Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.Cl.O[N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: On1ccnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(COn2ccnc2)cc1)c1ccccc1
Yield: 87 %

Procedure:
The title compound was prepared as its TFA salt in 87% yield as a solid using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1-hydroxyimidazole, hydrochloride. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.21 (s, 2H), 6.95 (s, 1H), 7.16–7.45 (m, 10H) 8.28 (br s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=1.92 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-methylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 320.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[CH3:12])=[O:9]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: Cc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Cl)ccc1O
Yield: 73.3 %

Procedure:
Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) was added cesium carbonate (5.04 g, 15.46 mmol) and 2-iodopropane (2.58 mL, 25.8 mmol). The mixture was heated at 100° C. overnight. After cooling to RT, H2O (300 mL) was added and the aqueous layer was extracted with EtOAC (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, and solvent was removed in vacuo. The resulting crude material was reconstituted in MeOH (1.0 mL) and purified by HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C12H21BN2O2, 237; found 237.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@:5]([CH3:45])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:21]([C:41]([F:44])([F:43])[F:42])[CH:20]=3)=[CH:17][N:18]=2)[CH2:4][O:3]1>C(#N)C.O>[NH2:6][C@@:5]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=3)=[C:21]([C:41]([F:44])([F:43])[F:42])[CH:20]=2)=[CH:17][N:18]=1)([CH3:45])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCc3ccc(C(F)(F)F)cc3)c(C(F)(F)F)c2)s1
Solvent: CC#N
Solvent: O
Product: C[C@](N)(CO)c1ncc(-c2ccc(OCCCCCc3ccc(C(F)(F)F)cc3)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared from (R)-tert-butyl 2,2,4-trimethyl-4-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.50 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=533.4; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.66 (d, 1H, J=2.0 Hz), 7.56 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.52 (d, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=8.8 Hz), 4.07-4.03 (m, 4H), 2.70 (t, 2H, J=7.8 Hz), 1.89-1.82 (m, 5H), 1.74-1.67 (m, 2H), 1.57-1.50 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]1[CH:11]=[CH:12][N:13]2[C:18]([CH:19]=1)=[C:17]([CH2:20][CH3:21])[C:16]1[S:22][NH:23][C:24](=[O:25])[C:15]=1[C:14]2=[O:26]>CS(C)=O>[CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([CH:19]=2)=[C:17]([CH2:20][CH3:21])[C:16]2[S:22][NH:23][C:24](=[O:25])[C:15]=2[C:14]3=[O:26])[CH2:4]1
Reactant: CN(C)C1CCNC1
Reactant: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(Cl)cc12
Solvent: CS(C)=O
Product: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(N3CCC(N(C)C)C3)cc12

Procedure:
(rac)-3-(Dimethylamino)pyrrolidine (30.0 μL, 0.239 mmol) is added to a yellow solution of 6 (11.4 mg, 0.041 mmol) in dimethyl sulfoxide (0.6 ml) at room temperature to give immediately an orange mixture. This mixture is irradiated in a microwave for 5 min. (120° C.; 300 W) to give an orange solution. The solution is evaporated under reduced pressure (˜1 mm Hg, 60° C.), and the remaining orange solid is washed with diethyl ether (3×15 mL) and water (3×15 mL). Subsequent drying in vacuo yields 7 as a yellow solid. Purity by HPLC: 97%; tR=10.86 min. mp 217–219° C. 1H NMR (DMSO-d6): δ1.11 (br t, J=6.5 Hz, 3H, CH2CH3), 1.85 (m, 1H, pyrrolidinyl H-4), 2.19 (m, 1H, pyrrolidinyl H-4′), 2.22 (s, 6H, N(CH3)2), 2.55 (br, 2H, CH2CH3), 2.84 (m, 1H, pyrrolidinyl H-3), 3.26 (m, 1H, pyrrolidinyl H-2), 3.44 (m, 1H, pyrrolidinyl H-5), 3.67 (m, 2H, overlapping pyrrolidinyl H-2′ and pyrrolidinyl H-5′), 6.14 (br, 1H, pyridone H-8), 6.84 (br d, J=8.0 Hz, 1H, pyridone H-6), 8.86 (d, J=8.0 Hz, 1H, pyridone H-5). 13C{1H} NMR (DMSO-d6): δ12.1 (CH2CH3), 21.8 (CH2CH3), 29.1 (pyrrolidinyl C-4), 43.8 (N(CH3)2), 46.9 (pyrrolidinyl C-5), 51.8 (pyrrolidinyl C-2), 64.6 (pyrrolidinyl C-3), 92.5 (C-8, CH), 95.7 (C-3a), 99.9 (C-9), 105.9 (C-6, CH), 129.3 (C-5, CH), 141.8 (C-8a), 148.3 (C-7, C—N), 153.3 (C-4, NC(O)), 154.9 (C-9a, C—S), 167.9 (C-3, CONS). LCMS m/z calcd for C18H22N4O2S 358 ([M+]); found 359 ([M+H]+). HRMS m/z calcd for C18H22N4NaO2S 381.1361 ([M+Na]+); found 381.1366. Anal. Calcd. for C18H22N4O2S.H2O: C, 57.43; H, 6.43; N, 14.88. Found: C, 57.29; H, 6.08; N, 14.87.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH:13]2[CH2:18][C:17]3([C:26]4[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:16][CH2:15][N:14]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH:13]2[CH2:18][C:17]3([C:26]4[C:21](=[CH:22][C:23]([C:44]5[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=5)=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:16][CH2:15][N:14]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(=O)N(c1ccc(F)c(Cl)c1)C1CC2(CCN1C(=O)OCc1ccccc1)CNc1cc(Br)ccc12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccc3c(c2)NCC32CCN(C(=O)OCc3ccccc3)C(N(C(N)=O)c3ccc(F)c(Cl)c3)C2)c1
Temperature: 90 °C
Yield: 35.9 %

Procedure:
To a solution of crude 1-(3-chloro-4-fluorophenyl)ureido-6-bromo-1′-benzyloxycarbonyl-spiro[indoline-3,4′-piperidine] (˜0.27 mmol) and Pd(PPh3)4 (0.011 g, 0.030 mmol, 10 mol %) in degassed toluene (5 mL) was added a solution of 3-cyanophenylboronic acid (0.067 g, 0.46 mmol, 1.7 eq.), aqueous Na2CO3 (2.5 mL of a 2N solution, 5 mmol), and EtOH (2.5 mL). The resulting mixture was heated at 90° C. for 16 h then partitioned between EtOAc (20 mL) and 10% aqueous NaHCO3 (20 mL). The organic phase was separated and washed with 10% aqueous NaHCO3 (3×10 mL) and saturated brine (10 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude residue was purified by flash column chromatography by eluting 10-20% EtOAc/hexane to give 1-(3-chloro-4-fluorophenyl)ureido-6-(3-cyanophenyl)-1′-benzyloxycarbonyl-spiro[indoline-3,4′-piperidine] as a yellowish oil (0.057 g, 0.097 mmol, 36%). 1H NMR (300 MHz, CD3OD): δ 7.23 to 8.31 (m, 15H), 5.27 (s, 2H), 4.32 (d, 2H), 4.21 (s, 2H), 3.17 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([F:28])=[CH:21][C:20]=1F>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:20]1[CH:21]=[C:22]([F:28])[C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[F:18])([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0° C. under nitrogen. The mixture was stirred for 0.5 h at room temperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester as yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 168.2, 155.1 (d, 1JCF=252.3 Hz), 150.9 (d, 1JCF=263.2 Hz), 135.7, 135.1, 120.0 (dd, 2JCF=26.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8.
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[C:17]3=[N:16][C:15]=2[CH3:33])=[O:13])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[N:2].[Cl-].[NH4+].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[F:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[CH2:24][O:23][C:22]1[C:17]2[N:18]([C:14]([C:12]([NH:11][C:3]3([C:1]4[N:36]=[N:37][NH:38][N:2]=4)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]3)=[O:13])=[C:15]([CH3:33])[N:16]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(C#N)COC(C)(C)OC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2nn[nH]n2)COC(C)(C)OC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Under a nitrogen gas flow, to a solution of 27.7 g of N-(5-cyano-2,2-dimethyl-1,3-dioxan-5-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 280 ml of DMF were added 10.0 g of ammonium chloride and 12.0 g of sodium azide at room temperature, followed by stirring at 120° C. for 2 hours. The reaction mixture was left to be cooled to room temperature, and the insoluble materials were then separated by filtration and washed with DMF. The filtrate was added to water, followed by stirring at room temperature for 2 days. The resulting insoluble materials were separated by filtration and washed with water. The obtained residue was dried under reduced pressure to obtain 29.2 g of 8-[(2,6-difluorobenzyl)oxy]-N-[2,2-dimethyl-5-(2H-tetrazol-5-yl)-1,3-dioxan-5-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10]>C(O)C>[C:1]([S:3][CH:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=C(c1ccccc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 1.25 g. of potassium thioacetate in 20 ml. of ethanol is added a solution of 3.54 g. of 1-(3-bromo-3-benzoylpropionyl)-L-proline (Example 20) in 20 ml. of ethanol. The mixture is stirred at room temperature for 2 hours. The mixture is concentrated to dryness under vacuum and the residue partitioned between dichloromethane and water. The dichloromethane layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed under vacuum to give 2.9 g. of product as a glass. A 2.3 g. sample is chromatographed over silica gel with solvent system, ethyl acetate-hexane-acetic acid (75:25:2) to give 1.07 g. of product as a pale yellow glass.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:21][C:20]([NH:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Product: COc1cc(CC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccc1O
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1 (5.29 g, 19.8 mmol) and TEA (4.29 mL, 29.7 mmol) in DCM (50 mL) at 0° C. was treated with benzyl carbonochloridate (3.00 mL, 21.1 mmol) dropwise over 5 min. After stirring for 10 min, the mixture was washed with 1M HCl (150 mL), dried over MgSO4, and concentrated. The residue was taken up in MeOH (20 mL) and treated with 2 N NaOH (5 mL). After 10 min, the mixture was acidified and the product was purified by chromatography (EA/hexanes) to afford 4.7 g (59%) of tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-2. LCMS-ESI (m/z) calculated for C22H27NO6: 401. Found 424 [M+Na]+, tR=2.47 min (Method 6).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1)=[O:42]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)n(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
Into a dry reaction vessel, methyl 2-[1-(4-aminobenzyl)-2-methyl-1H-indol-3-yl]acetate (260 mg, 0.843 mmol) was added, and dissolved in 10 mL dichloromethane. Triethylamine (0.36 mL, 2.59 mmol) was added, and 2-naphthoyl chloride (195 mg, 1.02 mmol) was added slowly in an ice bath. Upon completion of addition, it was reacted for 1 h in an ice bath, and stirred at room temperature for 3 days. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 150 mg, at a yield of 38.4%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:10][S:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(O)=[O:8]>CN(C=O)C.O1CCCC1>[CH2:25]1[O:26][C:20]2[C:21](=[CH:22][C:23]3[C:7](=[O:8])[CH2:10][S:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][C:18]=3[CH:19]=2)[O:24]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cc3c(cc2C(=O)CS1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.4 %

Procedure:
Oxalyl chloride (14.8 g) and DMF (3 drops) were successively added dropwise to a solution of methyl 2-carboxymethylthio-3-(3,4-methylenedioxyphenyl)propionate (29.0 g) in tetrahydrofuran (THF) (200 ml), followed by stirring for 1.5 hours at room temperature and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250 ml). To the solution was added dropwise tin(IV) chloride (SnCl4)(55.6 g) under ice-cooling. The mixture was stirred for an hour under ice-cooing, to which 2NHCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled off the solvent to give crystals of methyl 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (17.0 g, 63%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[N:6][S:5][N:4]=1.[NH2:9][CH2:10][CH2:11][SH:12].[O-]CC.[Na+]>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][N:6]=1
Reactant: Clc1nsnc1CBr
Reactant: NCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCSCc1nsnc1Cl

Procedure:
2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethylamine may be prepared by the following route: 3-Methyl(1,2,5)thiadiazole is chlorinated for 4 days in acetonitrile at 25° to give 4-chloro-3-methyl(1,2,5)thiadiazole (oil) which is treated with N-bromosuccinimide in carbon tetrachloride to give 3-bromomethyl-4-chloro(1,2,5)thiadiazole (oil), the 100 MHz n.m.r. in CDCl3 had singlet at 4.66δ. 3-Bromomethyl-4-chloro(1,2,5 )thiadiazole was treated with cysteamine and sodium ethoxide in ethanol to give 2-(4-chloro-3(1,2,5)thiadiazolylmethylthio)ethylamine (oil). A 60 MHz n.m.r. spectrum (CDCl3) gave a singlet at 3.91 attributed to the Het-CH2 -S protons.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][C:15]([C:14]1[CH:19]=[CH:20][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1ccc(C(=O)CCl)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)COc2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure given in Example 13a 2,4-dichlorophenol was interacted with an equimolar quantity of 4-methylphenacyl chloride in the presence of potassium carbonate to give w-(2,4-dichlorophenoxy)-p-methylacetophenone. Recrystallized from 2-ethoxyethanol, this product melted at 96.5-98.5° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[C:43]([CH3:44])=[CH:42][S:41][CH:40]=2)[CH:38]=1)[C:33](O)=[O:34])=[O:5])C.[CH3:45][NH:46][CH3:47]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[C:43]([CH3:44])=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:33](=[O:34])[N:46]([CH3:47])[CH3:45])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Reactant: CNC
Product: Cc1cscc1-c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(C(=O)N(C)C)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid and dimethylamine (27% yield after two steps).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 120 °C
Reaction time: 13 h
Yield: 57.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (3.0 g, 25 mmol) in N,N-dimethylformamide (15 mL) were added 1-benzylpiperazine (4.3 mL, 25 mmol) and potassium carbonate (3.4 g, 25 mmol). The reaction mixture was stirred at 120° C. for 13 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL) and the combined organic phases were washed twice with brine (10 mL) and dried (MgSO4). Evaporation of the solvent gave 7.6 g of crude product. Purification of the residue on a silica gel column using ethyl acetate/methylene chloride (1:9) as the eluent afforded 4.0 g (59% yield) of the title compound as a white solid: mp 104-105° C.; EIMS (70 eV) m/z (relative intensity) 277 (20, M+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([C:21]([C:23]2[CH:24]=[CH:25][C:26]3[N:31]([CH2:32][CH:33]=[CH2:34])C(=O)O[C:28](=[O:36])[C:27]=3[CH:37]=2)=[O:22])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2>CN(C=O)C>[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([C:21]([C:23]2[CH:37]=[C:27]3[C:26](=[CH:25][CH:24]=2)[N:31]([CH2:32][CH:33]=[CH2:34])[C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:28]3=[O:36])=[O:22])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CCn1c(=O)oc(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Solvent: CN(C)C=O
Product: C=CCn1c(C)c(C(=O)OCC)c(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.49 ml (3.80 mmol) of ethyl acetoacetate diluted in 20 ml of anhydrous DMF is added, under an inert atmosphere at ambient temperature, to 0.66 g (1.52 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-1-prop-2-en-1-yl-2H-3,1-benzoxazine-2,4(1H)-dione in 30 ml of DMF. The reaction medium is stirred at ambient temperature overnight and then extracted with ethyl acetate. The organic phase obtained is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure.