Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(OCC)(=O)C>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([NH:24][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:12])[CH:26]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(trifluoromethyl)phenyl]propanoic acid XII (0.93 g, 2.79 mmol) and 3-aminoquinoline XIII (0.45 g, 3.10 mmol) in ethyl acetate (30 mL) was added DMT-MM (1.0 g, 3.63 mmol). After being stirred at r.t. overnight, the reaction was washed with water, 1 N HCl, aq. sat. NaHCO3, water and dried over Na2SO4. The solvent was removed under reduced pressure to afford tert-butyl N-[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamate (1.19 g, 2.59 mmol, 93% yield). 1H NMR (DMSO-d6) 1.31 (s, 9H), 2.95-3.15 (m, 1H), 3.22-3.27 (m, 1H), 4.46-4.52 (m, 1H), 7.36 (d, J=8 Hz, 1H), 7.62-7.68 (m, 4H), 7.67 (t, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 8.13 (t, J=7 Hz, 2H), 8.99 (d, J=2 Hz, 1H), 9.24 (d, J=2 Hz, 1H), 11.18 (s, 1H); ESIMS found for C24H24N3O3F3 m/z 460 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[NH:4].CS(O)(=O)=O.[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[CH:21]=[C:22](N)[C:23]([NH2:37])=[CH:24][C:25]=1[O:26][C:27]1[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1>CN1CCCC1=O>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[C:25]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[CH:24][C:23]2[NH:37][C:3]([C:5]3[CH:10]=[N:9][CH:8]=[CH:7][N:6]=3)=[N:4][C:22]=2[CH:21]=1
Reactant: COC(=N)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1
Agent: CS(=O)(=O)O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2Cl)cn1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
15 mg of methylpyrazin-2-imidate (pyrazine-2-carboximidic acid methyl ester) and 0.0065 ml of methanesulfonic acid were added to an N-methylpyrrolidinone (0.5 ml) solution of 38 mg of 4-(2-chloro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 204 (step 1), and the reaction liquid was stirred at 120° C. for 20 minutes. The reaction liquid was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and then dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow solid.
Reaction SMILES: C(OC([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)(C)(C)C.[CH:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH:44]1([C:50]([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:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CCCCC1
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
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=12.N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2[N:5]=[C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]3=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[C:11]=2[CH2:10]1)=[O:13])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(N)c2C1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Yield: 56.8 %

Procedure:
10-Amino-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (0.77 g, 2.59 mmol) was added to pyridine (1.0 g, 12.7 mmol). Acetic anhydride (0.53 g, 5.18 mmol) was added to the mixture, followed by refluxing for 7.5 hours. Then, water was added thereto and the resulting mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain the desired compound (0.5 g, 1.47 mmol, 57%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:34][S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:11][CH:10]=3)[C:5]([F:23])=[CH:4][N:3]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:32])=[O:33]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-4-pyrimidineamine (34 mg, 0.096 mmol), 3-aminobenzenesulfonamide (33 mg, 0.19 mmol), and trifluoroacetic acid (11 μL, 0.14 mmol) were combined with iPrOH (0.40 mL) in a sealed vial and heated at 100° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). The crude product was isolated by filtration. Further purified by column chromatography (silica gel, dichloromethane ramped to methanol:dichloromethane (3:100)) provided N2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-2,4-pyrimidinediamine (I-4) as an off-white solid. 1H NMR (DMSO-d6): δ 9.57 (s, 1H), 9.47 (s, 1H), 8.15-8.08 (m, 2H), 7.99-7.95 (m, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.62 (t, J=5.7 Hz, 1H), 7.43-7.32 (m, 4H), 7.26 (s, 2H), 4.35 (s, 2H), 3.79-3.75 (m, 2H), 3.35 (t, J=2.4 Hz, 1H); LCMS: purity: 96%; MS (m/e): 492 (MH+).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([CH2:16][Zn+])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: [Zn+]CC1CCCCC1
Reactant: CSc1nsc(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.00 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 244 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 12 ml of tetrahydrofuran under nitrogen atmosphere, 13.2 ml of solution of (cyclohexyl)methyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 10 minutes, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 8 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 1.29 g of 3-methylthio-5-(cyclohexyl)methyl-1,2,4-thiadiazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=CC=C[C:24]=1[O:29][P:30]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)(=O)[O:31]C1C=CC=CC=1[N+]([O-])=O)([O-])=O.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:24][O:29][P:30]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)(=[O:31])[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: O=[N+]([O-])c1ccccc1OP(=O)(Oc1ccccc1[N+](=O)[O-])C1CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
The compound cyclohexylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 200 mg of 3-(1H-indol-2-yl)-H-indazol-5-ol (intermediate B) in solution with 325 mg of cyclohexylphosphonic acid bis(nitrophenyl)ester in 6 ml of dichloromethane (stabilized with amylene), to which 120 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 1 ml of dichloromethane are added. After stirring at ambient temperature for 4 hours 30 minutes, 325 μl of methanol in solution in 1 ml of dichloromethane are added. The mixture is left at ambient temperature overnight and the solvent is then evaporated off and the crude is purified by flash chromatography on 35-70 μm silica, eluent: cyclohexane/ethyl acetate 90/10 to 50/50. The fractions obtained are concentrated and purified by preparative LC/MS to obtain 64.5 mg of cyclohexylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH3:35])=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14]>C(O)(=O)C.[Zn]>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([C:24]4[S:28][C:27]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[N:26][C:25]=4[CH3:35])=[O:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2Cl)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A suspension of 1-(4,7-dichloroquinoline-3-sulfonyl)-4-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine (200 mg) and zinc powder (250 mg) in acetic acid (6 ml) was stirred at 80° C. for 2 hours, the mixture was concentrated. The residue was dissolved in dichloromethane-methanol, and insoluble materials were filtered off. The filtrate was concentrated to give brown solid which was successively washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and water, and dried to afford the title compound (43 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC(C1N=C[N:34]2[C:40]3[CH:41]=[CH:42][C:43](F)=[CH:44]C=3C(=O)N(C)CC=12)=O)C#C.IN1C(=O)CCC1=O.N1CCCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20][N:34]5[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]5)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1Cc2c(-c3ncc(CN4CCCCC4)o3)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 10.7 ml (0.109 mol) of piperidine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the beige-brown product was chromatographed over silica gel with ethyl acetate/methanol 4:1 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.85 g (17%) of 8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 191°-193°.
Reaction SMILES: [NH2:1][C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]4)[N:16]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[NH2:1][C:2]1([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]4)[N:16]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(C#CC4(N)CCCCC4)s3)n2)CC(C)(C)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC4(N)CCCCC4)s3)n2)CC(C)(C)N1

Procedure:
Compound of Example 78 (2.5 g, 5.7 mmol) was dissolved in 200 ml MeOH and 0.8 g palladium on charcoal 10% were added. Hydrogenation was performed at room temperature and 1 bar hydrogen pressure for 8 hours. Afterwards the mixture was filtered through Hyflo and evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:85/15/1.5). Yield: 1.6 g (64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 42.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.8 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:23][CH2:24][CH3:25])([C@@H:10]([NH:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH2:8]C)=[O:6])[CH3:2].O.OS(O)(=O)=O>O(C(C)C)C(C)C>[CH2:24]([O:23][C:4]([O:3][CH2:1][CH3:2])([C@@H:10]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:25]
Reactant: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OC

Procedure:
A diastereomeric mixture of (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate (6.4 g, d.r.: 85:15) was dissolved in 100 mL iPr2O and 2 mL water were added. The mixture was acidified to pH=2.21 with 50% H2SO4 and the resulting organic phase was concentrated to half its volume (50 mL). 1 mL water was added, and the mixture was acidified again to pH=2.22 with 50% H2SO4. The aqueous phase was combined with the aqueous phase from the previous extraction (V=1.5 mL) and extracted with 11 mL DIPET (diisopropyl ether) after adjusting the pH to 2.17 with 5M NaOH. The combined organic phases were concentrated (V=40 mL), 1 mL water was added and the mixture was acidified to pH=2.18 with 50% H2SO4. The organic phase was separated and the solvent was removed in vacuo to yield a 98:2 (syn:anti) mixture of diastereomers (37.5 mL solution, assay: 28%, 76% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]([NH2:17])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]#[N:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C#N)N2C(C)=O
Temperature: 25 °C

Procedure:
2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid methyl ester (0.084 mole) and 2M NH3 in methanol (500 ml) were combined and stirred at room temperature under argon over the weekend. The solution was concentrated to 100 ml, cooled in an ice bath, and filtered. The solid was rinsed with a small amount of cold methanol and dried. The residue was triturated in methanol/ACN and filtered, yielding 4.56 g of 2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 21, mp. 228-229° C.). b) Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196-197° C.). c) To a suspension of intermediate (22) (0.022 mole) in DCM (150 ml), cooled in an ice bath under argon, was added triethylamine (0.066 mole) then trichloroacetyl chloride (0.033 mole). The mixture was allowed to slowly warmed to room temperature overnight. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic phase was dried, concentrated and triturated in ether and the solid collected, yielding 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carbonitrile (intermediate 23, mp. 108-110° C.). d) To a solution of intermediate (23) (0.0154 mole) and ethanol (0.0231 mole) in 1M HCl/diethylether (200 ml), cooled in an ice bath was bubbled HCl (gas) for 60 minutes. The ice bath was maintained for 45 minutes, and the mixture was concentrated at room temperature under vacuum to 200 ml of an oily precipitate. The residue was triturated to a brown solid that became an oil after decanting off the diethylether. The residue was washed with diethylether twice, dissolved in methanol, and used without further purification for further synthesis, yielding ethyl 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboximidate monohydrochloride (intermediate 24).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(SCCCCCCCCCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 20 h

Procedure:
To a solution of 2,6-di-tert-butyl-4-mercaptophenol (II) (477 mg; 2 mmol) in dry ethanol (20 ml), water containing 12-bromododecanoic acid (558 mg; 2 mmol) and 97 % sodium hydroxide (250 mg; 6 mmol) was added, and the resultant mixture was allowed to stand at room temperature for 20 hours. The reaction mixture was made acidic with 10 aqueous acetic acid and extracted with ethyl acetate. The extract was washed two times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was chromatographed on silica gel and eluted with ethyl acetate. The collected fractions were concentrated under reduced pressure. The residue was recrystallized from a mixture of water and methanol (1 : 1 by volume) to give the objective compound (Ie) (680 mg). Yield, 78 %. m.p., 41°-42° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([OH:9])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:30]([NH2:41])[CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([NH:41][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1)=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N(CCC#N)CC(=O)O
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCC#N)CC(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
In a manner similar to the preparation of compounds of formula (Yc3) above, to 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]acetic acid (8.3 g, 39 mmol) dissolved in CH2Cl2 (100 mL) was added carbonyldiimidazole (6.2 g., 38 mmol). After stirring for 30 minutes, homopiperonylamine, hydrochloride (8.0 g, 41 mmol) and diisopropylethylamine (7.5 mL, 43 mmol) were added. After stirring for 18 hours, most of the solvent was removed in vacuo and the residue was partitioned with ethyl acetate and 1 N HCl. The organic layer was separated, washed with aqueous bicarbonate and brine, dried (Na2SO4), and the solvent was removed in vacuo to give 13 g of 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C@@H:23]3[C@@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([C:39]5C=CC=CC=5)[CH2:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[N:15]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].C([O:47]CC)C>>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C@@H:23]3[C@@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH:39]=[O:47])[CH2:35][CH2:34]4)=[O:32])=[CH:29][CH:30]=3)[N:15]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3]
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CCOCC
Agent: Cl
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C=O)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and piperazinylcarbaldehyde as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 143–144° C.