The mixture was stirred at room temperature for three hours then diluted with ethyl acetate (20 mL) and washed with HCl (1M, 2×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield 3-bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (181 mg) as a yellow solid. 1H NMR (MeOD): δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 4.58 (m, 1H), 2.74 (d, 3H). MS m/z 319.8 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CN(C(=O)Nc1ccccc1)[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.015 mL, 0.11 mmol) and phenylisocyanate (0.012 mL, 0.11 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 23 mg of the title compound of Example 109 as a white solid. 1H NMR (CDCl3): δ 7.40-7.22 (m, 9H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.92-6.88 (m, 1H), 6.28 (s, 1H), 5.19 and 4.22 (ABq, 2H), 3.92 (ABq, 2H), 3.56-3.50 (m, 1H), 3.48-3.40 (m, 2H), 3.33-3.27 (m, 1H), 3.13 (app t, 1H), 3.02 (app t, 1H), 2.35 (s, 3H). LRMS (ESI): 398.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[C:18]3[CH2:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.C(O)(C)C>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[C:18]3[CH2:25][CH2:26][CH2:27][C:28]([F:30])([F:29])[F:31])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cncc(CCCC(F)(F)F)c3c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: FC(F)(F)CCCc1cncc2ccc(OC3CCNCC3)cc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
42 mg of compound 89 were dissolved in 5M hydrochloric acid in isopropanol. The solution was stirred at room temperature for 2 hrs and another 2 hrs at 40° C., evaporated to dryness and taken up in water and lyophilized three times to give 32 mg of the desired product as the hydrochloride salt. LCMS Method # 1, retention time 0.98 min, detected mass 338.16 [M+H]+
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[N:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[N:26]=4)=[CH:23][CH:24]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CC(=O)OC(C)(C)C)n4)cc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(CC(=O)O)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)acetate (66 mg, 0.13 mmol) in DCM (1 mL) was added dropwise TFA (1 mL) at 0° C. under N2. The reaction mixture was stirred at ambient temperature overnight. The solvents were evaporated in vacuo. The residue was dissolved in saturated aqueous NaHCO3 solution and washed with Ether. The aqueous layer was acidified by slow addition of 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give (S)-2-(3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)acetic acid (48 mg, 82%). LCMS (APCI+) m/z 448.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:33][C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[CH3:32])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Reactant: CCOc1cccc([C@@H](C)N)c1
Agent: Cl
Product: CCOc1cccc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)NCCC(N)=O)cc3)C2)c1

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(3-ethoxyphenyl)-ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.37 (t, J=5.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.33 (br s, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.92 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.81 (br s, 1H), 6.74 (d, J=8.0 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.75-3.66 (m, 1H), 3.28-3.20 (m, 1H), 3.08-3.00 (m, 1H), 2.58-2.52 (m, 2H), 2.32 (t, J=7.3 Hz, 2H), 2.12-1.41 (m, 7H), 1.31 (t, J=7.0 Hz, 3H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:10]=1.[CH3:27][C@H:28]1[CH2:33][O:32][CH2:31][CH2:30][NH:29]1>C(Cl)Cl>[Cl:8][C:9]1[N:10]=[C:11]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][C@@H:28]2[CH3:27])[N:14]=1
Reactant: C[C@H]1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
Triethylamine (1.117 ml, 8.01 mmol) was added to 2,4-dichloro-6-[(4-fluorophenyl)sulfonylmethyl]pyrimidine (2.34 g, 7.29 mmol) in DCM (36.4 mL) at 0° C. followed by (3S)-3-methylmorpholine (0.737 g, 7.29 mmol) in DCM (20 mL) over 15 minutes. The reaction was then stirred at RT for 16 hours. The reaction mixture was washed with water (50 mL), the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a beige solid (1.530 g).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:38])[N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH2:21][C@@H:20]([NH2:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[C:41]([CH2:45][C:46](Cl)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CC#N>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C@H:22]2[CH2:21][C@@H:20]([NH:39][C:46](=[O:47])[CH2:45][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:19][NH:18][CH2:23]2)=[O:38])[CH2:36][CH2:37]1
Reactant: N[C@@H]1C[C@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)CC(=O)N[C@H]1CNC[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C1

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester; hydrochloride and tert-butyl acetyl chloride. MS (LC-MS): 440.5/442.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.28 min.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH2:1]([C@@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CC#N
Solvent: CO
Product: CC[C@@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 23.5 %

Procedure:
3-Ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Example 2 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile=660/170/170), and the compound having a shorter retention time was recrystallized (hexane/ethyl acetate) to give the title compound (47 mg).
Reaction SMILES: Br.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[N:13]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccc4ccccc4c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A mixture of 0.5 g of 4-(2-naphthyl)-thiazol-2-ylamine hydrobromide with 0.34 g of 4-methoxy-benzenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 10 ml of ethyl acetate and 15 ml of n-hexane yielded 0.19 g of 4-methoxy-N-(4-naphthalen-2-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:20][C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH:15]=[CH:14][C:13]=1[NH:16][CH:17]([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1N
Yield: 92.1 %

Procedure:
A solution of 14.7 parts of (4-fluorophenyl) [4-[(1-methylethyl)-amino]-3-nitrophenyl]methanone in 120 parts of ethanol was hydrogenated at 2.105Pa with 3 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 12.3 parts (92.1%) of [3-amino-4-[(1-methylethyl)amino]phenyl] (4-fluorophenyl)-methanone as a residue (int. 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#N>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1S
Product: CCOC(=O)Cc1nc2ccccc2s1
Temperature: 120 °C
Yield: 72 %

Procedure:
Ethyl 2-(benzothiazol-2-yl)acetate was prepared by the method of Abbotto, Bradamante et. al. ( J. Org. Chem. 2002, 16, 5753). A neat mixture of 2-aminothiophenol (6.94 g, 50 mmol) and ethyl cyanoacetate (5.65 g, 50 mmol) was heated at 120° C. for 3 hours at which time TLC analysis indicated that the reaction was complete as judged by the disappearance of starting material. The dark orange mixture was diluted with ethyl acetate/hexanes and purified by flash chromatography using 10-20% ethyl acetate/hexanes (Rf0.35, 10% ethyl acetate/hexanes) as an eluant. After concentration by rotary evaporator, ethyl 2-(benzothiazol-2-yl)acetate could be obtained as a yellow oil in 72% yield (7.97 g). LCMS: 222.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccsc1
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Cc1ccc(Cl)c(Cl)c1)c1cccs1

Procedure:
Using the procedure described in Example 4A, 100.0 g of 3,4-dichlorophenylacetic acid, 242.0 g of thiophene and 144.0 g of trifluoroacetic anhydride gave from methanol 61.7 g of 2-(3,4-dichlorophenyl)-1-(2-thienyl)ethanone, m.p. 59.5-60.5.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C@H:2]1[C@H:7]([O:8][C:9]2[N:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: C[C@H]1[C@H](Oc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NCCC[C@H]1Oc1ncc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To the title compound of step A (813 mg) in DCM (6 mL) was added TFA (2 mL). After 1 h, the reaction was diluted with saturated Na2CO3 (aq) and extracted with DCM. The organic layers were dried (MgSO4) and concentrated to give the title compound (452 mg) that was used without further purification.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:21][C:22]1[C:23](O)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=3)[CH2:8][CH2:7]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>CC#N>[Br:34][CH2:12][C:8]1[N:9]=[CH:10][S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ncsc1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1ncsc1-c1ccccc1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
Prepare a cold (0° C.) solution of (5-phenyl-thiazol-4-yl)-methanol (1.4 g, 7.3 mmol) in CH3CN (50 mL). Add PPh3 (2.6 g, 9.7 mmol) and CBr4 (3.2 g, 9.7 mmol). Stir the reaction at 0° C. for 3 hours, allow to warm to room temperature and then concentrate in vacuo to an oil. Chromatograph (silica gel, 4:1 Hex/ethyl acetate) to afford the title compound (400 mg). 1H NMR (CDCl3) δ 8.80 (s, 1H), 7.40-7.60 (m, 5H), 4.65 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH:17][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1ncccc1N
Yield: 71.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (9.4 g, 59 mmol), glycine ethyl ester hydrochloride (10.8 g, 77 mmol), and K2CO3 (21.3 g, 154 mmol) in toluene (100 mL) was refluxed overnight. The mixture was then filtered, concentrated, and subjected to chromatography (20% EtOAc/hexanes). The resulting yellow solid was dissolved in EtOH (300 mL), treated with Raney Ni (2 g) and hydrogenated at 40 psi H2 overnight. The mixture was filtered, concentrated and chromatographed (2-5% MeOH/CH2Cl2) to provide 34A (1.25 g, 14%) and N-(3-amino-2-pyridinyl)glycine ethyl ester (8.2 g, 71%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][CH3:7].O.Cl[CH2:10][C:11]([CH3:13])=[CH2:12]>C(Cl)(Cl)Cl>[OH:3][CH2:4][CH2:5][N:6]([CH3:7])[CH2:10][C:11]([CH3:13])=[CH2:12]
Reactant: CNCCO
Reactant: C=C(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)CN(C)CCO

Procedure:
20.0 g of sodium hydroxide was added to 56.33 g (0.75 mol) of 2-hydroxy-N-methylethylamine and 101.61 g water, after which 45.28 g (0.50 mol) of 1-chloro-2-methyl-2-propene was slowly added dropwise at room temperature. Upon completion of the dropping, the system was allowed to react for 15 hours at 80° C. Upon completion of the reaction, the 150 g of chloroform added and the system was washed with a sodium carbonate aqueous solution to remove the unreacted 2-hydroxy-N-methylethylamine, 2-hydroxy-N-methylethylamine hydrochloride, and sodium hydroxide, which yielded a chloroform solution of N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine. 150 g of a 4 N hydrochloric acid aqueous solution was added to the chloroform solution, the N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine was converted into a hydrochloride and extracted into the aqueous phase, and the water was removed by freeze drying, which yielded 55.50 g (0.34 mol; 67% yield) of 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride in the form of a white powder. The structure of the 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride thus obtained was confirmed by 1H-NMR (400 MHz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10](Cl)[CH3:11].[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][N:26]1[CH2:25][CH2:24][CH:23]([C:20]2[C:19]3[CH:29]=[CH:30][C:16]([F:15])=[CH:17][C:18]=3[O:22][N:21]=2)[CH2:28][CH2:27]1
Reactant: CC(Cl)CNc1cnn(C)c(=O)c1Cl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc(NCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
2.4 g (10 millimoles) of 4-chloro-5-(2-chloropropylamino)-2-methyl-2H-pyridazine-3-one, 40 ml of acetonitrile, 2.46 g (11 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 2.8 g of potassium carbonate and 0.18 g potassium iodide are admixed. The reaction mixture is heated to boiling under stirring for 24 hours, cooled to room temperature and filtered. The filtered product is suspended in 100 ml of water under stirring and refiltered. The crude product is recrystallized from acetonitrile. Thus 2.4 g of the desired compound are obtained. Yield 57.3%. Mp.: 200–202° C.