Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25][C@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=1)[CH2:33][C:32]1[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=1[Cl:26])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O)c1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Yield: 68 %

Procedure:
To a solution of 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (120 mg, 0.326 mmol) in DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (137 mg, 0.326 mmol), EDC (187 mg, 0.977 mmol) and DMAP (19.90 mg, 0.163 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The mixture was portioned between DCM and 1N HCl (50 ml) and the desired compound was extracted with DCM (3×50 ml). Crude (S)-4-(2-(2-(5-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained and used in the next step without any additional purification (170 mg, 0.221 mmol, 68% yield). MS/ESI+ 770.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13]C(C)(C)C)=[O:12]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\C1C(C(=O)O)C1(C)C

Procedure:
A solution containing 13.5 g of the product of Step B, 100 cm3 of toluene and 400 mg of hydrated p-toluene sulfonic acid was refluxed for 3 hours and then was evaporated to dryness under reduced pressure. The 11.2 g of residue were chromatographed over silica gel and was eluted with a 60-39-1 cyclohexane-ethyl acetate-acetic acid mixture. The eluate was evaporated to dryness under reduced pressure to obtain 9.6 g of (1R, cis) 2,2-dimethyl-3-[(Z)-2-(methoxy carbonyl)-ethenyl]-cyclopropane-carboxylic acid melting at 110° C. and having a specific rotation of [α]D20 =+75.4°±2° (c=1% in CHCl3).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.NN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][CH2:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=2)[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C.O>[O:56]=[C:55]([N:57]1[CH2:58][CH2:59][CH:60]([O:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:71])[F:72])[CH:65]=2)[CH2:61][CH2:62]1)[CH2:54][NH:53][C:21]([C:19]1[N:18]=[N:17][N:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1)=[O:23]
Reactant: O=C(O)c1cn(N2CCOCC2)nn1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(N2CCOCC2)nn1
Reaction time: 0.03 h
Yield: 84.7 %

Procedure:
DIPEA (200 mg, 1.54 mmol) was added to a stirred solution of 1-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 4-aminomorpholine) (70 mg, 0.35 mmol) in DMF (5 mL) followed by HOBt (52 mg, 0.38 mmol) and EDCI (170 mg, 0.88 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (120 mg, 0.35 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate was collected out. The solid obtained was purified by recrystallisation from a mixture of 20% ethyl acetate in hexane and MeOH to afford 144 mg (84.7% Yield) of 1-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 483.19, 92.7%. 1H NMR (300 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.4 (t, 1H), 7.6 (t, 1H), 7.36 (t, 3H), 4.9 (m, 1H), 4.2 (d, 2H), 4.0-3.6 (m, 6H), 3.4 (m, 2H), 3.2 (m, 2H), 2.1 (t, 2H), 1.7 (d, 2H).
Reaction SMILES: [C:1]1(=O)CCCC(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.CC1CC(=O)CC(=O)C1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:1])[CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(OC)c1
Reactant: O=C1CCCC(=O)C1
Agent: CC1CC(=O)CC(=O)C1
Product: COc1cc(C)cc(OC)c1
Yield: 60 %

Procedure:
In contrast cyclohexane-1,3-dione (R2 to R4 are H), for example, can be converted in 76% yield, to 1,3-dimethoxybenzene of type Ic over a Cu2O/thionyl chloride catalyst in methanolic solution. A 60% yield of 1,3-dimethoxy-5-methyl-benzene is obtained as the main product from 5-methyl-cyclohexane-1,3-dione under the same conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1(C(F)(F)F)CC1)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 701 mg (2.58 mmol) of [1-(trifluoromethyl)cyclopropyl]methyl trifluoromethanesulphonate and 1.73 ml (1.73 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 13 ml of THF were reacted according to General Method 7B. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 40 g silica cartridge, flow rate 40 ml/min), giving the title compound. Yield: 295 mg (45% of theory)
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]([C:8]1[Se:9][C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:12](=O)[CH:13]=1)([CH3:7])[CH3:6].[F:19][B-:20]([F:23])([F:22])[F:21].[H+]>O1CCCC1>[F:19][B-:20]([F:23])([F:22])[F:21].[CH3:4][C:5]([C:8]1[CH:13]=[C:12]([CH3:1])[CH:11]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[Se+:9]=1)([CH3:7])[CH3:6]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)c1cc(=O)cc(C(C)(C)C)[se]1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Methyl magnesium chloride (40 mL of a 3M solution in tetrahydrofuran, 0.12 mole) was added to a solution of 2,6-bis[1,1-dimethylethyl]selenopyran-4-one (22 g, 0.081 mole, prepared in Part C above) in dry tetrahydrofuran (100 mL) which was initially maintained at -20° C. using a cold bath; the addition was effected at such a rate that the temperature in the reaction vessel did not exceed -15° C. The cold bath was removed, and the pale yellow solution was allowed to stir at room temperature for four hours, during which time a thick slurry formed. The mixture was then poured into ice/water (1L) with rapid agitation, and tetrafluoroboric acid (200 mL of a 48% aqueous solution) was added. Stirring was continued for a further two hours, after which the mixture was extracted with dichloromethane (3×100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a tan residue, which was triturated with ether. The resultant solid was collected by filtration, washed with ether and dried to give 2,6-bis(1,1-dimethylethyl)-4-methylselenopyrylium tetrafluoroborate (24.7 g, 85% yield) as an off-white solid melting at 65-66° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:22]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:16]3[CH2:18][CH:17]3[CH:19]=[N:20]O)[N:10]2[N:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[N:22]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:16]3[CH2:18][CH:17]3[CH2:19][NH2:20])[N:10]2[N:9]=1
Reactant: Cc1nc2cccc(C3CC3C=NO)n2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cccc(C3CC3CN)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (141 mg, 3.70 mmol) in tetrahydrofuran (10 mL) was added 2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclopropanecarbaldehyde oxime (200 mg, 0.925 mmol) obtained in Reference Example 112 at room temperature, and the mixture was stirred at room temperature for 2 hr, and at 60° C. for 2 hr. Sodium sulfate decahydrate was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 1-[2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclopropyl]methanamine as a crudely purified product.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Product: COCOc1cc(SCc2ccc(C(F)(F)F)nc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-(chloromethyl)-6-trifluoromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[C:10]=1[Cl:11])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([CH3:36])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[C:10]=1[Cl:11])[C:5]([NH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([CH3:36])[CH:27]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: CC(C)Oc1cc(C(=O)O)cc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)c(OC(C)C)c2)cc1C
Yield: 68 %

Procedure:
Methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (237 mg, 68%) was prepared from 3,4-dichloro-5-isopropoxybenzoic acid (8) (200 mg, 800 μmol) using a procedure essentially the same as in step (i) for AAA-064 except that DIPEA was used instead of TEA, and methyl 4-amino-2-methylbenzoate (9) was used instead of methyl 4-amino-2-fluorobenzoate: m/z 396 [M+H]+ (ES+), 394 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 7.89 (1H, d), 7.81 (1H, d), 7.77-7.72 (2H, m), 7.64 (1H, d), 4.85 (1H, sep), 3.81 (3H, s), 2.54 (3H, s), 1.35 (6H, d).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2)=[O:27]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:26](=[O:27])[NH:25][CH2:24][CH2:23][OH:22])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-(2-hydroxyethyl)-1H-indole-5-carboxamide (intermediate-19) (0.110 g, 48.0%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C)CCN(C)C.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1.C([Li])(CC)C>[OH:28][CH:27]([C:24]1[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[CH2:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(C)C(=O)OC(C)(C)C
Reactant: COc1ccc(C=O)cn1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(C(O)CN(C)C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To a solution of tert-butyl dimethylcarbamate (1.8 g, 0.012 mol) and tetramethylethylenediamine (2.6 g, 0.022 mol) in THF (anhydrous, 30 mL) was added sec-butyllithium (1.4 M in cyclohexane, 11 mL, 0.015 mmol) at −78° C. The mixture was stirred at that temperature for 30 minutes before a solution of 6-methoxy-3-pyridinecarboxaldehyde (J.Org.Chem. 55; 1; 1990; 69-73)(1.4 g, 0.01 mol, in 5 mL of dry THF) was introduced. The reaction mixture was stirred for 30 minutes, warmed to room temperature and stirred for 3 hours. Saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction after the reaction mixture was cooled to −78° C. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine and dried over sodium sulfate and concentrated. The residue was purified with a silica gel column to give the title compound (1.2 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-acetylpyridine (5.00 g, 41.3 mmol) in acetic acid (100 ml) was added 47% hydrobromic acid (7.10 ml, 41.3 mmol), and a solution of bromine (2.12 ml, 41.3 mmol) in acetic acid (50 ml) was added dropwise under ice-cooling. After the completion of the dropwise addition, the reaction mixture was heated to 80° C. and the mixture was stirred for one hr. After cooling, the precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate and dried under reduced pressure to give white crystals.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:31])=[CH:27][CH:28]=1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CN
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
After dissolving N-[4-(6-aminomethyl-7-methoxy-quinolin-4-yloxy)phenyl]-N′-phenylurea trifluoroacetate (40 mg) in pyridine (1.0 ml) and acetic anhydride (1.0 ml), the solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the obtained crude product was crystallized with ethyl acetate to obtain the title compound (13 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]([C@@H:47]([N:56]([CH3:73])[C:57](=[O:72])[C@H:58]([NH:70][CH3:71])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[CH2:48][NH:49][C:50]([NH:52][CH:53]1[CH2:55][CH2:54]1)=[S:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:70]([C@@H:58]([C:57](=[O:72])[N:56]([C@H:47]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:48][NH:49][C:50]([NH:52][CH:53]1[CH2:54][CH2:55]1)=[S:51])[CH3:73])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[CH3:71])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (182 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (102 mg, 0.75 mmol) was added. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol) was added. The solution was stirred for 15 min at 0° C. (2R)-N-((1R)-1-Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (178 mg, 0.37 mmol) was dissolved in dichloromethane and added to the reaction mixture. Ethyidiisopropylamine (0.13 ml, 0.75 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (45 g) to give 89 mg of (3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butylester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[OH:21])=[O:13])[CH:8]=[C:7]2[CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=1.I[Si](C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[OH:21])=[O:13])[CH:8]=[C:7]2[CH2:22][C:23]1[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=1
Reactant: COc1ccc(Cc2cc(C(=O)N[C@H]3CCOC[C@@H]3O)nc3c(F)cccc23)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(O)nc2)c2cccc(F)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 19 (31.2 mg, 0.076 mmol) in CH2Cl2 (506 μl) at 0° C. was added iodotrimethylsilane (20.6 μl, 0.152 mmol). The mixture was stirred at room temperature for overnight. Second portion of TMSI was added and the reaction was heated to 50° C. for 2 h. The reaction mixture was quenched w/H2O, extracted w/EtOAc. The combined organic layers were dried (Na2SO4), filtered, cone. The residue was purified by reverse phase HPLC (C-18 column, 3-70% MeCN in H2O with both containing 0.05% TFA) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=6.8 Hz, 1H), 8.16 (s, 1H), 7.75 (dd, J=2.4, 9.2 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.63 (dt, J=4.8, 8.0 Hz, 1H), 7.50 (dd, J=8.0, 10.0 Hz, 1H), 7.45 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.41 (s, 2H), 4.13 (dd, J=4.8, 11.2 Hz, 1H), 4.07-4.03 (m, 1H), 3.76 (dt, J=4.8, 9.6 Hz, 1H), 3.52 (dt, J=2.4, 11.6 Hz, 1H), 3.28 (dd, J=10.0, 11.2 Hz, 1H), 2.15-2.10 (m, 1H), 1.95-1.85 (m, 1H). HRMS (ES) [M+1]+ calcd for C22H21FN3O4: 398.1517, Found: 398.1511.
Reaction SMILES: CC(N=C=NC(C)C)C.[CH3:10][O:11][C:12](=[O:25])[C@H:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH2:14].[CH3:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[C:31]([CH3:33])[CH:32]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:14][C@@H:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([O:11][CH3:10])=[O:25])=[O:36])[CH:30]=[C:31]([CH3:33])[CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)Cc1cc(C)cc(C)c1

Procedure:
DMAP (122.2 mg, 0.5 mmol) and DIC (N,N-diisopropylcarbodiimide) (235 μl, 1.5 mmol) were added to a solution of tryptophan methyl ester (255 mg, 1.0 mmol) and 3,5-dimethylphenylacetic acid (164 mg, 1.0 mmol) in dry DCM (11 ml). After 17 h at room temperature the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (DCM containing 1% EtOH) to afford (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate. An aqueous solution of LiOH (1N, 4.5 ml, 4.5 mmol) was added to a solution of (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate (365 mg, 1 mmol) in methanol (24.5 ml) and the reaction mixture was stirred at room temperature for 4.5 h. Then water was added and methanol was removed under reduced pressure. The aqueous residue was washed with DCM (5×20 ml), treated with HCl 2N to obtain a pH 4 and extracted with DCM (3×25 ml). The organic phases were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propionic acid (93% c.y.).
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[CH3:39][O:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH2:50]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:2])[NH:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[CH:17][CH:16]=1
Reactant: COCCCc1ccccc1N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Product: COCCCc1ccccc1NC(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 3a, 0.537 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.207 g of 2-(3-methoxypropyl)phenylamine are reacted. The title compound is obtained as a yellow oil. Rf=0.19 (1:1 EtOAc-heptane); Rt=5.94.