Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:56]([C:60]1[CH:61]=[C:62]([NH2:67])[C:63]([NH2:66])=[CH:64][CH:65]=1)([CH3:59])([CH3:58])[CH3:57]>CN(C)C=O>[NH2:67][C:62]1[CH:61]=[C:60]([C:56]([CH3:59])([CH3:57])[CH3:58])[CH:65]=[CH:64][C:63]=1[NH:66][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:29]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.52 g, 4.01 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanoic acid (1.7 g, 2.7 mmol) and N,N-Diisopropylethylamine (1.54 ml, 8.82 mmol) and 4-tert-butylbenzene-1,2-diamine (0.527 g, 3.21 mmol) in N,N-Dimethylformamide (16.6 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) added. Them mixture was extracted with EtOAc 3× and the combined organics were dried with MgSO4 filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.71 g) as a solid,
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:18]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 154 %

Procedure:
A stirred solution of 2.0 grams (0.007 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1) in 25 ml of methylene chloride was placed under an argon atmosphere and cooled to 0° C. To this was added 0.98 gram (0.007 mole) of benzoyl chloride in 5 ml of methylene chloride followed by 0.63 gram (0.008 mole) of pyridine. Upon completion of addition the reaction mixture was heated under reflux for 16 hours. The reaction mixture was diluted with methylene chloride and washed with 100 ml of water, 100 ml of aqueous 10% hydrochloric acid and finally 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel. The appropriate fraction was concentrated under reduced pressure to give 4.1 grams of solid. The solid was recrystallized from ethyl acetate/cyclohexane. A precipitate was collected by filtration; mp 117°-120°. Nuclear magnetic resonance spectroscopy indicated the precipitate to be benzoic acid. The mother liquor was concentrated under reduced pressure and the residue redissolved in 60 ml of methylene chloride. The solution was washed with five portions of 20 ml each of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. Volatiles were removed from the oil under reduced pressure using a short-path distilling system. There remained as a residue 1.0 gram of N-benzoyloxy-3-chloro-N-(2-chlorophenyl)methyl-2,2-dimethylpropanamide.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:15]([Sn](C)(C)C)[CH:14]=1>CN(C)C=O.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.[Cu]I>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[C:15]([C:2]2[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: C[Sn](C)(C)c1cc(Cl)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cc(Cl)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100° C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1>>[CH:6]12[CH2:5][CH:9]([CH:3]([CH:1]=[O:2])[CH2:4]1)[CH:8]=[CH:7]2
Reactant: C=CC=O
Reactant: C1=CCC=C1
Product: O=CC1CC2C=CC1C2

Procedure:
The exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; and endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture) can be prepared by a process comprising reacting acrolein and cyclopentadiene in a Diels-Alder reaction to give a 2-norbornene-5-carboxaldehyde, and hydroformylating the 2-norbornene-5-carboxaldehyde.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:22])=[CH:23][CH:24]=1
Reactant: NCCCCCn1ccnc1
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1)NCCCCCn1ccnc1
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (6.48 g) was added to a solution of 4-chlorophenoxyacetic acid (7.46 g) in THF (144 ml) at ambient temperature. The mixture was stirred for 2 hours and then 1-(5-aminopentyl)imidazole (6.1 g) was added. The mixture was stirred at ambient temperature for 18 hours and then worked up as described in Example 9a to give an oil which was purified by flash chromatography on silica using ethyl acetate/methanol/triethylamine, 18:2:1 as the mobile phase to give 2-(4-chlorophenoxy)-N-[5-(imidazol-1-yl)pentyl]acetamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:29](=[O:31])[CH3:30])[C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3ccc(Br)cc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
A 2-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirring, and thermocouple was charged with (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (45.0 g, 118 mmol), dichloromethane (900 mL), and pyridine (14.32 mL, 177 mmol). The mixture was cooled to 0° C. and acetyl chloride (10.07 mL, 142 mmol) was added slowly while maintaining the internal temperature below 10° C. The reaction mixture was held cold (ca. 30 min) and then warmed to rt. After 1 h, the reaction was diluted with dichloromethane (200 mL), and the solution was washed with 1 M aqueous HCl (2×100 mL) and water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluting with 3:1 dichloromethane-ethyl acetate) to afford (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (54.15 g, 108%), which contained 4.1 wt % ethyl acetate, as a colorless to yellow oil. MS (ESI, pos. ion) m/z 424 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]#[N:16])=[N:8][C:7]=1[CH:6]=[CH:5]2.N[C@@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3[S:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[N:16]=3)=[N:8][C:7]=1[CH:6]=[CH:5]2
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1nc2ccc3cc(N)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(ccc3nc(C4=NC(C(=O)O)CS4)sc32)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A solution of 7-aminonaphtho[2,1-d]thiazole-2-carbonitrile (24 mg, 0.106 mmol) in acetonitrile was treated with an aqueous solution containing D-cysteine (41 mg, 0.233 mmol) and K2CO3 (45 mg, 0.326 mmol). After stirring at RT for 20 min, the product was isolated by preparative HPLC eluting with a gradient of 5→100% MeCN in 10 mM aqueous NH4OAc. The appropriate fractions were concentrated under reduced pressure and then lyophilized to afford 12 mg of a yellow solid. 1H NMR (DMSO-d6) d 7.77-7.87 (m, 2H); 7.59 (d, 1H); 7.01 (dd, 1H); 6.94 (d, 1H); 5.69 (br s, 2H); 5.18 (t, 1H); 3.57-3.68 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:31][C:30]=1[O:29][CH3:28])=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-methoxy-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 603122-41-4]. MS (m/e)=550.3 [M+H+].
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH2:28])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:26])(=[O:27])[NH2:28])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(N)(=O)=O
Yield: 8.1 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g), 2-(aminomethyl)-4-fluorobenzenesulfonamide hydrochloride obtained in Step 3 (1.23 g) and potassium carbonate (1.76 g) were stirred in ethanol (20 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (68 mg).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(F)ccc1OCc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(COc2ccc(F)cc2C(=O)O)cc1

Procedure:
8.0 g (25 mmol) of methyl 2-(4-tert-butylbenzyloxy)-5-fluorobenzoate are dissolved in 64 ml of methanol and 32 ml of 40% strength sodium hydroxide solution and stirred under reflux for 12 h. The crystals which have separated out are filtered off with suction, washed with water, 1 N hydrochloric acid and petroleum ether and dried on a clay dish. 7.10 g (23.5 mmol, 94% of theory) of the title compound are isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[S:21][N:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][CH:27]4[CH2:26][CH2:25][N:24]([C:22]5[S:21][N:20]=[C:19]([CH3:18])[N:23]=5)[CH2:29][CH2:28]4)[N:16]=[C:12]3[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2cncc(-c3ccc(F)cc3)n2n1
Product: Cc1nsc(N2CCC(Nc3nc4cncc(-c5ccc(F)cc5)n4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:5]=1
Reactant: CN(C)CCCO
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCCCN(C)C)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 3-hydroxy-4-nitro benzoic acid methyl ester. (394 mg, 2.0 mmol), triphenyl phosphine (525 mg, 2.0 mmol), arid 3-(dimethylamino)-propanol (237 μL, 2.0 mmol) in dry tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (394 μL, 2.0 mmol in 1 mL of tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with hydrochloric acid (30 mL of a 1M solution) and extracted with ethyl acetate (2×50 mL). The aqueous solution was basified with 10% aqueous sodium carbonate (50 mL) and the product was extracted with ethyl acetate (3×100 mL). The ethyl acetate was washed with brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product (86% yield). 1H-NMR (400 MHz, CDCl3) δ7.81 (d, 1H), 7.78 (s, 1H), 7.65 (d, 1H, 4.23 (t, 2H), 3.91 (s, 3H),2.44 (t, 2H), 2.22 (s, 6H), 2.05 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: COC(C(=O)O)c1c(O)cccc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F

Procedure:
(RS)-(2-Fluoro-6-hydroxy-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide. Colorless solid. MS 315.1 ([M+H]+)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][CH:28]([CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:27][CH2:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:5](=[O:7])[CH3:6])[CH:28]([CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:27][CH2:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
74 μL (0.77 mmol) acetic anhydride are added to a solution of 220 mg (0.51 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 5 mL DCM and the mixture is stirred for 2 h at RT. Another 0.37 mL (3.85 mmol) acetic anhydride are added and the reaction is stirred for a further 4 days at RT. The solvent is eliminated i.vac. The purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [C:1]([N:5]([C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)[NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[O:14][C:13]=2[C:21]=1[CH3:22])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[C:39](O)=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[F:33][C:34]1[C:39]([O:19][C:18]([CH:15]2[O:14][C:13]3[C:21]([CH3:22])=[C:9]([C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:32])[C:24]4[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=4)=[O:8])[CH:10]=[CH:11][C:12]=3[O:17][CH2:16]2)=[O:20])=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C(=O)O)CO3)C(C)(C)C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CO3)C(C)(C)C)c1

Procedure:
In a vial, 97 mg (0.32 mm) of 7-[N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazinocarbonyl]-8-methyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid, 60 mg (0.35 mm) of pentafluorophenol, 60 mg (0.32 mm) of DCC and 3 mL of ethyl acetate were stirred at room temperature for 24 hours. The reaction mixture was transferred to a round bottom flask and evaporated to dryness. The residue was redissolved in CH2Cl2 and chromatographed on silica gel. Elution with 40% ethyl acetate in hexane yielded the pentafluorophenol ester, 7-[N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazinocarbonyl]-8-methyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid pentafluorophenyl ester, in a quantity of 80 mg. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.60 (d, 1H), 7.03 (s, 2H), 6.95 (d, 1H), 6.6 (q, 1H), 6.3 and 6.0 (d+d, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.251 and 2.230 (s+s, 6H), 2.052 and 1.903 (s+s, 3H), 1.58 and 1.574 (s+s, 9H) (many signals split); TLC. Rf=0.52 (1:1 hexane:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(C(C)C)CC)(C)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([NH:1][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:34])=[CH:26][CH:27]=2)=[O:32])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2ccc(C)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To 1.20 g (5.74 mmol) of methyl 5-amino-3-(methoxycarbonyl)benzoate, compound 87, suspended in 50 mL of chloroform and 1.05 mL (6.00 mmol) of diisopropylethylamine was added 836 μL (6.32 mmol) of p-toluoyl chloride in 10 mL of chloroform over 30 min. The reaction was allowed to stir at ambient temperature for 2 hr. Then, another 100 μL (0.60 mmol) of diisopropylethylamine and 100 μL (0.76 mmol) of p-toluoyl chloride in 2 mL of chloroform was added. After an addition 30 min, the volatiles were removed by rotary evaporation and the resulting residue was dissolved in ethyl acetate and extracted with 0.1 N aqueous NaOH followed by extraction with water. The organic layer was dried (MgSO4), filtered, and volatiles removed in vacuo. This provided 1.86 g (5.68 mmol) of the desired compound. The product was identified by 1H NMR and mass spectroscopy and purity was assessed by RP-HPLC.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:5].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][CH2:3][C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)cc1
Yield: 53 %

Procedure:
In the same manner as in Reference Example 6, ethyl 4-(2-amino-1-oxoethyl)benzoate hydrochloride and 4-trifluoromethylbenzoyl chloride were condensed to obtain ethyl 4-[2-(4-trifluoromethylbenzoylamino)-1-oxoethyl]benzoate. Yield: 53%. NMR (CDCl3) δ 1.43 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz), 5.01 (2H, d, J=4 Hz), 7.31 (1H, brs), 7.75 (2H, d, J=8 Hz), 7.95-8.25 (6H, m).