Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C[O:26][B:27](OC)[O:28]C>O1CCCC1>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]4[C:17]([B:27]([OH:28])[OH:26])=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc3sc4ccccc4c3c2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1sc1ccc(-c3ccccc3)cc12
Temperature: -78 °C

Procedure:
2-bromo-dibenzo[b,d]thiophene (10 g), phenylboronic acid (5.1 g) tetrakis(triphenylphosphine)palladium (2.2 g) and potassium carbonate (18.38 g) were refluxed in a mixture of toluene (110 mL), ethanol (20 mL) and water (90 mL) overnight. The reaction was quenched with water and the toluene layer was removed and passed through a celite column and the toluene layer was evaporated in a rotary evaporator to yield 5.2 g 2-phenyl-dibenzo[b,d]thiophene. 2-phenyldibenzo[b,d]thiophene (5.2 g) was dissolved in anhydrous tetrahydrofuran (50 mL) under nitrogen atmosphere, and the solution was then cooled to −78° C. 20.0 mL of n-butyl lithium (1.6 M solution) was added dropwise into the reaction mixture, and continuously stirred to equilibriate to room temperature. The reaction mixture was then cool to −60° C., and trimethyborate (5.67 mL) was added and the reaction was allowed to stir overnight. The reaction was then quenched with 20% aqueous hydrochloric acid, and extracted the organic layer with ethyl acetate; ethyl acetate layer was then washed thoroughly with water and dried over anhydrous sodium sulfate, and was evaporated to dryness to yield 4.2 g of 8-phenyldibenzo[b,d]thiophene-4-boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ccnc4ncc(=O)[nH]c34)c2)n(-c2ccccc2)n1
Yield: 29 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a yellow solid (57 mg, 29%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:23]([O:30][CH3:31])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-])=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:31][O:30][C:23](=[O:29])/[CH:24]=[CH:25]/[C:26]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[O:27]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCCN)C(=O)OCC[Si](C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)/C=C/C(=O)NCCCC[C@@H](C(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirring mixture of (S)-tert-butyl 6-amino-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (800 mg, 2.31 mmol), monomethyl fumarate (361 mg, 2.77 mmol), DIEA (1.1 mL, 6.93 mmol) in 10 mL acetonitrile was added HATU (1.14 g, 3.00 mmol) in one portion at 0° C. under an inert atmosphere of argon. The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc (50 mL) and washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S,E)-tert-butyl 6-(4-methoxy-4-oxobut-2-enamido)-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (900 mg, 85%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:19](=O)[CH2:18][CH:17]2[CH2:21][NH:22][CH2:23][CH:16]2[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.C(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]2[CH2:21][NH:22][CH2:23][CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CC2CNCC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CN2CCC3CNCC3C2)cc1
Temperature: 10 °C
Yield: 81.4 %

Procedure:
A suspension of 266 mg of LAH in 10 mL of ether was stirred at 10° C. under N2. To this suspension was added 540 mg of the compound from step 457d dissolved in 10 mL of methylene chloride. The mixture was stirred under N2 for 1.5 hours. The reaction was quenched by the sequential dropwise addition of 0.3 mL water, 0.3 mL of 15% NaOH and 0.6 mL of water, then the mixture was stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 389 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:25]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1Br

Procedure:
A mixture of 2-(3-bromo-4-methylphenyl)-1,3-benzoxazole (240 mg, 0.83 mmol), n-bromosuccinimide (180 mg, 0.99 mmol), and benzoyl peroxide (10 mg, 0.041 mmol) in carbon tetrachloride (15 mL) was refluxed for 3 h. The white precipitate was filtered and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5) to afford 2-[3-bromo-4-(bromomethyl)phenyl]-1,3-benzoxazole as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:23])=[C:10]([C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[C:17]=2[F:18])[NH:11][CH:12]2[CH2:14][CH2:13]2)[CH2:4][CH2:3]1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[CH:27][N:11]([CH:12]1[CH2:13][CH2:14]1)[C:10]1[C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[C:17]([F:18])=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]=1[CH3:23])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:33]
Reactant: Cc1c(NC2CC2)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1c(C)c(N2CCN(C)CC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline (1.65 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane : methanol=100 : 1) to give diethyl[N-cyclopropyl-N-[3-(4-methyl-l-piperazinyl)-4 -fluoro-2,5-dimethyl-6-nitrophenyl]aminomethylene]malonate (1.58 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane : methanol =10 : 1) and recrystallization from ethanol--diethyl ether to give ethyl 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylate (28 mg), as yellow crystals, m.p. 146°-147° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH2:6])[CH2:3][CH2:2]1.[CH3:7][C:8]1[N:9]=[C:10]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[O:18])[S:11][C:12]=1[C:13](O)=[O:14]>>[CH:1]1([CH2:4][CH2:5][NH:6][C:13]([C:12]2[S:11][C:10]([NH:16][C:17](=[O:18])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:9][C:8]=2[CH3:7])=[O:14])[CH2:3][CH2:2]1
Reactant: NCCC1CC1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCC1CC1
Yield: 20 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-cyclopropylethylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 20% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.82-8.80 (m, 2H), 8.08-7.72 (m, 3H), 3.27-3.16 (m, 2H), 2.45 (s, 3H), 1.41-1.34 (m, 2H), 0.73-0.65 (m, 1H), 0.48-0.25 (m, 2H), 0.12-0.80 (m, 2H); MS (ES+) m/z 331.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:35])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][NH:23]C(OC(C)(C)C)=O)[N:18]=3)[CH:15]=2)[N:10]([C:31](=[O:33])[CH3:32])[C@@H:9]([CH3:34])[CH2:8]1)[CH3:3].[ClH:36]>O1CCOCC1>[ClH:36].[C:31]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][NH2:23])[N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:35])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)N1c2ccc(-c3nc(CNC(=O)OC(C)(C)C)no3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3nc(CN)no3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 4 °C
Reaction time: 16 h
Yield: 10.35 %

Procedure:
To a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1,2,4-oxadiazol-5-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 62) (100 mg, 0.205 mmol) in 1,4-dioxane (0.5 mL) at room temperature was added HCl (4N in 1,4-dioxane, 2 mL, 8 mmol) and the resulting mixture was stirred at this temperature for 3 h than at 4° C. for 16 h before being warmed to room temperature. The residue was triturated with Et2O then purified using MDAP (modifier: ammonium bicarbonate). The residue obtained was dissolved in 1,4-dioxane (2 mL) and treated with HCl (4N in dioxane, 1 mL). The resulting mixture was concentrated in vacuo and the residue triturated with Et2O to give 1-methylethyl {(2S,4R)-1-acetyl-6-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (9 mg, 0.021 mmol, 10.35% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(Cl)c(C(=O)O)cc1OC
Product: COc1cc(Cl)c(C(=O)Cl)cc1OC
Temperature: 120 °C
Yield: 96.2 %

Procedure:
2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl5 (0.54 g, 2.6 mmol) were placed in a round bottomed flask fitted with a reflux condenser. The mixture was heated in an oil bath at 120° C. for 70 min. The mixture was allowed to cool and the formed phosphorus oxychloride was removed under vacuum to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl)ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 0.53 g (54%) of methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. 1H-NMR (DMSO-d6; 300 MHz) δ2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]2[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:11][CH:12]=1)(=O)=O.[CH3:23][NH:24][CH:25]([CH3:27])[CH3:26]>>[Cl:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:24]([CH:25]([CH3:27])[CH3:26])[CH3:23])=[CH:8][N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[N:17]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(COS(C)(=O)=O)cn2)c1=O
Reactant: CNC(C)C
Product: CC(C)N(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1

Procedure:
Following Example 186c, 180c and methylisopropylamine were reacted to give 180d.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:53]=[CH:52][C:48](C(Cl)=O)=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16](O)=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:7]([C:16]([NH2:39])=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
335.0 mg (0.824 mmol) of the compound from Example 41A are introduced into 10 ml of ethyl acetate, and 167.1 mg (0.537 mmol) of 1,1′-carbonyldiimidazole are added. The suspension is then stirred at room temperature overnight. Since a clear solution is not produced, 2 ml of DMF are added and the mixture is stirred at room temperature for a further two hours. Complete conversion is then established by TLC check. The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 2.293 ml of ammonia (28% by weight solution in water, 16.5 mmol) and 10.1 mg of 4-N,N-dimethylaminopyridine are added. The reaction mixture is heated at 100° C. in a closed vessel for thirty minutes. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The product fractions are concentrated and the residue is taken up in a little dichloromethane, and diisopropyl ether is added until the solution is cloudy. The precipitated solid is isolated and dried in vacuo. 207 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([CH:64]([CH3:66])[CH3:65])[C:8]([NH:10][C@@H:11]([CH3:63])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH:23]3[CH:29]=[N:28][C:27]4[CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]5[C:42]([O:59][CH3:60])=[CH:43][C:44]6[C:50](=[O:51])[N:49]7[CH:52]=[C:53]([CH:55]8[CH2:57][CH2:56]8)[CH2:54][CH:48]7[CH:47]=[N:46][C:45]=6[CH:58]=5)[C:32]([O:34][CH3:35])=[CH:33][C:26]=4[C:25](=[O:61])[N:24]3[CH:62]=2)=[CH:17][CH:16]=1)=[O:13])=[O:9])C=C.N1CCCC1>C(Cl)Cl.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>[NH2:6][C@@H:7]([CH:64]([CH3:66])[CH3:65])[C:8]([NH:10][C@@H:11]([CH3:63])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH2:22][CH:23]3[CH:29]=[N:28][C:27]4[CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]5[C:42]([O:59][CH3:60])=[CH:43][C:44]6[C:50](=[O:51])[N:49]7[CH:52]=[C:53]([CH:55]8[CH2:57][CH2:56]8)[CH2:54][CH:48]7[CH:47]=[N:46][C:45]=6[CH:58]=5)[C:32]([O:34][CH3:35])=[CH:33][C:26]=4[C:25](=[O:61])[N:24]3[CH:62]=2)=[CH:19][CH:20]=1)=[O:13])=[O:9]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(C7CC7)CC5C=N6)cc4N=CC3C2)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(C4CC4)CC1C=N3)N=CC1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Reaction time: 1 h

Procedure:
The starting material 16 (170 mg, 0.185 mmol) was dissolved in dry CH2Cl2 (5 mL) in a round bottom flask filled with argon, before pyrrolidine (41 μL, 0.21 mmol) was added. The flask was purged/refilled three times with argon before Pd(PPh3)4 (14 mg, 0.084 mmol) was added and the flushing operation repeated. After 1 hour, complete consumption of starting material was observed (the reaction was followed by LC/MS) and Et2O (50 mL) was added to the reaction mixture which was allowed to stir until all the product had crashed out of solution. The solid was filtered through a sintered funnel and washed twice with Et2O (2×25 mL). The collecting flask was replaced and the isolated solid was dissolved in CHCl3 (100 mL or until all the product had passed through the sintered funnel). The volatiles were then removed by rotary evaporation under reduced pressure to afford the crude product 17 which was used directly in the next step (168 mg). LC/MS method 2 (2.70 min (ES+) m/z (relative intensity) 830.27 ([M+H]+, 50), 660.13 (80), 171.15 (100)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])[N:3]=1.[C:18](Cl)([Cl:20])=[O:19]>C1(C)C=CC=CC=1>[Cl:20][C:18]([N:9]([C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[Cl:17])=[O:19]
Reactant: Cc1cc(C)nc(Nc2cc(Cl)ccc2Cl)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(C(=O)Cl)c2cc(Cl)ccc2Cl)n1
Yield: 95.1 %

Procedure:
5.0 g (0.018 mole) of N-(4,6-dimethyl-pyrimidin-2-yl)-2,5-dichloroaniline are dissolved in 100 ml of toluene and heated to reflux. A gentle stream of phosgene is then introduced for a period of 4 hours. The excess phosgene is blown out with nitrogen, and the toluene solution is washed cold with water, dried with magnesium sulfate and then concentrated by evaporation. 5.8 g (95.1%) of the title compound of formula ##STR20## are isolated in the form of crystals having a melting point of 121°-123° C.
Reaction SMILES: [OH-].[K+].C([CH:5]([C:11]1([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=2)[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#N>O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:17]([N:14]1[CH2:13][CH2:12][C:11]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:24]2[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH2:16][CH2:15]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C#N)C1(c2cc(C)cc(C)c2)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(c2cc(C)cc(C)c2)CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of potassium hydroxide (3.4 g) in water (20 ml) was added to a solution of ethyl 2-cyano-2-(1-benzyl-4-(3,5-dimethylphenyl)piperidin-4-yl)ethanoate (4.7 g) (see Preparation 8) in ethanol (24 ml) and the mixture microwaved at 345 kPa (100 psi)/100% power for 2.5 hours. The solvent was removed under reduced pressure and the residue azeotroped with toluene to remove any residual water. The residue was dissolved in ethanol (100 ml), cooled in an ice-bath and the solution saturated with hydrogen chloride gas. The mixture was left to stand at room temperature overnight before re-saturating the solution with hydrogen chloride gas and leaving to stand for a further 24 hours. The solution was filtered and the solvent removed from the filtrate under reduced pressure to give a residue which was dissolved in saturated aqueous sodium carbonate solution and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 97:3 changing to 90:10, by volume, dichloromethane:methanol to give the title compound (2.0 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[CH:4][C:3]=1F.COC(=O)C1C=C(OC2C=CC(N)=C([F:37])C=2)C=NC=1>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[C:4]([F:37])[CH:3]=1
Reactant: CNC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Product: CNC(=O)c1cncc(Oc2ccc(N)cc2F)c1

Procedure:
The title compound was prepared in the same manner described for 5-(4-amino-3-fluorophenoxy)-N-methylnicotinamide, substituting 5-(4-amino-2-fluorophenoxy)-nicotinic acid methyl ester for 5-(4-amino-3-fluorophenoxy)nicotinic acid methyl ester. 1H NMR (DMSO-d6) 67.80 (d, J=1.8 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 6.83 to 6.81 (m, 1H), 6.15 (t, J=8.7 Hz, 1H), 5.78 to 5.67 (m, 2H), 4.07 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[N:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)[CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>CO.[Pd]>[CH2:1]([NH:8][C:9](=[O:32])[N:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)[CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(CCC(=O)OCC)cc2)c1

Procedure:
A solution of 460 mg of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate (prepared in step 21f) in 10 ml of methanol is stirred for 12 hours at room temperature in the presence of 100 mg (22% by mass) of 10% palladium-on-charcoal under a hydrogen atmosphere. The palladium is filtered off and the solvent is evaporated off. The oil is used directly in the following step.