Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:11]
Reactant: COc1ccccc1C(C)=O
Reactant: COC(OC)N(C)C
Product: COc1ccccc1C(=O)C=CN(C)C

Procedure:
A mixture of o-methoxyacetophenone and dimethylformamide dimethylacetal is reacted as described in Example 51 to give the product of the Example.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: O=CC1CC1
Reactant: Nc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1ccccc1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50° C. for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. This mixture was stirred for 2 hours while warming to ambient temperature and then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate in heptane) to provide the title compound (1.05 g, 93% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][C:40]3=[O:49])[CH2:35][CH2:34]2)=[O:32])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)[C:9]1=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:30][C:31]([N:33]2[CH2:34][CH2:35][CH:36]([N:39]3[CH2:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][C:40]3=[O:49])[CH2:37][CH2:38]2)=[O:32])([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C:9]1=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(Cc2ccc(OCc3ccccc3)cc2)CCCCN(Cc2ccccc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(NC1(Cc2ccc(O)cc2)CCCCN(Cc2ccccc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 32 h
Yield: 73.9 %

Procedure:
10% Palladium on carbon (23 mg) was added to a solution N-{1-benzyl-3-[4-(benzyloxy)benzyl]-2-oxoazepan-3-yl}-4-(2-oxo-1,4-dihydroquinazolin-3 (2H)-yl)piperidine-1-carboxamide (67 mg, 0.100 mmol) in ethanol (5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 32 h, the mixture was filtered and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→10% methanol/dichloromethane) gave the title compound (43 mg). MS 582 (M+1).
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(C)c2)c1CCOCCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1c(O)cc(O)c(-c2cccc(C)c2)c1CCOCCOC
Yield: 45 %

Procedure:
In the same manner as in Example 118, 1-{4,6-bis(methoxycarbonyloxy)-2-[2-(2-methoxyethoxy)ethyl]-3-(3-methylphenyl)phenyl}ethanone was obtained from Compound 139 (410 mg, 1.2 mmol) obtained in Example 139, using methyl chlorocarbonate (0.2 mL, 2.6 mmol), triethylamine (0.4 mL, 2.9 mmol) and tetrahydrofuran (5.0 mL); and from the resulting compound, obtained was 4-ethyl-1,5-bis(methoxycarbonyloxy)-3-[2-(2-methoxyethoxy)ethyl]-2-(3-methylphenyl)benzene, using sodium borohydride (210 mg, 5.5 mmol), water (3.0 mL) and tetrahydrofuran (5.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 149 (180 mg, 45%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]3[O:13][CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]=3[CH:10]=2)O1.Br[C:28]1[N:33]=[C:32]([C:34]([O:36][CH3:37])=[O:35])[C:31]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].S1C2C=CC=CC=2N=C1NC(N1C2C(=CC=C(C3SC(C4C=CC(OC)=CC=4)=C(C(O)=O)N=3)C=2)CCC1)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOC(C)=O>[CH3:37][O:36][C:34]([C:32]1[N:33]=[C:28]([C:9]2[CH:25]=[CH:24][C:12]3[O:13][CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:11]=3[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccc(-c2sc(-c3ccc4c(c3)N(C(=O)Nc3nc5ccccc5s3)CCC4)nc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCO3)ccc1OCCCOc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (53B) (72 mg, 0.20 mmol), methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C) (72 mg, 0.20 mmol), K2CO3 (30 mg, 0.22 mmol in 0.5 mL of water), tetrabutyl ammonium bromide (64 mg, 0.20 mmol) and dichlorobis(triphenylphosphine)palladium (1) (10 mg, catalytic amount) in 1,4-dioxane (5 mL) was heated to 90° C. for 6 hours. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 20% EtOAc in hexanes to provide the desired product tert-butyl 6-(6-(methoxycarbonyl)-5-(3-phenoxypropoxy)pyridin-2-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (53C). 1H NMR (300 MHz, CDCl3): 8.49 (1H, s), 7.74 (1H, d), 7.60 (1H, d), 7.38 (1H, d), 7.24 (2H, m), 6.90 (4H, m), 4.31 (2H, t), 4.18 (2H, t), 4.25 (2H, t), 3.95 (3H, s), 3.85 (2H, t), 2.3 (2H, m), 1.58 (9H, s). LCMS (APCI): m/z 521.1 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 97.8 %

Procedure:
A solution of 2.03 g (6.36 mmol) of methyl (R)-3-(4-allylphenyl)-2-tert-butoxycarbonylaminopropionate (prepared as in Synlett, 2005, 12, 1877-1880) in 20 ml of dioxane/water (1:1, v/v) and 0.30 g (12.71 mmol) of lithium hydroxide was stirred at RT for 2 h and then neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over Na2SO4, filtered and concentrated. 1.90 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([O:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:49]([O:48][C@@H:45]1[CH2:44][CH2:43][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:47][CH2:46]1)[CH3:50]
Reactant: CCO[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166A). 1H NMR (DMSO-d6, 400 MHz): δ=1.15-1.22 (m, 9H), 1.44-1.56 (m, 4H), 1.69-1.82 (m, 2H), 1.95 (d, J=11.62 Hz, 2H), 2.53-2.63 (m, 1H), 3.07 (s, 3H), 3.22-3.30 (m, 2H), 3.45 (q, J=6.99 Hz, 2H), 3.60 (br. s., 1H), 3.75 (s, 3H), 3.94-4.04 (m, 4H), 4.49 (s, 2H), 6.91 (d, J=7.58 Hz, 1H), 7.06 (s, 1H), 7.18 (br. s., 1H), 7.49 (br. s., 1H), 8.22-8.48 (m, 2H), 9.00 (br. s., 1H), 10.56 (s, 1H). MS (ES+): m/z 706.30 [MH+] (TOF, polar).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[CH:16]([O:19][CH:20]([O:35][CH:36]([CH3:38])[CH3:37])[C:21]([CH3:34])([CH3:33])[C:22](=[O:32])[C@H:23]([CH3:31])[C@@H:24]([OH:30])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:18])[CH3:17].[Na+].[Cl-]>C(Cl)Cl>[CH:36]([O:35][CH:20]([O:19][CH:16]([CH3:18])[CH3:17])[C:21]([CH3:33])([CH3:34])[C:22](=[O:32])[C@H:23]([CH3:31])[C@@H:24]([O:30][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:38])[CH3:37]
Reactant: C=CC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Reaction time: 5 h

Procedure:
Trichloroethyl chloroformate (2.5 mL) and pyridine (2.95 mL) are added to a solution of (4R,5S,6S)-1,1-diisopropoxy-5-hydroxy-2,2,4,6-tetramethyl-8-nonen-3-one (3.0 g) in 40 mL of CH2Cl2 at 0° C., and the mixture is stirred for 5 hours before pouring into sat. aq. NaCl and extracting with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (2% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[N:15][C:16]([C:17](O)=[O:18])=[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=2[CH:20]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:34][C:35]1[C:36](=[O:48])[N:37]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[N:38]([CH3:41])[C:39]=1[CH3:40].C(N(CC)CC)C>C(Cl)Cl.O>[CH:42]1([N:37]2[C:36](=[O:48])[C:35]([NH:34][C:17]([C:16]3[N:15]=[N:14][N:13]4[C:7]5[CH:6]=[CH:5][C:4]([O:3][C:2]([F:21])([F:22])[F:1])=[CH:20][C:8]=5[CH2:9][CH2:10][CH2:11][C:12]=34)=[O:18])=[C:39]([CH3:40])[N:38]2[CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C(O)c1nnn2c1CCCc1cc(OC(F)(F)F)ccc1-2
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(NC(=O)c2nnn3c2CCCc2cc(OC(F)(F)F)ccc2-3)c(=O)n(C2CCCCC2)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 8-(trifluoromethoxy)-5,6-dihydro-4H-benzo[f][1,2,3]triazolo[1,5-a]azepine-3-carboxylic acid (169 mg, 0.540 mmol) in dry DCM (2 mL) under nitrogen was added oxalyl chloride (0.052 mL, 0.593 mmol) and DMF (0.084 mL, 1.079 mmol) and the mixture was stirred for 15 mins. 4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) (124 mg, 0.593 mmol) was added followed by triethylamine (0.226 mL, 1.619 mmol) and the mixture was stirred at RT for 16 hrs. The resultant mixture was diluted with DCM and water and stirred vigorously. The mixture was passed through a phase separating cartridge and the organic portion was concentrated under reduced pressure to give a yellow oil. The oil was absorbed onto silica and purified by chromatography eluting with 100% TBME. The product fractions were combined and concentrated under reduced pressure to give a glassy solid which was recrystallised from 1:1 diethylether:EtOAc. The resulting crystals were filtered under gravity to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]([CH2:7]Br)=[O:6])([F:4])([F:3])[F:2].[C:9]([C:13](OCC)=[O:14])([F:12])([F:11])[F:10].O1CCCC1>[Zn].CN(C)C=O>[C:1]([C:5]([CH2:7][C:13]([C:9]([F:12])([F:11])[F:10])=[O:14])=[O:6])([F:4])([F:3])[F:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(CBr)C(F)(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F

Procedure:
CF3COCH2Br (1.91 gr, 10 mmol), CF3CO2C2H5 (1.42 gr, 10 mmol), and zinc powder (1.3 gr) were put into a flask (100 ml) together with a mixed solvent comprising tetrahydrofuran (20 ml) and dimethylformamide (10 ml), and they were subjected to the reaction for a period of one hour while being irradiated with ultrasonic waves by means of an ultrasonic cleaner (35W, 32 kHz). After the reaction, impurities contained in the mixed liquid were filtered, then water (500 ml) was added to the filtered liquid, whereby an oil layer generated was extracted by means of diethylether. After drying the extracted liquid with magnesium sulfate, the solvent was removed. The product (CF3COCH2COCF3) (bp: 70° to 72° C.) was obtained through distillation with a yield by 69%.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1([OH:21])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:2].C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:2]
Reactant: CCc1ccsc1C1(O)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccsc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(3-ethylthien-2-yl)-9H-fluoren-9-ol and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4](=[O:21])[CH2:5][C@@H:6]([CH2:18][CH:19]=[CH2:20])[C:7]([NH:9][C@@H:10]([CH2:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.Cl.C(N(CC)CC)C.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4](=[O:21])[CH2:5][C@H:6]([C:7]1[O:17][CH2:16][C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:9]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)N[C@@H](CO)C(=O)OCC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)CC(C)(C)C)C1=N[C@H](C(=O)OCC)CO1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of ethyl (2S)-2-{[(2R)-2-(4,4-dimethyl-2-oxopentyl)-4-pentenoyl]amino}-3-hydroxypropanoate (Preparation 113) (23.8 g, 72.3 mmol) in anhydrous tetrahydrofuran (300 ml), under a nitrogen atmosphere, was treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide triethylamine hydrochloride salt (43.5 g, 79.4 mmol) and stirred at reflux for 1.5 hours. After allowing to cool to room temperature the mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 (hexane:diethylether) gradually changing to 50:50 (hexane:diethylether) to afford the title compound as a colourless oil (11.0 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[NH2:13][C:14]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23](=[O:25])[CH3:24].C(C1C(NC(C2SCC(C(F)(F)F)N=2)=O)=C(C)C(OC)=CC=1)(=O)C>>[C:23]([C:15]1[C:14]([NH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:19]([Cl:20])[C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: COc1ccc(C(C)=O)c(NC(=O)C2=NC(C(F)(F)F)CS2)c1C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Yield: 65 %

Procedure:
N-(6-Acetyl-2-chloro-3-methoxyphenyl)-4-trifluoromethylthiazole-2-carboxamide 202d was synthesized from 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid and 1-(2-amino-3-chloro-4-methoxyphenyl)-ethanone as a beige solid in 65% yield, following the procedure as described for compound 202b.
Reaction SMILES: CCN(CC)CC.[Cl-].[C:9]([C:12]1[C:39]([F:40])=[CH:38][C:15]2[NH:16][C:17]([C:19]3[CH:20]=[C:21]([C:26]4[C:27]([O:32][CH2:33][CH2:34][NH+:35]([CH3:37])[CH3:36])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:22]=[CH:23][C:24]=3[OH:25])=[N:18][C:14]=2[CH:13]=1)(O)=[O:10].[NH2:41][CH2:42][CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:27]1[C:26]([C:21]2[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([C:17]3[NH:16][C:15]4[CH:38]=[C:39]([F:40])[C:12]([C:9]([NH:41][CH2:42][CH2:43][C:44]5[NH:48][CH:47]=[N:46][CH:45]=5)=[O:10])=[CH:13][C:14]=4[N:18]=3)[CH:20]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: NCCc1c[nH]cn1
Reactant: C[NH+](C)CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4cnc[nH]4)c(F)cc3[nH]2)c1
Yield: 53 %

Procedure:
Et3N (0.079 mL, 0.568 mmol, 8.0 eq.) was added to a mixture containing the crude carboxylic acid salt 9c (0.071 mmol, 1.0 eq.), histamine.2HCl (16 mg, 0.085 mmol, 1.2 eq.), EDC (15 mg, 0.078 mmol, 1.1 eq.) and HOBt (11 mg, 0.078 mmol, 1.1 eq.) in dry DMF (2 mL) and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography [10% (5% aq NH4OH/MeOH)/DCM] to afford the title compound (Rf=0.40) as a light yellow powder (20.1 mg, 53%). ES-MS MH+ 530.30.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[C:12]1([CH2:11][N:18]2[CH2:19][CH:20]=[C:21]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:22][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Product: Oc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1

Procedure:
A mixture of 5-hydroxyindole (0.66 g) and 1-benzyl-4-piperidone (0.95 g) in glacial acetic acid was purged with nitrogen and heated to reflux for 50 min. The mixture was concentrated in vacuo, treated with toluene and concentrated in vacuo, and the residue was purified by chromatography (silica gel, 20-30% ethanol/dichloromethane) to afford the title compound which was recrystallized from ethanol (0.4 g). mp 223-227° C.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.Cl.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][C:33](=[O:35])[NH2:34])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][C:33](=[O:35])[NH2:34])=[O:14])=[CH:11][CH:10]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNCCO)cc3)ccc2c1
Reaction time: 2 h
Yield: 114.3 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.02 g of 4-[(2-hydroxyethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 884 mg of DCC and 43.6 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Thereafter, the same procedure as in Example 1 was carried out to obtain 1.17 g of the desired product.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:30][C:31]1[C:36]([OH:37])=[C:35]([F:38])[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:33]([CH3:45])[C:32]=1[C:46]#[N:47].[CH2:48]([O:55][C:56]([N:58]([CH3:63])[CH2:59][C:60](O)=O)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.C(#N)C>[C:46]([C:32]1[C:31]2[N:30]=[C:60]([CH2:59][N:58]([CH3:63])[C:56](=[O:57])[O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:37][C:36]=2[C:35]([F:38])=[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]=1[CH3:45])#[N:47]
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(F)c2oc(CN(C)C(=O)OCc3ccccc3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
At room temperature, 1-hydroxybenzotriazole (184 mg, 1.36 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (249 mg, 1.30 mmol) and triethylamine (190 μl, 1.36 mmol) were added to an acetonitrile (12 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (300 mg, 1.24 mmol) and N-[(benzyloxy)carbonyl]-N-methylglycine (290 mg, 1.30 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was dissolved in xylene (20 ml), then pyridinium p-toluenesulfonate (120 mg) was added, followed by heating under reflux in an oil bath at 160° C. for 6 hours. The reaction liquid was concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by filtration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (242 mg, 46%) as a colorless foamy substance.