Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]4([OH:23])[CH2:22][NH:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:24]=1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]4([OH:23])[CH2:20][N:21]([C:29]([CH:26]5[CH2:28][CH2:27]5)=[O:30])[CH2:22]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:24]=1
Reactant: NC(=O)c1nc2n(c1C1(O)CNC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: O=C(O)C1CC1
Product: NC(=O)c1nc2n(c1C1(O)CN(C(=O)C3CC3)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with tert-butyl 3-oxoazetidine-1-carboxylate similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L then deprotected with 4N HCl in dioxane (5 eq) at room temperature to provide 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclopropane carboxylic acid similar to as described in Example 2 with non-critical modifications to afford crude 10-bromo-3-(1-(cyclopropanecarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was then reacted with 2-Methyl-3-butyne-ol via General Procedure F to afford 7.9 mg (71.8%) 3-[1-(cyclopropanecarbonyl)-3-hydroxy-azetidin-3-yl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [ClH:1].CC1(C)[O:8][C:7]2[CH:9]=[CH:10][C:11]([CH:13]([OH:20])[CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C:6]=2[CH2:5][O:4]1>CO>[ClH:1].[ClH:1].[OH:4][CH2:5][C:6]1[C:7]([OH:8])=[CH:9][CH:10]=[C:11]([CH:13]([OH:20])[CH2:14][NH:15][C:16]([CH3:18])([CH3:17])[CH3:19])[N:12]=1
Reactant: CC(C)(C)NCC(O)c1ccc2c(n1)COC(C)(C)O2
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 10 ml. of methanol and 10 ml. of 10% hydrochloric acid is added 227 mg. of 2,2-dimethyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-pyrido[3,2-d]-1,3-dioxin, and the resulting reaction mixture allowed to stir at room temperature for 1.5 hrs. Removal of the solvents under vacuum at 70° C. provides 230 mg. of the desired product, which is identical by nuclear magnetic resonance spectroscopy to the product in U.S. Pat. No. 3,700,681.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26])=[O:14]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(trans-2-hydroxy-cyclohexyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.27 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.40 mmol of trans-2-aminocyclohexanol. LC/MS [6.40 (10 min) min; 640 (M+1)]
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14]>C1(C)C=C(C)C=C(C)C=1>[C:2]([C:3]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:4]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: CC(C)(C)C#Cc1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1C(C)(C)C
Yield: 15.4 %

Procedure:
A solution of (3,3-Dimethylbut-1-ynyl)benzene (400 mg, 2.53 mmol) and dimethyl nitromalonate (0.853 mL, 6.32 mmol) in mesitylene (5 mL) was heated at 150° C. for 48 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-tert-butyl-5-phenylisoxazole-3-carboxylate (101 mg). The compound had an HPLC ret. time=3.39 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=260+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[C:16]([NH:15][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:21]=2)=[CH:25][CH:26]=1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4ccc(Cl)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (85 mg, 0.41 mmol) was reacted with the product from Example 143a (146 mg, 0.41 mmol) for 26 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (89 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3 H) 1.83 (sext, J=7.35 Hz, 2 H) 3.00 (dd, J=7.35 Hz, 2 H) 5.13 (s, 2 H) 6.27 (d, J=6.99 Hz, 1 H) 6.64 (d, J=8.82 Hz, 2 H) 7.05-7.25 (m, J=8.45 Hz, 4 H) 7.48 (m, 4 H) 7.83 (d, J=8.45 Hz, 1 H) 8.40 (d, J=6.99 Hz, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.78 (s, 1 H) 11.03 (br s, 1 H) 14.40 (br s,1 H); MS (ESI+) m/z, 528, 530 (M+H−TFA)+; (ESI−) m/z, 526, 528 (M−H−TFA)−.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:21][S:22]([C:25]1[CH:35]=[CH:34][C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=2[CH:26]=1)(=[O:24])=[O:23]>>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:31]3[CH2:30][CH2:29][C:28]4[CH:34]=[CH:35][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][C:27]=4[CH2:33][CH2:32]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCNCC2
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)CCN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)CC2

Procedure:
The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.20 g) and 7-methanesulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (WO00/21951) (0.17 g) using the procedure described for Example 1 and isolated as a white solid (0.24 g). MS electrospray (+ion) 471 (MH+). 1H NMR δ (DMSO-d6): 9.83 (1H, s), 7.71 (2H, m), 7.44 (1H, s), 7.35 (2H, d, J=8.5 Hz ), 7.01 (2H, d, J=8.6 Hz), 4.11 (2H, t, J=5.9 Hz), 3.71-3.45 (6H, m), 3.18 (6H, m), 3.05 (3H, s) 2.87 (2H, m), 2.20 (2H, m), 1.83-1.37 (6H, m).
Reaction SMILES: Cl[CH:2](OC)[CH2:3][CH2:4][CH:5](Cl)OC.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH2:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([N:32]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(Cl)CCC(Cl)OC
Reactant: CCOC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
1,4-dichloro-1,4-dimethoxybutane (3.30 g) was added to a solution of ethyl 3-(4-benzyloxyphenyl)-2-aminopropionate (3.30 g) in dichloromethane (80 ml) and then amberlyst A-21 (20 g) was added to the mixture. The mixture was stirred at ambient temperature for 18 hours and the reaction mixture was filtered. The filtrate was concentrated and the residue was purified via chromatography on a silica gel column using ethyl acetate/hexane=1/5 as the eluant to afford the desired compound (1.00 g) as a syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])[CH3:2].C(Cl)[Cl:16].C(Cl)(=O)C(Cl)=O>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([Cl:16])=[O:8])[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cc(C(=O)O)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-ethoxy-4-methoxybenzoic acid (5 g, 25.5 mmol) was added to a solution of CH2Cl2 (40 mL) and benzene (20 mL) in a flame-dried 150 mL round bottom flask. Anhydrous DMF (9 drops) was added and the solution was cooled on ice. Oxalyl chloride (11 mL, 128 mmol) was added dropwise, and the reaction was then allowed to warm to RT. The reaction was stirred at RT for 90 minutes, then concentrated in vacuo yield an off-white solid. The solid was placed on a high-vacuum line for 2 hours, and then taken onto the next step without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][N:19]=2)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([C:15]2[S:16][C:17]([CH2:20][O:32][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CCl)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(COc3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
A mixture of 4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonyl-phenol (731 mg, 1.0 eq.) and K2CO3 (878 mg, 1.5 eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the solid was filtered off through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05˜2.32 (4H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N(C1C=CC=CN=1)C.CO.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[N:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH3:25])=[O:20])[C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccn1
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1OC(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)(C)ON1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of (3S-trans)-2-[[3-(benzyloxycarbonyl)amino4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid (1.68 g, 5.0 mmol) (see example 29) in 10 ml of dry dichloromethane were added 4 dimethylaminopyridine (30 mg), dry methanol 0.81 ml, 210 mmol) and dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. The precipitate (dicyclohexylurea) was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in ether, filtered, washed with aqueous buffer solution pH 4 (citrate/HCl), NaHCO3 solution, dried over MgSO4 and filtered. Evaporation in vacuo gave the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[F:19][C:2]([F:1])([F:18])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(OCCOCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCOCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Methyl 6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridine-3-carboxylate (Intermediate 243, 0.453 g, 1.62 mmol) was dissolved in MeOH (5 mL), 2M aq. sodium hydroxide (1.62 mL, 3.24 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated under vacuum and acidified with 2M hydrochloric acid. The resultant precipitate was filtered off and dried under vacuum to afford the title compound as a white solid (0.245 g, 57%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.79 (1H, d), 8.23 (1H, dd), 6.90 (1H, d), 4.55 (2H, dd), 4.03 (2H, q) and 4.01 (2H, dd).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:49])[C@H:15]([CH2:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[NH:16][C:17](=[O:37])[C@H:18]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[CH3:12][O:13][C:14](=[O:49])[C@H:15]([CH2:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[NH:16][C:17](=[O:37])[C@H:18]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:22]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(N)c1
Product: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Yield: 56 %

Procedure:
By coupling 4-cyanobenzoic acid with N-[N-(m-aminobenzoyl)-3-(t-butoxycarbonyl)-L-alanyl]-3-(1-naphthyl)-L-alanine methyl ester there is obtained N-[3-(t-butoxycarbonyl)-N-[m-(p-cyanobenzamido)benzoyl]-L-alanyl]-3-(1-naphthyl)-L-alanine methyl ester, yield: 56% of theory, MS: 649 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C)C)C1C=CC=CC=1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH:1]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 72.6 %

Procedure:
1.12 ml (0.005 millimol) of palladium acetate, 7.04 g (50 millimols) of benzoyl chloride, 5.22 g (50 millimols) of styrene and 6.76 g (50 millimols) of N-benzyldimethylamine in 100 ml of p-xylene are stirred for 11.5 hours at 130° C. 6.54 g (63% of theory) of stilbene are obtained. This corresponds to 6,300 mols of stilbene per mol of catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@H:43]([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@H:43]([O:45][C:50](=[O:51])[N:49]([CH3:53])[CH3:48])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 100 mg of (R)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propan-2-ol (diastereomer 1) (from example 34b) in 10 ml tetrahydrofuran, are added 35 mg of potassium hydride and 0.14 ml of N,N-dimethylcarbamoyl chloride at room temperature. The reaction mixture is stirred for one additional hour, diluted with water and extracted with tert-butyl methyl ether. The combined organic phases are dried and concentrated under reduced pressure to afford the crude title compound. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.37 (EtOAc-heptane 2:1); Rt=5.44.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:42]([O:46][C:47](=[O:62])[C@H:48]([CH2:60]O)[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[C:42]([O:46][C:47](=[O:62])[C@@H:48]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:60][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 7.73 g (50 mmol) of 6-chloropurine in 350 ml of absolute THF were added 14.43 g (55 mmol) triphenylphosphine at −10 to 0° C. followed by 9.57 g (55 mmol) of diethyl azodicarboxylate and 14.8 g (50 mmol) of N-benzyloxycarbonyl-L-serine tert-butyl ester in 100 ml of absolute THF, and the mixture was stirred at 0° C. for 48 h. The solvent was evaporated, the residue was dissolved in EE/heptane (2:1), filtered and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (EE/n-heptane (1:1) and DCM/EE (85:15)). Yield: 6.6 g.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH:3]([C:9]([C:11]1[CH:25]=[CH:24][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:13]=2[CH:12]=1)=[O:10])[CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Li+].O.Cl>O1CCOCC1>[CH3:1][CH:2]([CH3:26])[CH:3]([C:9]([C:11]1[CH:25]=[CH:24][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:13]=2[CH:12]=1)=[O:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CC(C(=O)c1ccc2nc(-c3ccccc3)oc2c1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
100 mg (285 μmol) methyl 4-methyl-3-(2-phenyl-benzoxazole-6-carbonyl)-pentanoate, 10 mg (418 μmol) lithium hydroxide, 1 ml of water and 1 ml dioxane are stirred for 24 h at RT. The reaction mixture is acidified with conc. hydrochloric acid and extracted with diethyl ether, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].CN(C=O)C.[Br:27]N1C(=O)CCC1=O>O>[Br:27][C:16]1[CH:17]=[C:11]([C:2]([F:1])([C:3]([F:6])([F:5])[F:4])[C:7]([F:10])([F:9])[F:8])[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[C:14]=1[NH2:15]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
100 g (0.273 mol) of 4-(heptafluoropropan-2-yl)-2-(trifluoromethyl)aniline was charged to 500 ml of DMF, and 52.1 g (0.287 mol) of N-bromosuccinimide was charged in separate portions thereto over 30 minutes. After stirring at 60° C. for 2 hours, and then cooling to room temperature, the mixture was discharged to 2000 ml of water. The mixture was extracted with ethyl acetate, then washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=20:1) to prepare 89.0 g (yield 80%) of a target compound.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH2:1]([N:8]([CH3:38])[N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)n1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21
Reaction time: 0.25 h
Yield: 4 %

Procedure:
To a solution of tert-butyl 4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (prepared in example 25: 125 mg, 0.26 mmol) in 3.0 mL of DMF at 0° C. was added NaH (60% in oil, 31 mg, 0.78 mmol) in one portion. After 15 min, the mixture was treated with methyl iodide. HPLC check shows disappearance of starting material. Solvent was removed and the residue dissolved in ethyl acetate, washed with aqueous NaHCO3. The organic solution was dried, evaporated and then the residue was treated with methanol (0.5 mL) and HCl (4.0M in dioxane, 2.0 mL) at room temperature for 30 min. The solvent was removed and the residue was purified by preparative HPLC to give product as a white solid (4.1 mg, yield 4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9].FC(F)(F)C([O-])=O.C(N(C(C)C)C(C)C)C.Cl[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][N:47]=1.Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH:18][C:46]3[N:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Temperature: 100 °C

Procedure:
1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate were stirred into 10 ml of N-ethyl-diisopropylamine and heated to 100° C. for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyano-pyridine the reaction mixture was heated to 125° C. for 2 hours. After cooling to ambient temperature and stirring with about 20 ml of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down. Yield: 1.05 g (67% of theory), C26H25N7O (483.6) Mass spectrum: (M+H)+ =484