Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:3]([C:16]2([CH2:19]/[CH:20]=[CH:21]/[C:22](/[CH3:27])=[CH:23]/[C:24]([OH:26])=[O:25])[CH2:18][CH2:17]2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CC1(C)CCC(C)(C)C2C=C(C3(C/C=C/C(/C)=C/C(O)=O)CC3)C(OC)=CC1=2.CC1(C)CCC(C)(C)C2C=C(C3(C/C=C/C(/C)=C/C(O)=O)CC3)C(OCC)=CC1=2.C(C1C=C(C2(C/C=C/C(/C)=C/C(O)=O)CC2)C=C(C(C)(C)C)C=1)(C)(C)C.C(C1C=C(C2(C/C=C/C(/C)=C/C(O)=O)CC2)C=CC=1CC)C.C(C1C=C2C(CCC2(C)C)=C(C2(C/C=C/C(/C)=C/C(O)=O)CC2)C=1)(C)(C)C.CC1(C)CCC(C)(C)C2C=C(C3(C/C=C/C(/C)=C/C(O)=O)CCCC3)C=CC1=2>>[CH3:12][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]2[CH:4]=[C:3]([C:16]3([CH2:19]/[CH:20]=[CH:21]/[C:22](/[CH3:27])=[CH:23]/[C:24]([OH:26])=[O:25])[CH2:17][CH2:18]3)[CH:2]=[CH:11][C:10]1=2
Reactant: CC(/C=C/CC1(c2cc3c(cc2C)C(C)(C)CCC3(C)C)CC1)=C\C(=O)O
Agent: CC(/C=C/CC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1)=C\C(=O)O
Agent: CC(/C=C/CC1(c2cc(C(C)(C)C)cc3c2CCC3(C)C)CC1)=C\C(=O)O
Agent: CC(/C=C/CC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1)=C\C(=O)O
Product: CC(/C=C/CC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1)=C\C(=O)O

Procedure:
(2E, 4E)-6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 102); (2E, 4E)-6-[(5,5,8,8-tetramethyl-3-methoxy-5,6, 7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 103); (2E, 4E)-6-[(5,5,8,8-tetramethyl-3-ethoxy-5,6, 7,8-tetrahydronaphthalen-2-yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 104); (2E, 4E)-6-[(3,5-di-t-butyl phenyl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 105); (2E, 4E)-6-[(3,4-diethyl phenyl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 106); (2E, 4E)-6-[1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-3-methyl hexadienoic acid (Compound 107); and (2E, 4E)-6-[(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl) cyclopentane-1-yl]-3-methyl hexadienoic acid (Compound 108)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:12]2[CH:13]=[C:7]3[CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9][N:8]3[N:11]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COCCN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 25 °C
Yield: 65 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), 296e (588 mg, 3.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (800 mg, 3.0 mmol), and cesium carbonate (1.96 g, 6.0 mmol). After bubbling nitrogen through the suspension for 20 minutes, xantphos (173 mg, 0.30 mmol) and tris(dibenzylideneacetone)dipalladium(0) (137 mg, 0.15 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×15 mL). The combined filtrate was concentrated under reduced pressure. The residue solid was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 296f (745 mg, 65%) as yellow solid. MS-ESI: [M+H]+ 382.9
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH:38]([N:41](C(C)C)CC)(C)C>>[N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[NH:41][CH3:38])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and methylamine hydrochloride/diisopropylethylamine Rf value: 0.3 (aluminium oxide, methylene chloride/ethanol=20:1) C29H30N4O2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([CH:24]4[CH2:27][N:26]([CH2:28][C@@H:29]([OH:31])[CH3:30])[CH2:25]4)[C:19]([F:23])=[C:20](Cl)[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[CH3:34][N:35]1CCCC1=O>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([CH:24]4[CH2:27][N:26]([CH2:28][C@@H:29]([OH:31])[CH3:30])[CH2:25]4)[C:19]([F:23])=[C:20]([CH:21]=3)[C:34]#[N:35])[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12
Reactant: CN1CCCC1=O
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a microwave vial containing (2S)-1-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]propan-2-ol (16 mg, 0.032 mmol, from Example 76) was added zinc (1.0 mg, 0.016 mmol), bis(tri-t-butylphosphine)palladium (6.5 mg, 0.013 mmol) and N-methylpyrrolidinone (0.20 mL, 2.0 mmol). The mixture was degassed with N2 for a few minutes before adding zinc cyanide (7.5 mg, 0.064 mmol). The resulting mixture was stirred at 130° C. overnight and then cooled and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.8 mg, 11.2%). The product was isolated as a racemic mixture. LCMS calculated for C22H25F3N7O2 (M+H)+: m/z=476.2; Found: 476.2
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]1([C:50](O)=[O:51])[CH2:49][CH2:48]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NNc1cnc2ccc(Br)cc2n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in DMF (3 mL) was added HATU (380 mg, 1 mmol), DIPEA (0.205 mL, 1 mmol) and cyclopropanecarboxylic acid (71 mg, 0.83 mmol). After stirring at r.t. for 5 h, the mixture was diluted with EtOAc. The organic layer was washed with water for three times, then concentrated to afford N′-(7-bromoquinoxalin-2-yl)cyclopropane-carbohydrazide as yellow solid which was used directly in the next step. m/z 309 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([OH:19])[CH2:16][C:17]#[CH:18].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>O1CCOCC1.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]#[C:17][CH2:16][CH2:15][OH:19])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCCO
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C#CCCO)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 33.4 %

Procedure:
4-Bromo-3-(trifluoromethyl)nitrobenzene (500 mg, 1.85 mmol) was dissolved in 1,4-dioxane (10 mL), and but-3-yn-1-ol (389 mg, 5.56 mmol), copper iodide (35 mg, 0.18 mmol), palladium acetate (21 mg, 5 mol %), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl bisphenyl (88 mg, 10 mol %), and cesium carbonate (1207 mg, 3.70 mmol) were added thereto. The resulting mixture was stirred under nitrogen atmosphere at 80° C. for 10 hours, and a saturated ammonium chloride aqueous solution was added thereto to quench the reaction. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(4-nitro-2-(trifluoromethyl)phenyl)but-3-yn-1-ol (160 mg, 33%) as a brown oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)Nc2nccs2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of triphenylphosphine (100 mg, 0.38 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (68 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (85 mg, 0.22 mmol) in methylene chloride (3 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (55 mg, 0.55 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (42 mg, 41 %) as a white solid: mp 148-154° C.; EI-HRMS m/e calcd for C20H24N6O3S2 (M+) 460.1351, found 460.1356.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>ClCCl.CCCCCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][O:13][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCC1(c2ccccn2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC1(c2ccccn2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of (1-pyridin-2-yl-cyclopentyl)-methanol (432) (1.8 g, 10.169 mmol) in dichloromethane (20 mL), triethylamine (2.827 mL, 20.339 mmol) and mesylchloride (0.94 mL, 12.203 mmol) were added at 0° C. The reaction mixture was allowed to stir for 2 h at room temperature while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.6) The reaction was quenched with water (30 mL) and extracted with dichloromethane (2×70 mL). The organic part was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 25% ethyl acetate in hexane as eluent to get methanesulfonic acid 1-pyridin-2-yl-cyclopentylmethyl ester (433) (2.05 g, 79%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 30.9 %

Procedure:
To a solution of 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 622 μmol) in NMP (2.07 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture heated at 140° C. for 20 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture stirred for a further 7 h. A final portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture heated for 16 h, then cooled, diluted with ethyl acetate, and washed with brine (4×). The organic layer was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (96 mg, 192 μmol, 31%) as a light brown solid. MS (EI/CI) m/z: 500.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C.C1(C)C(C)=CC=CC=1.N12CCN(CC1)CC2>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: COc1nc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 100 ml of dry acetonitrile, and then 0.1 g of 1,4-diazabicyclo[2,2,2]octane was added thereto. To this mixture was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 30 ml of xylene over an hour. During this addition, the reaction was accompanied by slight heat generation, and therefore cooling was applied as necessary. After the addition, the reaction was continued at room temperature for 5 hours and then at 40° C. for 5 hours. After allowing the mixture to cool to room temperature, the precipitated colorless crystals were filtered, washed with ether and dried to obtain 33.9 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea; m.pt. 190°-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([CH3:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COC[C@H](N)c2ccccc2)CC1
Reactant: Cc1c[nH]c2cc(C(=O)O)ccc12
Product: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)ccc12

Procedure:
Using coupling method A, 4-[(R)-2-amino-2-phenylethoxy-methyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.0 mmol) and 3-methylindole-6-carboxylic acid (0.54 g, 3.0 mmol) afforded the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [C:1]([CH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[Li]N(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37]([CH:44]([CH3:46])[CH3:45])([CH2:40][CH2:41][CH2:42]I)[C:38]#[N:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([CH:6]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:42][CH2:41][CH2:40][C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[CH:30]=1)([C:38]#[N:39])[CH:44]([CH3:46])[CH3:45])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Agent: [Li]N(C(C)C)C(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)N=Cc1ccc(OC)c(OC)c1

Procedure:
The resulting imine of formula 24 is then deprotonated using a suitable strong base, and allowed to react with a compound of formula 22 to produce a compound of formula 25 (step 2). For example, 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24) is suspended in a solution of LiNiPr2 in THF/HMPA at -78° C., then reacted with 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) to produce N-[1-carboethoxy-5-(3,4-dimethoxyphenyl)-5-cyano-5-(isopropyl)pentyl]iminomethyl-3,4-dimethoxybenzene (25).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([OH:8])/[CH:5]=[CH:6]/[I:7].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([O:8][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:5]=[CH:6]/[I:7]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)(C)CC(O)/C=C/I
Product: CCCC(C)(C)CC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 6.0 g. of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol (Example 1000) with 6.9 g. of triphenylmethyl bromide in 30 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2/[CH:32]=[CH:33]/[C:34]([O:36]CC)=[O:35])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2/C=C/C(=O)O)cc1
Yield: 97.6 %

Procedure:
To a mixture of ethyl (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoic acid as colorless crystals (0.37 g, yield 97%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19]1[S:23][CH:22]=[N:21][C:20]=1[NH2:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: Nc1ncsc1-c1ncccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Cl)cc1Nc1ncsc1-c1ncccn1

Procedure:
Method A was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (69 mg, 0.22 mmol), 5-(pyrimidin-2-yl)thiazol-4-amine (26 mg, 0.15 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), xantphos (14 mg, 0.029 mmol) and cesium carbonate (97 mg, 0.30 mmol) in dioxane (3.5 ml).
Reaction SMILES: Cl.[CH2:2]([N:9]([S:15]([C:18]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:32])=[CH:23][N:24]=[C:25]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.NC(N)=N.[C:38](OC(=O)[C@H](C)N(CC1C=CC=CC=1)S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:41])([CH3:40])[CH3:39]>COCCOC>[C:38]([O:13][C:12](=[O:14])[C@H:10]([CH3:11])[N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:15]([C:18]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:32])=[CH:23][N:24]=[C:25]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: C[C@@H](C(=O)O)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: C[C@@H](C(=O)OC(C)(C)C)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 56.3 %

Procedure:
N-Benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine hydrochloride ##STR30## NaH (30 mg, 80% dispersion by wt in mineral oil, 1.01 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (154 mg, 1.61 mmol) in DME (5.0 mL) and the mixture was heated at 60° C. under N2 for 45 min. A solution of N-benzyl-N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (200 mg, 0.40 mmol) in DME (2.0 mL) was added and the mixture heated at 95° C. for 4 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 20:80) as eluant to give N-benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (120 mg, 0.225 mmol) as pale yellow foam after repeated evaporation from CH2Cl2,