Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>O.C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: O=CCCl
Reactant: COc1nc(N)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1nc(Cl)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 1.7 g (0.011 mole) of 4-amino-6-chloro-2-methoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled in an ice bath with concomitant neutralization with sodium bicarbonate. The mixture was extracted with three 50 ml portions of chloroform which were then dried over magnesium sulfate and evaporated. The residue obtained was dissolved in boiling benzene, treated with decolorizing charcoal, and filtered. The residue which was obtained by evaporation of the filtrate was triturated with diethyl ether to provide a yellow solid. The solid was purified on a preparative scale high pressure liquid chromatograph, using a mixture of 75% ethyl acetate/25% hexanes as the eluent. Recrystallization from cyclohexane gave white solid 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine, m.p. 115°-118° C. Analysis: Calculated for C7H6H3OCl: %C,45.8; %H, 3.3; %N, 22.9; Found: %C, 45.4; %H, 3.1; %N, 23.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 46.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and morpholine (41.1 μl, 472 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (33 mg, 46.6%) as white solid. mp: >280° C., MS: m/z=451.1 (M+H+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C@H:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:7][C:5]([C@H:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)[C@@H](O)[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](CC(C)C)[C@H](O)C(=O)OC
Reaction time: 8 h

Procedure:
2.1 ml of allyl bromide were added to a solution of 4.52 g of methyl 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoate and 7.9 g of caesium carbonate in 30 ml of dimethylformamide. The mixture was stirred overnight and then evaporated. The residue was dissolved in dichloromethane and washed with 2M aqueous hydrochloric acid. The dichloromethane phase was then dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetatelhexane (1:9 increasing to 2:8) for the elution. There were obtained 2.88 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-hydroxy-5-methylhexanoate in the form of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH2:26])[CH2:19][CH2:18][CH2:17][C:16]2=1>>[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH:26][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[CH2:19][CH2:18][CH2:17][C:16]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1c(F)cccc1F
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1c(F)cccc1F

Procedure:
N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide was prepared from 2,6-difluorobenzoylchloride and 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid: 1H-NMR (CDCl3): δ 8.80 (s, 1H), 7.60 (m, 1H), 7.35 (m, 1H), 7.23 (overlapped dd and d, 2H), 6.94 (t, 2H), 6.37 (d, 1H), 5.35 (m, 1H), 2.7 (m, 2H), 2.26 (m, 1H), 1.95 (m, 3H); MS m/z 404 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Fc1ccc([C@H]2C[C@@H](CI)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1.74 g of cis-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 1.5 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one and 0.8 g of potassium carbonate in 20 ml of dimethylformamide is heated with stirring at 70° C. for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue is recrystallized from ethanol to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one as colorless prisms, melting at 207.5°-208.5° C. The corresponding maleate melts at 207° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[C:13]([CH3:20])=[C:14]([N:19]3[CH2:30][C:25]4[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: BrCc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.55 mmol), 1,2-bis(bromomethyl)benzene (1.03 g, 3.91 mmol), potassium carbonate (540 mg, 3.91 mmol), and N, N-dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added into the reaction mixture and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain 208 mg (15% yield) of the title compound. Melting point: 164-166° C. (Ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[C:13]([CH3:20])[C:12]=2[N:21]2[CH2:26][CH:25]3[CH:23]([CH2:24]3)[CH2:22]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>O1CCOCC1>[F:28][C:2]([F:1])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:21]3[CH2:26][CH:25]4[CH:23]([CH2:24]4)[CH2:22]3)=[C:13]([CH3:20])[C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: C1COCCO1
Product: Cc1c(N2CC3CC3C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c12

Procedure:
The title compound is prepared in analogy to 6c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-aza-bicyclo[3.1.0]hex-3-yl]-3-methyl-4-methylamino-5-amino-benzoic acid amide (80 mg, 0.195 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (62 mg, 0.19 mmol), DIC (36 μL) and dioxane (5.0 mL).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=1.Cl>Cl[Ni]Cl.C(OCC)C>[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: Clc1ccc(Cl)cc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCc1ccc(CCCCCC)cc1
Reaction time: 3 h

Procedure:
Nitrogen was introduced into a flask (250 ml), and 10 ml of anhydrous diethyl ether was added, and 15 g of magnesium was added, and stirred. Hexyl bromide (0.61 mole) of 100 g mixed with 50 ml of diethylether was poured into a dropping funnel, and the mixture therein was slowly added into the flask over 1 hour. The reaction was carried out at 45° C. for 3 hours. The reaction product, Grignard, was poured into a dropping funnel. To the reactant was slowly added a mixture of 42 g of 1,4-dichlorobenzene (0.29 mol), 0.3 g of NiCl2 and 80 ml of diethylether, and the reaction was carried out at room temperature for 24 hours to obtain solid reaction product. 6 N HCl was slowly added so as to neutralize the solid reaction product, the product was extracted with diethyl ether and dried with anhydrous MgSO4, and the reaction product was separated by vacuum distillation (122° C./0.1 mmHg). The structure analysis of the compound was confirmed by 1H-NMR, which was shown in FIG. 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].I[CH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27].[OH-].[Li+]>CN1CCCC1=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([CH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCC(CC)CI
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A mixture of 2-benzyloxycarbonylaminomalonic acid diethyl ester (Bladon, C. M. J. Chem. Soc. Perkin Trans. 1990, 1, 1151–1158) (1.237 g), iodo-2-ethylbutane (1.272 g) and lithium hydroxide (0.287 g) in N-methylpyrrolidone (8 mL) was stirred for 2 days at room temperature and then diluted with ice water. The aqueous solution was extracted with ether and the product purified by chromatography on silica gel to give 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl ester (0.520 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][C@H:17]3[O:21][C:20](=[O:22])[N:19]([C:23]4[CH:24]=[CH:25][C:26]5[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=5[CH:33]=4)[CH2:18]3)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:43][CH2:42]1>O>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:42]=[CH2:43])[CH:11]=2)[C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][C@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]2)[C:8]1=[O:13]
Reactant: C1COCCO1
Reactant: Cn1c(=O)n(CCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c(=O)c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc2c(=O)n(CCC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c(=O)n(C)c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of the compound of Example 46 (0.33 mmol), tetrakis(triphenylphosphine)palladium(0) complex (0.016 mmol), vinylboronic anhydride pyridine complex (0.165 mmol) and K2CO3 (0.33 mmol) in dioxane (2.5 ml) and water (0.8 ml) was purged with argon. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed cooling to rt and was diluted with water and EA. The org. layer was separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The resulting material was sequentially crystallized from TBME/MeOH, EA/MeOH and finally DCM, affording the title compound as colourless crystals in quantitative yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[N:18]1([C:16]([C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
Methanesulfonyl chloride (0.179 mL, 2.302 mmol) was added to a solution of (2-amino-4-nitrophenyl)(morpholino)methanone (0.5783 g, 2.302 mmol) in pyridine (3 mL) at 0° C. After 30 min at 0° C., the pyridine solvent was evaporated under reduced pressure. The resulting brown oil was triturated with hot CH2Cl2 and filtered. The filtrate was concentrated and purified by silica gel chromatography, eluting with 30-100% EtOAc in hexanes, to give the expected product as yellow solid (108 mg, 14% yield). LCMS: (M+H)+=330.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.83 (1H, s), 8.24 (1H, d, J=2.26 Hz), 8.07 (1H, dd, J=8.41, 1.88 Hz), 7.61 (1 H, d, J=8.53 Hz), 3.69 (2H, d, J=4.02 Hz), 3.61 (2H, br. s.), 3.57 (2H, d, J=4.27 Hz), 3.16-3.22 (2H, m), 3.10 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH:12]([CH3:23])[C:13]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:22][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH:12]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33])[CH3:23]
Reactant: CC(C(=O)N(C)c1ccccc1)N(C(=O)CN)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C)C(=O)N(C)c2ccccc2)c1
Yield: 35.7 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.0 g of (RS)-2-(2-amino-N-phenylacetamido)-N-methyl-N-phenylpropionamide and 0.42 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from a mixture of acetonitrile and dimethylformamide (93-7 by volume), 0.5 g of (RS)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-N-phenylpropionamide melting at 214° C. is obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:13]=1[N+:20]([O-:22])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(-c2ccccc2)s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1sc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
2-Ethoxalylamino-5-phenylthiophene (2.75 g, 10 mmol) was dissolved in 20 ml of acetic anhydride, cooled to -15° C., and treated with a solution of 0.63 ml (10 mmol) of fuming nitric acid dissolved in 5 ml of acetic acid over a period of 30 minutes. After 10 minutes at this temperature, the solvents were evaporated, and traces of acetic acid were removed by stripping with toluene. The solid residue was suspended in 50 ml of ethanol, and 50 ml of water was slowly added. The mixture was stirred overnight, and the precipitate was isolated by filtration to yield 2.62 g (82%) of 2-ethoxalylamino-5-phenyl-3-nitrothiophene, melting at 139°-144° C. 1H-NMR (DMSO-D6, δ): 1.3 (t, 3H), 4.4 (q, 2H), 6.9 (t, 1H), 7.0 (t, 2H), 7.8 (d, 2H), 8.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:20]3[CH:21]=[CH:16][N:17]=[C:18]([NH:22][CH:23]4[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)[N:19]=3)[S:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2cc(B(O)O)sc2c1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: COc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1

Procedure:
The title compound was prepared analogous to Method C, starting 6-methoxy-benzo[b]thiophen-2-boronic acid and (4-Chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([O:28][CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:2][C:3]2[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Yield: 36.1 %

Procedure:
4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 164, 100 mg, 0.27 mmol), (4-chloro-2-methoxyphenyl)boronic acid (55 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), aqueous potassium carbonate solution (1.8 M, 0.45 mL, 0.804 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 6 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (1×30 mL). The organic layer was separated and back-washed with brine (2×20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give an orange oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (38 mg, 36%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH4+:18].[OH-]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:18])=[N:13][CH:12]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccc(Br)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cn2)cn1
Temperature: 120 °C

Procedure:
5-Bromo-2-((6-chloro-3-pyridinyl)sulfonyl)pyridine (298 mg, 0.89 mmol), NH4OH (aqueous, 3 mL), and EtOH (3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 120° C. for 2 h. After cooling to room temperature, the solvent was partially removed under vacuum. The white precipitate obtained was filtered, washed with ether, and dried under vacuum to provide 5-((5-bromo-2-pyridinyl)sulfonyl)-2-pyridinamine (280 mg) as a white solid that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:16](OC(C)=C)(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([C:12]([F:15])([F:13])[F:14])[C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:18])[CH3:17]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1ccc2c(c1C(F)(F)F)CNCC2
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(N)c(C(F)(F)F)c2C1

Procedure:
7-Amino-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (8.7 g., 0.04 m.) is treated with isopropenyl acetate (8.0 g., 0.08 m.) in refluxing ethyl acetate to give N-acetyl-7-amino-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:15]1([CH:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]1([CH:21]([N:23]2[CH2:24][CH2:25][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:27][CH2:28]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.80 mmol), 1-(1-phenylethyl)piperazine (342 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.98 mmol) in DMF (4 mL) were stirred and heated at 80° C. for 30 minutes. The mixture was cooled to ambient temperature then applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Fractions containing pure product were evaporated to give a solid which was recrystallised from MTBE/isohexane to give 6-[4-(1-phenylethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (516 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]([N:13]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([N:13]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(N(CC)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(CC)c2ccccc2)cc1)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a three-necked flask, 40 ml of toluene, 9.9 g (60 mmol) of triethoxysilane and 0.018 mmol of diplatinum (0) tris(tetramethyldivinyldisiloxane)in toluene were placed, and 20 ml of a toluene solution containing 7.6 g of 4-(N-ethyl-N-phenylamino)styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and then the solvent was removed under reduced pressure to obtain oily pale yellow 4-(N-ethyl-N-phenylamino)-[2-(triethoxysilyl)ethyl]benzene in an amount of 7.8 g.