Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C([BH3-])#N.[Na+]>[Pd].CO>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][C:54]3[CH:2]=[CH:3][CH:4]=[CH:5][C:53]=3[CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2Cc3ccccc3CO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C

Procedure:
20 mg (0.021 mmol) of Intermediate 164 were used, in analogy to the preparation of Intermediate 97, with benzyl 6-oxohexyl carbamate in the presence of sodium cyanoborohydride and subsequent hydrogenolytic detachment of the Z protecting group (with 5% palladium on charcoal as a catalyst, in methanol as a solvent), to prepare the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[CH:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1>[Pd].CCO>[CH3:13][C:7]1[CH:8]=[C:9]([OH:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[CH:2][CH:11]=2
Reactant: Cc1cc(O)c2cc(Br)ccc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)c2ccccc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A slurry of 7-bromo-3-methylnaphthalen-1-ol (100 mg, 0.421 mmol), 10% w/w Pd/C (45 mg, 42.1 μmol Pd), and absolute EtOH (2.0 mL) was purged under vacuum and backfilled with H2 from a balloon several times. The suspension was stirred under a balloon of H2 at 23° C. overnight. The reaction was filtered over Celite, the cake was washed with EtOAc. The filtrate was concentrated and dissolved in DCM. The solution was loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.22 (s, 1H), 6.67 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:57]1([N:60]2[CH2:65][CH2:64][N:63]([C:66]3([CH2:72][NH:73][C:74](=[O:81])[C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][CH2:61]2)[CH2:59][CH2:58]1>ClCCl.CN(C=O)C>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:69]2[CH2:68][CH2:67][C:66]([CH2:72][NH:73][C:74](=[O:81])[C:75]3[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=3)([N:63]3[CH2:62][CH2:61][N:60]([CH:57]4[CH2:58][CH2:59]4)[CH2:65][CH2:64]3)[CH2:71][CH2:70]2)=[O:23])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)COCCN(C1CC1)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(N2CCN(C3CC3)CC2)CCN(C(=O)COCCN(C2CC2)S(=O)(=O)c2ccccc2C(F)(F)F)CC1)c1ccncc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-2-(trifluoromethyl)phenylsulfonamido)-ethoxy)acetic acid AC9 (0.472 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 55%. MS, Rt=2.8 min, m/z=693.5 [MH]+.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]2[C@H:26]([CH:27]=O)[O:25][CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]2[C@H:26]([CH:27]=[CH2:1])[O:25][CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=C[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (3.59 g) in THF (30 mL) was cooled under nitrogen purging to −78° C., and 1.6 M n-butyllithium/hexane solution (5.79 ml) was added. The mixture was warmed to 0° C., and stirred for 20 min, and a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (2.89 g) in THF (50 ml) was added. After stirring at 0° C. for 20 min, and at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-30%)) to give the title compound (1.10 g) as a colorless oil.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH:19]1([CH:27]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([CH:39]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[NH:29][NH:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:28][CH:27]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([NH2:29])[CH:39]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCCC(C2CCCCCCCCC(C3CCCCCCC3)NN2)CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: NC(CCCCCCCCC(N)C1CCCCCCC1)C1CCCCCCC1

Procedure:
The procedure described in (a) is repeated, starting from 65 g (0.168 mole) of 3,12-dicyclooctyl-1,2-diazacyclododecane and using correspondingly reduced amounts of catalyst and solvent, affording after purification by chromatography 43.6 g (66% of theory) of 1,10-diamino-1,10-dicyclooctyldecane as a colourless oil [nD20 =1.5050; IR spectrum (liquid) includes bands at 3333, 3278, 1613 cm-1 ].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[C:10]2=[N:11][C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:14]=[C:9]2[CH:8]=[C:7]1[C:20]([O:22]CC)=O)[CH3:5].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:5][CH:4]1[N:6]2[C:10]3[N:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:20](=[O:22])[NH:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCN)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CCNC(=O)c2cc3ccc(C(=O)O)nc3n21
Temperature: 60 °C
Reaction time: 16 h
Yield: 53.6 %

Procedure:
To a solution of diethyl 1-(4-aminobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (1.20 g, 3.60 mmol) in ethanol (35 mL) is added potassium carbonate (1.49 g, 10.8 mmol). The mixture is stirred at 60° C. for 16 h and is then cooled to room temperature. The ethanol is removed in vacuo and the aqueous mixture is acidified to pH 5 with 1N hydrochloric acid and is extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (500 mg, 54%). LCMS: (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:28]1(=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:41]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ccc(CC2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C=C2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(cyclohexyl-methyl)-aniline (Eur. J. Med. Chem. Chim. Ther. 1992, 27, 537-544) Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C30H30N2O3
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:20][O:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][O:21][C:22]([N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[C:3]([Cl:2])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: Clc1ccc2c(n1)CCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2nc(Cl)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (1.54 g, 7.5 mmol) in DCM (25 mL) was added Et3N (3.1 mL, 22 mmol). After the addition and stirring at room temperature for 5 min, the solution was cooled to 0° C., followed by the addition of methylchloroformate (0.85 mL, 11 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with satd. aq. NaHCO3 solution and brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 40 g, 30% EtOAc in hexane) then afforded the tile compound (1.53 g, 90%) as a white solid. MS: 227.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu].[Cu]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl[Cu]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound, mp 98-105° C., was prepared from 4-[4-(3,4-dichlorophenyl)butyl]phenylamine (0.50 g, 1.7 mmol), 2-chlorobenzoic acid (0.24 g, 1.56 mmol), anhydrous potassium carbonate (0.71 g, 5.15 mmol), copper powder (0.21 g, 3.28 mmol), and copper(I) chloride (0.015 g, 0.15 mmol) in dry DMF (5 mL) using the procedure described in Example 1, Step C, Method B.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][CH2:31][C:26]([OH:32])([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1

Procedure:
The compound of Example 25 was prepared according to the general preparation protocol A from 3,5-bis(trifluoromethyl)benzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Reactant: CC[C@@H](N)C(=O)O
Product: CC[C@@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using D-2-aminobutyric acid (310 mg, 3 mmol) to give (R)-2-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4R)-5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:21])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CI.Cl>O1CCCC1>[CH3:1][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:21])=[O:20]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 100 ml. of dry tetrahydrofuran containing 11.8 ml. of dry diisopropylamine and 55 ml. of 1.6M n-butyl lithium was added 5.4 ml. of n-heptanoic acid and the mixture allow to stir at room temperature for one hour. The resulting solution was cooled to 0° C. and 7.2 ml. of methyl iodide was added. The reaction was stirred at room temperature under nitrogen for 1.5 hours, and was then poured into 10% hydrochloric acid and extracted with diethyl ether (3×100 ml.). The extracts were combined, washed with 10% hydrochloric acid, water, 20% sodium bisulfite and a brine solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue, 5.61 g., dissolved in methanol containing 5.1 g. of potassium hydroxide. After stirring overnight the mehtanol was removed and the residue dissolved in 150 ml. of water. The aqueous layer was washed with ether (2×100 ml.) and acidified with 10% hydrochloric acid. The product was extracted with ether, washed with a 20% sodium bisulfite solution and brine and dried over magnesium sulfate. Removal of the ether gave 5.0 g. of the product as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:15]=[C:14]([CH3:16])[C:6]([C:7](/[N:9]=[CH:10]/N(C)C)=[O:8])=[C:5]([F:17])[CH:4]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][N:2]([CH3:18])[C:3]1[CH:15]=[C:14]2[C:6](=[C:5]([F:17])[CH:4]=1)[C:7](=[O:8])[NH:9][CH:10]=[CH:16]2
Reactant: Cc1cc(N(C)C)cc(F)c1C(=O)/N=C/N(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)c1cc(F)c2c(=O)[nH]ccc2c1
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To the clear solution of 4-Dimethylamino-N-[1-dimethylamino-meth-(E)-ylidene]-2-fluoro-6-methyl-benzamide (0.709 g, 2.82 mmol) in THF (2 mL) was added potassium tert-butoxide (2.8 mL, 1.0 M THF, 1.0 eq.), and the resultant brown, homogeneous reaction mixture was refluxed. After 1 h., the reaction mixture was quenched with 1M citric acid (1 eq.), dried (MgSO4), filtered, and concentrated in vacuo to give a yellow solid, which was purified by preparative plate (50% 60/10/1 CH2Cl2/MeOH/NH4OH in CH2Cl2) to give 6-Dimethylamino-8-fluoro-2H-isoquinolin-1-one as a white solid (0.104 g, 18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH2:30])[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(=[O:39])[CH3:38].O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH:30][C:37](=[O:39])[CH3:38])[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(N)cs3)ccc2c1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Yield: 82.3 %

Procedure:
A solution of tert-butyl[6-(4-amino-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.4 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) in N,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl{6-[4-(acetylamino)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.18 g, 85.7%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetate (1.0 g, 2 mmol) in dioxane (10 mL) was added 4N HCl solution in 1,4-dioxane (20 mL, 549 mmol) followed by concentrated HCl (1.0 mL, 27 mmol). The reaction was stirred at 50° C. for 6 h and concentrated under vacuum. The crude product was triturated with EtOAc or diethyl ether, filtered, and dried to give the title compound (0.8 g, 77% yield). MS (ESI, pos. ion) m/z: 345.1 (M+1-2HCl).
Reaction SMILES: C1(C)C=CC=CC=1.C([O:20][C:21]([C:23]1[CH:24]=[C:25]2C(=O)N(O)C(=O)[C:26]2=[CH:33][CH:34]=1)=[O:22])CCCCCCCCCCC.O=O>>[C:21]([OH:22])(=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Agent: O=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Yield: 1440 %

Procedure:
A mixture of 47 mmol of toluene, 0.1 mmol of 4-dodecyloxycarbonyl-N-hydroxyphthalimide and 0.01 mmol of acetylacetonatocobalt(II) was stirred at 100° C. in an atmosphere of oxygen gas (1 atm=0.1 MPa) for 65 hours and thereby yielded 1.44 mmol of benzoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:25]=[CH:24][C:16]([CH:17]([CH3:23])[CH2:18][C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:17]([CH3:23])[CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[O:9])=[CH:26][CH:27]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)CC(C)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1
Solvent: CO
Product: CC(CC(=O)O)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1
Reaction time: 8 h

Procedure:
113 mg of methyl rac-p-[2-(p-amidinobenzamido)ethyl]-β-methylhydrocinnamate were dissolved in methanol/2 N sodium hydroxide solution and stored at room temperature overnight. The residue after removal of the solvent was dissolved in hot methanol, and ether was added. The crystals precipitated were filtered off with suction and dried over high vacuum, resulting in 52 mg of the sodium salt of rac-p-[2-(p-amidinobenzamido)ethyl]-β-methylhydrocinnamic acid. The melting point in dimethyl formamide was greater than 200° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([N:9]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH3:10])=[O:8])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([N:9]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH3:10])=[O:8])(=[O:3])[NH2:2]
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(N)=O)c1
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 3-(2-(2-(2-(3-(carbamoyl)-N-methylbenzamido)ethoxy)ethoxy)ethoxy)propanoate (120 mg, 0.14 mmol, 1.00 equiv, 90%) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) dropwise with stirring and the resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum and the crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 45 mg (45%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): 10.95 (s, 1H), 10.87 (s, 1H), 9.19 (s, 2H), 8.35-8.38 (t, 2H), 8.04-8.07 (d, J=9 Hz, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.51-7.60 (m, 5H), 7.34 (s, 1H), 3.43-3.62 (m, 17H), 3.98 (s, 3H), 2.38-2.42 (t, J=6, 6 Hz, 2H), 1.51-1.71 (m, 6H). MS (ES, m/z): 739 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH3:28][O:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:34][CH:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1Cl
Reactant: CCC(N)COC
Product: CCC(COC)Nc1nccc(-c2cc(Cl)c(OC)cc2C)c1[N+](=O)[O-]
Yield: 38.5 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.38 g, 0.89 mmol) and 1-methoxymethyl-propylamine (0.23 g, 2.23 mmol) were treated substantially as described in Part C of Example 19a to produce 0.13 g (40%) of crude [4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 380.19 [(M+H)+, 100].