Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2C=[CH:29][CH:28]=[CH:27][C:26]=2Cl)[N:8]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:9](=[O:19])[NH:10][C:11]=1[CH2:12][O:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])=[O:5])[CH3:2].C(N(CC)CC)C.[C:39](Cl)(=[O:48])[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[CH2:50]([Cl:52])Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:50]=2[Cl:52])[N:8]([CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:9](=[O:19])[NH:10][C:11]=1[CH2:12][O:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(=O)N(CCCNC)C1c1ccccc1Cl
Reactant: O=C(Cl)CCc1ccccc1
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(=O)N(CCCN(C)C(=O)CCc2ccccc2)C1c1ccccc1Cl
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of crude 6-(2-azido-ethoxymethyl)-4-(2-chloro-phenyl)-3-(3-methylamino-propyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (40 mg, 0.89 mmol) in CH2Cl2 (2 mL) was added triethylamine (25 μl, 18 mg, 0.179 mmol) followed by a solution of hydrocinnamoyl chloride (25 mg, 0.148 mmol) in CH2Cl2 (0.5 ml). After 3 h, the mixture was taken up in EtOAc (50 mL) and then washed with H2O (25 mL) and brine (25 mL). The organic extract was dried (Na2SO4), filtered, concentrated in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (35 g Redisep silica gel, 20 to 100% EtOAC in hexanes for 20 min, hold at 100% EtOAc for 15 min at 30 mL/min) to afford 27.6 mg (53%) of the purified material as a thick oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:32]
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), iodoethane (0.040 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (94.1 mg, 88% yield) as an off-white
Reaction SMILES: [CH2:1]([N:5]1[C:14]([O:15][C@H:16]2[CH2:20][N:19](C(OC(C)(C)C)=O)[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:32])[CH2:2][CH:3]=[CH2:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]([O:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:32])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cc2ccccc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCn1c(O[C@H]2CN[C@H](C(=O)OC)C2)cc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
A portion of the product from Step 1 (150 mg, 0.34 mmol) was dissolved in CH2Cl2 (4 ml), cooled in an ice bath, and then added TFA (4 ml). The reaction was allowed to warm to room temperature and stir for 1.5 hours. The reaction was concentrated and the resulting oil was partitioned between CH2Cl2 and sated NaHCO3, extracted with CH2Cl2 (2×), combined organics, washed with brine, dried organics over Na2SO4, filtered, concentrated in vacuo to yield the title compound as a oil (113 mg, 97%). LCMS (ES+) m/z 342.9 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)[CH2:3]1.CN(C)C=O.C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:37][S:38]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)[CH2:3]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide (prepared as described in example 4) (5.6 mg, 171 μmol) in tetrahydrofuran (1 mL) was added N,N-dimethylformamide (0.5 mL) to form a clear solution. Diisopropylethylamine (59.9 μL, 343 μmol) was added followed by methanesulfonyl chloride (20 μL, 257 μmol) and the mixture left to stir overnight at ambient temperature under argon. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (5 mL) and extracted with ethyl acetate (5×2 mL), the combined organic extracts were washed with brine (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a C-18 column gradient eluted from 10% acetonitrile in water to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo. The residue was lyophilized from water/ethanol to give (R)-2-(3-(methylsulfonamido)piperidin-1-yl)-5-(pyridin-2-ylamino)thiazole-4-carboxamide as an off-white lyophilized powder (41 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].I.CS[C:19](=[NH:28])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[NH:28][C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CSC(=N)Nc1ccc(O)cc1
Reactant: NNC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(Nc2nnc(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
4-chloro-3-trifluoromethylbenzoic acid hydrazide (2.89 g, 12.1 mmol) and S-methyl N-(4-hydroxyphenyl)isothiourea hydroiodide (3.75 g, 12.1 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a white solid (1.95 g). Yield 45.5%.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=[C:11](Cl)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:18]([NH:21][C:11]1[N:12]=[C:7]([NH:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=1)[CH:19]=[CH2:20]
Reactant: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCNc1nc(NNC(C)(C)C)c2scc(C)c2n1
Yield: 31.6 %

Procedure:
270 mg (1.0 mmol) of 4-(2-t-butylhydrazino)-2-chloro-7-methylthieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4] to give 92 mg (yield: 31.6%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CO.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:18]1([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 1B (7.65 g, 28 mmol) in THF (50 mL)-MeOH (50 mL) at RT was added phenylboronic acid (6.83 g, 56 mmol), PXPd (500 mg, 0.93 mmol), followed by K2CO3 (15.5 g, 112 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for 1 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was poured into water (100 mL), and the resultant mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (120 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an off-white solid (5.4 g, 72%). LC/MS (method A): retention time=3.07 min, (M+H)+=271.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:49]=1[NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:50][C:49]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:48]=4[Cl:47])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cc(C)ccc2Cl)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-chloro-5-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:16](Br)[CH:17]=[CH2:18].[In]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:18][CH:17]=[CH2:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Reactant: C=CCBr
Agent: [In]
Solvent: C1CCOC1
Product: C=CC[C@H](N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
To round bottomed flask equipped with a reflux condensor was charged 161A (2.4673 g, 8.56 mmol), allyl bromide (0.889 mL, 10.27 mmol) and THF (40 mL) to which was added indium (1.180 g, 10.27 mmol) and the mixture heated to 60° C. under nitrogen where it was stirred for overnight. The reaction mixture was quenched by addition of water (40 mL) and the mixture stirred for 15 min, diluted with EtOAc (30 mL), and the phases separated. The aqueous phase was extracted with EtOAc (2×) and the combined organics washed with brine, dried (Na2SO4), filtered and evaporated to give a faint yellow colored oil which was placed under vacuum for overnight to give 161B (3.18 g, 89%). 1H NMR (500 MHz, CDCl3) δ 7.50 (t, J=1.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.27-7.21 (m, 2H), 5.79-5.69 (m, 1H), 5.24-5.22 (m, 1H), 5.22-5.19 (m, 1H), 4.48 (ddd, J=8.1, 5.5, 2.1 Hz, 1H), 3.69 (s, 1H), 2.64-2.58 (m, 1H), 2.47 (dt, J=14.0, 8.4 Hz, 1H), 1.23 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[CH:11]=2)[CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH2:33].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH:33][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[CH:11]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Temperature: 140 °C
Yield: 13.2 %

Procedure:
A mixture of N-[6-(6-chloro-2-methoxy-pyrimidin-4-yl)-benzothiazol-2-yl]-acetamide (160 mg, 0.48 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (362 μL, 2.4 mmol), and K2CO3 (359 mg, 2.6 mmol) in N-methylpyrrolidinone (2.6 mL) is heated to 140° C. Water (20 mL) is added after 1 hour of heating and extracted with EtOAc (20 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. This residue is subjected to chromatography on silica gel eluting with 90% ethyl acetate:heptane to afford a solid which is triturated with 1:1 methanol:ethyl acetate. The solid is collected to afford N-(6-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzothiazol-2-yl)-acetamide [31 mg, 13%, Example 94]. LCMS RT=2.49 minutes, MS: 488 (M+H). IC50=11 nM
Reaction SMILES: S1C2C=CC=CC=2N=C1COC1C2C=C(F)C=CC=2SC=1C(NC(C)(C)C(O)=O)=O.C[O:32][C:33](=[O:62])[C:34]([NH:37][C:38]([C:40]1[S:44][C:43]2[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:42]=2[C:41]=1[O:50][CH2:51][C:52]1[CH:53]=[N:54][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:56][CH:57]=1)=[O:39])([CH3:36])[CH3:35]>>[F:49][C:47]1[CH:46]=[CH:45][C:43]2[S:44][C:40]([C:38]([NH:37][C:34]([CH3:35])([CH3:36])[C:33]([OH:62])=[O:32])=[O:39])=[C:41]([O:50][CH2:51][C:52]3[CH:53]=[N:54][C:55]([C:58]([F:60])([F:59])[F:61])=[CH:56][CH:57]=3)[C:42]=2[CH:48]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1OCc1ccc(C(F)(F)F)nc1
Agent: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1)C(=O)O
Product: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1ccc(C(F)(F)F)nc1)C(=O)O

Procedure:
2-{[5-Fluoro-3-(6-trifluoromethyl-pyridin-3-ylmethoxy)-benzo[b]thio-phene-2-carbonyl]-amino}-2-methyl-propionic acid was prepared in similar manner as 2-{[3-(benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid (example 158) via 2-{[5-fluoro-3-(6-trifluoromethyl-pyridin-3-ylmethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester (C21H18F4N2O4S (470.45), LCMS (ESI): 471.10 (MH+)).
Reaction SMILES: C[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].Cl[CH:23](C)C(N(C)C)=O>>[CH2:20]([CH:14]([N:5]1[C:6]([CH3:23])=[CH:2][C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4]1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH3:21]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CCC(Br)C(=O)N(C)C
Product: CCC(C(=O)N(C)C)n1nc(-c2ccccc2)cc1C

Procedure:
Following the procedure of Example 1, but substituting 3-methyl-5-phenylpyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide there was obtained α-ethyl-N,N,5-trimethyl-3-phenylpyrazole-1-acetamide having a melting point of 117°-119.5° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[C:13]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[C:7]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:6]=1)#[N:2].CO[C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[CH2:50][C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][CH:52]=1.[C:61]([O-:64])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.CCO.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>[CH2:25]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[CH:6][C:7]=2[CH2:29][CH:30]([CH3:32])[CH3:31])[CH:16]=[CH:15][C:14]=1[C:38]1[CH:39]=[CH:40][C:35]([O:64][CH3:61])=[C:36]([CH2:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[CH:37]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Cc1cc(-c2ccc(CCC#N)cc2CC(C)C)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cc1cccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2CC(C)C)cc1Cc1cccc2ccccc12
Temperature: 80 °C
Yield: 79.86 %

Procedure:
202.8 mg (0.43 mmol) Trifluoro-methanesulfonic acid 4′-(2-cyano-ethyl)-3,2′-diisobutyl-biphenyl-4-yl-ester (75), 186.7 mg (0.50 mmol, 1.16 eq.) 2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (64) and 74.5 mg (64.4 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 10 ml DME/EtOH (9+1). To this yellow solution 0.43 ml (0.86 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 22 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (CH2Cl2) yielded 194.3 mg (0.34 mmol, 79.86%) 3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile (76) as a clear oil. Rf (hexanes/EtOAc (6+1))=0.23. 1H-NMR (500 MHz, CDCl3): δ=0.52 (d, 6H, J=6.62 Hz, 2*CH3), 0.69 (d, 6H, J=6.62 Hz, 2*CH3), 1.46 (m, 1H, CH), 1.64 (m, 1H, CH), 2.23 (d, 2H, J=7.41 Hz, CH2), 2.45 (d, 2H, J=7.41 Hz, CH2), 2.61 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.93 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.91 (s, 3H, OCH3), 4.44 (s, 2H, CH2Naphthyl), 6.84 (d, 1H, J=2.21 Hz), 6.95 (d, 1H, J=8.67 Hz), 6.97-7.16 (m, 8H), 7.36 (m, 1H), 7.41-7.45 (m, 2H), 7.70 (m, 1H), 7.81 (m, 1H), 8.01 (m, 1H). MS (EI): m/z=565 (23), 468 (30), 467 (100), 425 (13), 374 (11), 368 (13), 335 (23), 334 (72), 327 (13), 324 (17), 319 (31), 293 (22), 292 (55), 279 (14), 278 (45), 277 (13), 276 (17), 264 (24), 263 (19), 251 (13), 250 (24), 249 (26), 248 (89), 237 (20), 236 (18), 235 (22), 234 (15), 233 (26), 221 (20), 220 (37), 217 (25), 215 (31), 179 (71), 178 (57), 165 (30), 160 (20), 142 (22), 141 (62), 115 (15), 91 (14), 57 (86), 55 (16). HR-MS (EI): Calcd. for C41H43NO: 565.334464. Found: 565.334507.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1cccnc1)c1ccc(Br)cc1
Yield: 94.1 %

Procedure:
According to the procedure described for example 26a the use of 4-bromo-benzenesulfonyl chloride (1.278 g, 5.0 mmol) in 10 mL dichloromethane and C-Pyridin-3-yl-methylamine (541 mg, 5.0 mmol) and triethylamine (708 μL, 5.0 mmol) in 5 mL dichloromethane gives 4-bromo-N-pyridin-3-ylmethyl-benzenesulfonamide (1.54 g) as a pale yellow oil which slowly crystallizes upon storage at ambient temperature. Further purification is not necessary. MS (m/e): 328 (M+H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(N([CH2:28][CH3:29])CC)C.[C:30]1([S:36]([Cl:39])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:39].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([N:22]([S:36]([C:29]4[CH:28]=[CH:32][CH:31]=[CH:30][CH:35]=4)(=[O:38])=[O:37])[S:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:38])=[O:37])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamide hydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) of N,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and 27.2 μl (0.21 mmol) of benzenesulfonyl chloride are added and the mixture is stirred at room temperature for 16 h. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 1N aqueous hydrochloric acid and acetonitrile, then again concentrated and dried under high vacuum. 33 mg (50% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[Cl:15])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
A mixture of 3.4 g (15.1 mmol) of 6-(4-hydroxy-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared according to the methods described in Eur. Pat. Appl. 178,189A2, 4.87 g (18.2 mmol) of N-(3-bromopropyl)phthalimide, and 2.30 g (16.6 mmol) of anhydrous K2CO3 in 80 ml of DMF is heated for 3 hrs at 100° C. The DMF is removed under vacuum and 150 ml of 1:1 EtOAc-H2O is added to the residue and stirred vigorously for 10 min. The solid precipitate is collected by suction filtration, washed with water (2×150 ml), washed with EtOAc (2. 50 ml), and dried under vacuum at 80° C. to give 5.45 g of 6-[4-(3-phthalimidopropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 230°-232° C.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:8]1(C)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=C[CH:20]=1>>[C:10]1([CH3:20])[C:11]([S:14]([O:7][CH2:6][CH:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)(=[O:15])=[O:16])=[CH:12][CH:13]=[CH:8][CH:9]=1
Reactant: c1ccncc1
Reactant: OCC1CC=CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Yield: 83.2 %

Procedure:
A mixture of (cyclopent-3-en-1-yl)methanol (1.96 g, 20 mmol) and para-toluenesulfonylchloride (3.81 g, 20 mmol) were stirred at room temperature for 2 hrs in pyridine (30 ml). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed 1N HCl, dried with MgSO4, concentrated and separated by the column chromatography to give the desirable product (4.20 g).