Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][C:11](=[O:43])[NH:10][C@H:9]([CH:44]([CH3:46])[CH3:45])[C:8](=[O:47])[NH:7][C@H:6]([CH3:48])[C:5](=[O:49])[NH:4][C@@H:3]1[CH:50]([CH3:52])[CH3:51].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][SH:23])[CH2:12][C:11](=[O:43])[NH:10][C@H:9]([CH:44]([CH3:46])[CH3:45])[C:8](=[O:47])[NH:7][C@H:6]([CH3:48])[C:5](=[O:49])[NH:4][C@@H:3]1[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCS)OOC(=O)C[C@@H]1O
Reaction time: 1 h

Procedure:
To a solution of 9 (24.7 mg, 0.035 mmol) in CH2Cl2 (1.4 mL) was added triethylsilane (28 μL, 0.175 mmol) followed by the dropwise addition of TFA (0.35 mL, 25% v/v). After stirring for 1 h the reaction mixture was concentrated in vacuo and put under high vacuum for 2 h to give the crude thiol 10. At 0° C. to a solution of thiol 10 in CH2Cl2 (0.45 mL) was added diisopropylethylamine (30 μL, 0.172 mmol) followed by acetyl chloride (2.43 μL, 0.034 mmol) in CH2Cl2 (0.1 mL). After stirring for 2 h 10 min 1M HCl (1 mL) was added followed by EtOAc (10 mL) the layers were separated and the organic layer was washed with sat. brine (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave the product 11 (7.3 mg, 0.014 mmol, 41%) as a white solid: Rf 0.47 MeOH/CH2Cl2 (1:9).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClC(Cl)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][C:13](=[O:14])[N:12]([CH3:16])[CH3:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1O
Reactant: CN(C)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc(F)ccc1C#N
Yield: 67 %

Procedure:
Under N2, a stirred solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606 mg, 6 mmol) in dichloroethane (10 mL) was heated at reflux for 20 hrs. The cooled mixture was diluted with dichloroethane (10 mL) washed with water, and brine. The organic layer was separated, dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2, 5% ethyl acetate-CH2Cl2) to provide 700 mg (Yield 67%) of the title compound as a white crystalline solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C10H10N2O2F (M+H) 209.0726. found 209.0722.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][SH:11]>>[NH2:8][CH2:9][CH2:10][S:11][CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1
Reactant: NCCS
Reactant: OCc1csnn1
Product: NCCSCc1csnn1

Procedure:
Reacting 4-hydroxymethyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[(2-aminoethyl)thiomethyl]-1,2,3-thiadiazole. From this compound by the procedures of Example 1, 2 and 3, the following products are prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[N:15]([CH3:28])[C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)[C@H](c2ccccc2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-chloro-phenoxy)-phenyl]-5-(S)-phenyl-imidazolidine-2,4-dione (10.0 mg, 0.026 mmol) in anhydrous DMF (0.5 mL) are added K2CO3 (7.3 mg, 0.052 mmol) and MeI (4.93 μL, 0.078 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparative LC/MC to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.31 (m, 7H), 7.26 (d, 2H), 6.90 (m, 4H), 5.42 (s, 1H), 3.16 (s, 3H); HPLC-MS calculated for C22H17ClN2O3 (M+H+) 393.1, found 393.1.
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:29][NH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]1=[O:36])C1C=CC=CC=1>C(O)C.CN(C)C=O.[Pd]>[CH2:34]([O:33][C:31]([NH:30][NH:29][C:11]1[C:10](=[O:36])[N:9]([OH:8])[C:18]2[C:13]([N:12]=1)=[CH:14][C:15]([N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH3:28])=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)=[O:32])[CH3:35]
Reactant: CCOC(=O)NNc1nc2cc(-n3ccnc3C)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)NNc1nc2cc(-n3ccnc3C)c(C(F)(F)F)cc2n(O)c1=O

Procedure:
A solution of 1.4 g (~2.8 mmol) 1-benzyloxy-3-(2-ethoxycarbonylhydrazino)-6-(2-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in a mixture of 100 ml ethanol and 50 ml N,N-dimethylformamide was hydrogenated at atmospheric pressure by using 0.15 g 5% Pd-C as a catalyst. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound as a crude product (1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccccc21

Procedure:
44.1 g (0.3 mol) of isatin, 62.5 g (0.45 mol) of potassium carbonate and 66.2 g (0.34 mol) of bromoacetic acid tert-butyl ester (from Aldrich) are stirred in 100 ml of N,N′-dimethylformamide at room temperature for 24 hours. The mixture is then poured into 800 ml of water, and the precipitate formed is filtered off, washed with water and dried at 60° C. After recrystallising once from toluene-hexane (1:1), 608 g (78% of theory) of product having a melting point of 119-121° C. are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C)C=O>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2nc3ccccc3[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4nc5ccccc5[nH]4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-benzimidazol-2-yl)-benzenamine (0.048 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541F: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[OH-].[K+].O>CS(C)=O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2-chloro-5-trifluoromethylpyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 2.5 hours. The solution was cooled to room temperature and poured slowly into water (200 mL). After cooling with an external ice-bath, the precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.56 g, 95% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].C1C2C=CC3C(=CC=C4C=3C=CC=C4)C=2C=C(C=O)C=1.NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]2[CH:27]=[CH:26][C:25]3[C:24]([C:15]=2[CH:14]=1)=[CH:23][CH:22]=[C:21]1[C:16]=3[CH:17]=[CH:18][CH:19]=[CH:20]1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CC(N)(CO)CO
Agent: O=Cc1ccc2ccc3c4ccccc4ccc3c2c1
Product: CC(CO)(COS(C)(=O)=O)NCc1ccc2ccc3c4ccccc4ccc3c2c1

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-3-carbaldehyde (19G) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((3-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 180°-182° (dec), (EtOH/Et2O), (C, H, N, S).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][O:57][CH2:56][CH2:55][O:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:58][O:57][CH2:56][CH2:55][O:54]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3COCCO3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6COCCO6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dioxane-2-carboxamide (68 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (44 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:25]=[C:26](/[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)\[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (69 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol) L-proline (7 mg, 0.063 mmol) and potassium phosphate (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) followed by HPLC. Yield: 13 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.62 (d, 2H), 7.58 (d, 1H), 7.22 (m, 2H), 7.10 (s, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.20 (m, 2H), 3.15 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: NNc1cc(Br)c(Cl)cc1C(=O)O
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Cl)c(Br)c23)C1
Temperature: 105 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105° C. overnight. After 16 h, more acetic acid (6 mL) and ethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was heated at 110° C. for 4.5 h. The mixture was concentrated, and the residue was combined with toluene (100 mL) and TFA (20 mL). The suspension was heated at 90° C. overnight. The cooled mixture was concentrated and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with EtOAc and air-dried to give 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[CH:15]=[CH:14][S:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2sccc2c1O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sccc2c1O
Temperature: 190 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (0.447 g) and 4-chlorobenzylamine (2.43 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene (5 mL). The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield an off-white solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.285 g (45%) of the title compound as a white solid.
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3]([NH2:5])=[S:4].Br[CH:9]1[CH2:14][CH:13]([CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][C:10]1=O.C(OCC)(=O)C>C(O)C>[CH:15]([CH:13]1[CH2:14][CH2:9][C:10]2[N:5]=[C:3]([NH:2][C:1]([NH2:7])=[NH:6])[S:4][C:11]=2[CH2:12]1)([CH3:17])[CH3:16]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: NC(=S)N=C(N)N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C1CCc2nc(NC(=N)N)sc2C1

Procedure:
2-imino-4-thiobiuret (5 mmol) is added accompanied by stirring to a solution of 2-bromo-4-isopropyl-cyclohexanone (5 mmol) in ethanol (10 ml) and the reaction mixture is then refluxed for 16 hours. After evaporating-off of the solvent ethyl acetate is added to the residue and the precipitated-out product is isolated by filtering off: tR 2.75 min (LC-1, one peak); ESI-MS (+/−): m/z 239.25 [M+H]+/237.24 [M−H]−.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:20]([Mg]Br)[CH3:21].C(OCC)C>C1COCC1>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:20][CH3:21]
Reactant: CCOC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(C(O)CC)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Ethyl 4-(6-formylpyridin-3-yl)benzoate (500 mg, 1.9 mmol) in THF (15 mL) was cooled to 0° C., 3M Ethyl magnesium bromide in diethyl ether (1.3 mL, 3.9 mmol) was slowly added at 0° C., and the reaction mixture was stirred for 2 h at 0° C., while monitoring reaction progress by TLC. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120 microns) using 15% ethyl acetate in hexane eluent to afford ethyl 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzoate as a brown liquid (250 mg, 44.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.13-8.11 (d, 1H), 8.04 (d, 2H), 7.87 (d, 2H), 7.57 (d, 1H), 5.33 (d, 1H), 4.57-4.53 (m, 1H), 4.35-4.30 (m, 2H), 1.89-1.76 (m, 1H), 1.68-1.34 (m, 1H), 1.24 (t, 3H), 0.86 (t, 3H), LC-MS m/z calcd for [M+H]+ 286.14. found 286.2.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>O.C(Cl)Cl>[C:12]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:15])[CH:13]=[CH2:14]
Reactant: NCCCCCC(=O)O
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.4 %

Procedure:
Sodium hydroxide (7.6 g, 190 mmol) and 6-aminohexanoic acid (10 g, 76 mmol) were dissolved in distilled water (50 mL) at room temperature. Acryloyl chloride (8.24 g, 91 mmol) in dry CH2Cl2 (50 mL) was slowly added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 10 h. The reaction was quenched by adding 10% HCl (20 mL, pH 3) at room temperature and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated to give a product as a white solid (11.6 g, 82%). This compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].I[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Reactant: CCI
Product: CCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and iodoethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 291 (M+, 6), 278 (29), 277 (11), 276 (bp), 70 (50).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CCN(CC)CCN
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Solvent: CC#N
Product: CCN(CC)CCNCCC(=O)Nc1nc(C)c(-c2ccnc(Nc3ccc(Cl)cc3)n2)s1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with N′,N′-diethyl-ethane-1,2-diamine. Anal. RP-HPLC: tR=11.8 min (10-70% MeCN, purity>97%). 1H-NMR (DMSO-D6) δ: 1.20 (t, 6H, J=7.0 Hz, CH3), 1.53 (d, 2H, J=6.5 Hz, CH2), 2.52 (s, 6H, CH3), 3.18 (m, 4H, CH2), 3.28 (m, 4H, CH2), 7.13 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 7.30 (m, 2H, Ph-H), 7.81 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).