Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]([C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: CNc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C(=O)c1ccc(Cl)nc1)c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
6-Chloronicotinoyl chloride (353 mg, 2.0 mmol) was dissolved in anhydrous DMF (2 mL) and slowly added to a stirring solution of 4-fluoro-N-methylaniline (242 μL, 2.0 mmol) and DBU (300 μL, 2.0 mmol) in anhydrous DMF (2 mL). After 90 minutes, the DMF was removed in vacu and the reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and dried in vacu. The crude solid was purified by silica plug (1:1 ethyl acetate/hexanes) to yield 6-Chloro-N-(4-fluoro-phenyl)-N-methyl-nicotinamide as an off-white, glassy solid (411 mg, 77%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccncc1
Product: Cc1c2n(c3c(-c4ccncc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (29 mg, 38%), MS (ISP) m/z=303.5 [(M+H)+], mp 307° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyridin-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: Cl.O.C([NH:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[C:12]3[S:13][C:9]=2[CH:8]=1)(=O)C>COCCO>[NH2:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[C:12]3[S:13][C:9]=2[CH:8]=1
Reactant: CC(=O)Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a mixture of 100 ml of concentrated hydrochloric acid solution and 300 ml of methylcellosolve was added 8.5 g of 7-acetamido-2-phenylimidazo[2,1-b]benzothiazole mono-hydrate and the mixture was stirred for 4 hours at 100°-110° C. The reaction mixture was cooled to form crystals, which were recovered by filtration. The crystals were suspended in 200 ml of methylcellosolve and after alkalifying the suspension by adding concentrated aqueous ammonia, 80 ml of water was added to the mixture followed by cooling, thereby crystals precipitated. The crystals precipitated were recovered by filtration and dried to provide 5.76 g of 7-amino-2-phenylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1ccc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To a solution of 50 mg (0.15 mmol) 2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid methylamide in 2 ml THF 0.2 ml of a 1 M solution (0.2 mmol) of potassium hexamethyldisilazide in THF was added at 0°. After 20 min. 0.028 ml (0.15 mmol) 3,5-bis(trifluoromethyl)benzyl bromide was added dropwise to the resulting suspension. The reaction was quenched with water after 1.5 h. The mixture was diluted with 5 ml 2 N NaOH solution and extracted with 3 5-ml portions of ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated. Chromatography (SiO2, CH2Cl2/methanol 19:1) gave 25 mg (29%) 2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, MS (ISP): 550.5 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:41])[CH2:20][S:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:41])[CH2:20][SH:21])[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CS
Yield: 25.2 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(tritylthio)acetyl)phenyl)benzamide 114 (0.799 mmol, 475 mg), trifluoroacetic acid (40.4 mmol, 3 mL) and triethylsilane (0.799 mmol, 0.129 mL) in CH2Cl2 (10 mL) was stirred 1 h at room temperature. Evaporated to dryness and purified by chromatography (10% ethyl acetate in CH2Cl2) gave 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetyl)-4-methylphenyl)benzamide 115 (71 mg, 25%). NMR (400 MHz, CDCl3) 1.79 (s, 6H), 2.51 (s, 3H), 3.93 (d, J=7.4 Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.54 (m, 2H), 7.72 (dq, J=7.8 Hz and 1.2 Hz, 1H), 7.80 (dt, J=7.8 Hz and 1.6 Hz, 1H), 7.90 (br s, 1H), 8.00 (t, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:24]([O:28][C:29]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:30])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)COC(=O)Cl
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)COC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with isobutylchloroformate (54 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.42 min, m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH2:38][N:39]([C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:34]
Reactant: CCOC(=O)CCNCCc1ccccc1
Reactant: Cc1ccnc(CC(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(CCc1ccccc1)C(=O)Cc1cc(C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
(4-Methyl-pyridin-2-yl)-acetic acid (1.0 g), carbonyldiimidazole (CDI, 1.07 g) and DIPEA (0.856 g) were added to THF (15 ml) and the light brown suspension was allowed to stir at RT for 1 hour. To the mixture was added 3-phenethylamino-propionic acid ethyl ester (0.898 g) dropwise and the resulting mixture was stirred at 55° over night. The mixture was poured into ice/water and the pH was adjusted to 5.0. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 2:1) to give the desired product as a light brown liquid (0.462 g). MS (ESI): 355.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][CH2:31]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: CCc1ccccc1N1CCNCC1
Product: CCc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Yield: 70.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:15]=1)=[O:13])[CH3:9]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 63.3 %

Procedure:
The general procedure 1 was then followed using 1-chloro-3-dimethylaminopropane (7 mmol, 0.75 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)ethyl]-1H-indol-3-yl}-2-oxoacetate (3.8 mmol, 63%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=3023; 2962; 2917; 1732; 1630. EI-MS m/z (rel. int.)=302 (8.21%; M+•.). 1H NMR (300 MHz, CDCl3) 8.43 (m; 1H; indole-H); 8.39 (s; 1H; indole-H); 7.33 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.27 (t; 3J=6.8 Hz; 2H; indole-CH2CH2CH2N); 2.22 (s; 6H; N(CH3)2); 2.20 (m; 2H; indole-CH2CH2CH2N); 2.00 (quint; 3J=6.7 Hz; 2H; indole-CH2CH2CH2N); 1.42 (t; 3J=7.1 Hz; 3H OCH2CH3).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.[Br:19]Br.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:19][C:13]1[C:12](=[O:14])[C:11]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[O:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: CSc1ccc(C2=CC(=O)C3(CCCC3)O2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 147 mg of 2-{4-(methylthio)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one in 30 ml carbon tetrachloride, were added 1 ml bromine and 0.1 ml acetic acid. The reaction mixture was stirred for 1 hour at room temperature. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate solution until the characteristic color of bromine disappeared. The quenched solution was extracted with dichloromethane (10 ml×3). The organic layer was concentrated under reduced pressure and the resulting residue was purified by column chromatography (hexane/ethylacetate) to yield 50 mg of 3-bromo-2-{4-(methylthio)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one. NMR: δ1.98 (m, 4H), 2.11 (m, 4H), 2.55 (s, 3H), 7.32 (d, J=8.7 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH:15]([Mg]Br)=[CH2:16].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:16]=[CH:15][NH:12][C:5]2=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccc(Cl)c2ncccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2cc[nH]c2c2cccnc12
Reaction time: 0.67 h
Yield: 20.6 %

Procedure:
To a stirred solution of 8-chloro-5-nitroquinoline (5.0 g, 24 mmol) in tetrahydrofuran (70 mL) at −78° C. under Ar was added a solution of vinylmagnesium bromide (1.0 M in tetrahydrofuran, 72 mL, 72 mmol) over 5 min. The mixture was stirred for 40 minutes, poured into aqueous ammonium chloride solution (200 mL) and extracted with ether (3×100 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give 5-chloro-1H-pyrrolo[2,3-f]quinoline as an orange solid (1.0 g, 21%): mp 248-250° C.; IR νmax (Nujol)/cm−1 3198, 2924, 2854, 1500, 1465, 1377, 1364, 1290, 1162, 1126, 1085, 949, 887, 810, 780, 744, 706, 633, 599 and 512; NMR δH (400 Mz, CDCl3) 6.64 (1H, d, J 3 Hz) 7.56 (1H, t, J 4 Hz) 7.65 (1H, dd, J2.5, 8.5 Hz) 8.14 (1H, s) 8.83 (1H, d, J 8.5 Hz) 8.88 (1H, d, J 2.5 Hz) 12.37 (1H, m).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][C:12]2([CH2:24][O:25][C:26](=[O:34])[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[S:14][CH2:13]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[C:28]1([NH:27][C:26]([O:25][CH2:24][C:12]2([CH2:11][O:10][C:8](=[O:9])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[S:14](=[O:36])[CH2:13]2)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1cccc2c1C(=O)C(COC(=O)Nc1ccccc1)(COC(=O)Nc1ccccc1)CS2
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc2c1C(=O)C(COC(=O)Nc1ccccc1)(COC(=O)Nc1ccccc1)CS2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,3-bis(phenylcarbamoyloxymethyl)-5-methylthiochroman-4-one (190 mg, 0.4 mmol) in MeOH (5 ml) was admixed with a solution of sodium metaperiodate (92 mg, 0.43 mmol) in water (1 ml), and stirred at RT for 72 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 1:1 cyclohexane/EtOAc), the desired product was obtained as a white solid (190 mg, 89% of theory, m.p. 76-82° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14](OC)=[O:15])[CH2:12][N:11]([CH3:18])[C:10]2=[O:19])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[BH4-].[Na+]>CCO>[F:23][C:20]([F:21])([F:22])[C:4]1[CH:5]=[C:6]([N:9]2[C@@H:13]([CH2:14][OH:15])[CH2:12][N:11]([CH3:18])[C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)[C@H]1CN(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1C[C@H](CO)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 69.5 %

Procedure:
To a solution of (R)-methyl 3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylate (25f) (0.330 g, 1.01 mmol) in EtOH (20 mL), cooled to 0° C., Sodium borohydride (0.045 g, 1.21 mmol) was added portion wise maintaining the temperature at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for further 6 h. After completion (by TLC) the volatiles were removed under reduced pressure and the crude residue was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude reaction mixture which was purified by column chromatography to afford the alcohol 25g (0.21 g, 69%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2s1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2s1
Temperature: 120 °C

Procedure:
To a glass microwave vial was added benzo[d]thiazol-2-yl(4-(3-bromopyridin-2-yloxy)phenyl)methanone (1.0902 g, 2.65 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.114 g, 5.30 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.149 g, 0.212 mmol), and sodium carbonate (0.843 g, 7.95 mmol) in DMF (6.63 mL) and water (2.209 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 120° C. for 20 min. Solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 5% to 50% EtOAc in hexane, to provide benzo[d]thiazol-2-yl(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 414.8 (M+1).
Reaction SMILES: [NH4+]=S.C(O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([N+:13]([O-])=O)[CH:12]=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([F:17])([F:18])[F:19])=[C:11]([CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1C(F)(F)F
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1C(F)(F)F
Temperature: 75 °C

Procedure:
Aqueous ammonium sulfide (60 g., 52-60%) is added dropwise to a warm (75° C.), stirred ethanol solution of 5-chloro-2-trifluoromethylnitrobenzene (22.6 g., 0.1 mole) and the resulting mixture is heated for four hours at a heating bath temperature of 97° C. and then allowed to cool to room temperature. The reaction mixture is poured into water, and the organic product is extracted with diethyl ether. After washing and drying the ether solution, the ether is removed by evaporation to give 5-chloro-2-trifluoromethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:22])=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: O=C(O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reaction time: 2.5 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid (100 mg, 0.33 mmol) in dry DCM (1 mL), was added DMF (1 drop) followed by addition of oxalyl chloride (35 μL, 0.40 mmol) slowly. The mixture was stirred for 2.5 hrs, then concentrated to yield 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl chloride, which was dissolved in DCM (1 mL). 2-Methylamino-phenol (45 mg, 0.36 mmol) was added followed by the slow addition of diisopropylethylamine (88 μL, 0.5 mmol). The mixture was stirred at room temperature for 12 hrs, concentrated and purified by preparative TLC (DCM/MeOH=9/1) followed by preparative LCMS to yield 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide 19-1. MS (M+H)+: 409.0, tR=7.55 min (method 2)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[CH3:36][O:35][C:33]1[CH:32]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:34]=1)[C:29]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:30]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1cc(OC)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethoxy-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH:19]1([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:24][C:25]([NH:12][C:10]2[S:11][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[C:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)CC3CCCC3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and cyclopentyl-acetyl chloride.
Reaction SMILES: ON=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([OH:17])C.S(=O)(O)[O-].[Na+]>O>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:3](=[O:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Reactant: CCO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)c1csc(N)n1
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.37 g), ethanol (5 ml), water (5 ml) and sodium bisulfite (0.72 g) was stirred for 12 hours at 65° to 70° C. The reaction mixture was concentrated and water (10 ml) was added to the residue. The resulting mixture was subjected to salting-out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give yellow crystals of ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate (0.18 g), mp 115° to 120° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:26])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:26])[CH2:15][N:16]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1

Procedure:
To a solution of 8.7 g (45.2 mmol) of 4-hydroxybenzenesulfonyl chloride in 80 ml of CH2Cl2, a solution of 6.75 g (32.3 mmol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 20 ml of CH2Cl2 and 12 ml (79.2 mmol) of triethylamine were added dropwise at 0° C. The resulting mixture is stirred for 4 h at r.t., neutralized with cold 1N aqueous HCl and extracted with CH2Cl2. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:CH2Cl2=50:1˜5:1) to give [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester; NMR (CDCl3): 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.40 (s, 2H), 5.59 (s, 1H), 6.84 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=10.64 Hz), 7.15 (d, 2H, J=8.6 Hz), 7.82 (d, 2H, J=10.64 Hz).