Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CC(C)([O-])C.[K+].[NH2:18]Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH2:18])[CH:7]=[CH:6]2
Reactant: NCl
Reactant: COc1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 5-methoxy-1H-indole (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (169.2 mL) is added drop-wise for 15 minutes at rt. The reaction mixture is stirred at rt for 2 h, quenched with 5% Na2S2O3 aqueous solution (100 mL), and stirred at rt overnight. The mixture is extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-20% EtOAc in heptane to afford 5-methoxy-indole-1-ylamine (388 mg, 14%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.78 (br, 2N—H), 6.35 (d, H), 6.94 (d, H), 7.08 (d, H), 7.17 (d, H), 7.30-7.39 (d, H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].OC1C=C(N[C:23]2[C:28]3=[CH:29][C:30](C)=[CH:31][N:27]3[N:26]=[CH:25][N:24]=2)C=CC=1C>C(O)(C)C.C(Cl)Cl>[N:26]1[N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]([NH:13][C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][N:4]3[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)=[N:24][CH:25]=1
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Reactant: CC(=O)N1CCc2ccc(N)cc21
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(Nc3ncnn4cccc34)cc21
Yield: 4 %

Procedure:
Example 10 was prepared as a white solid in 4% yield from Compound A of Example 1 and 1-acetyl-6-aminoindoline as described for Compound B of Example 1, using 10% isopropanol/methylene chloride for extraction, and with purification by chromatography on silica gel with ethyl acetate. (M+H)+=294.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[N:21][N:22]=[C:11]2CN=1.S(=O)(=O)(O)O.N([O-])=[O:41].[Na+].[C:44](=[O:47])([O-])O.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH2:23][NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[N:21][N:22]=[C:11]1[CH2:44][OH:47])=[O:41]
Reactant: O=C([O-])O
Reactant: O=N[O-]
Reactant: CCc1cc2c(s1)-n1c(nnc1CNC(=O)c1ccc(Cl)c(Cl)c1)CN=C2c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CO)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Water (20 ml) and dioxane (20 ml) were added to N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethyl)-3,4-dichlorobenzamide (3.0 g), and conc. sulfuric acid (1.2 ml) was dropwise added with vigorous stirring. Then, the mixture was stirred at 80° C. for 1.5 hours. Sodium nitrite (3.9 g) was added, and the mixture was further stirred for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developing solvent:ethyl acetate) and recrystallized from a mixed solvent of ethyl acetate-hexane to give 0.9 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl[1,2,4]triazol-5-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: [Cl:1][C:2](Cl)([F:11])[C:3](Cl)([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6].ClC(F)C(Cl)OC(F)(F)F>[Zn]>[Cl:1][C:2]([F:11])=[C:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)OC(Cl)(Cl)C(F)(Cl)Cl
Agent: FC(Cl)C(Cl)OC(F)(F)F
Agent: [Zn]
Product: FC(Cl)=C(Cl)OC(F)(F)F
Temperature: -75 °C
Yield: 83 %

Procedure:
In a 1 l three necked flask, equipped with magnetic stirrer, thermometer, dropping funnel, and connected through a Vigreux column and a condenser to a trap maintained at -75° C., 80.0 g of zinc powder, activated by washing with HCl 3N, 550 ml of DMF and 50 mg of KI were charged under nitrogen atmosphere. The internal temperature was brought to 80° C. and 102.0 g of 1,1,2,2-tetrachloro-l-fluoro-2-trifluoromethoxyethane (377 mmoles), were added dropwise. During the addition, the temperature increased up to 90° C. When the addition was over, the reaction mixture was stirred for 1 additional hour at 90° C. In the cold trap 62.8 g (315 mmoles) of 1,2-dichloro-1-fluoro-2-trifluoromethoxyethane (cis/trans 50%/50%) condensed. The 1,2-dichloro-1-fluoro-2-trifluoromethoxyethene (trans+cis) yield was 83%.
Reaction SMILES: Cl.C([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]([OH:6])=[O:17])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2× s), 2.12 and 2.17 (3H, 2× s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2× s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][OH:10])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([O:10][CH2:9][CH2:8][O:7][C:4]1[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]([NH2:1])[O:6][N:5]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1c(OCCO)noc1N
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCOc1noc(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirring solution of tert-butyl 5-amino-3-(2-hydroxyethoxy)-4-isoxazolecarboxylate (R. Neidlein, J.Heterocyclic Chem., 1989, 26,1335) (5.60 g) and triethylamine (3.36 ml) in tetrahydrofuran (50 ml) at room temperature was added dimethylaminopyridine (280 mg) followed by acetic anhydride (2.81 g). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo to yield the crude material (6.0 g). The crude material was purified using the Biotage™ Flash 40i System (silica, 90 g), eluting with ethyl acetate:hexane (1:1) to yield the product as an off white solid (5.0 g)
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)OC2CCCCC2)cc1
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (115 mg, 0.186 mmol) in a 1:1 mixture of ethanol : ethyl acetate (6 mL) was added Palladium on charcoal (10 wt %, 30 mg). The starting material was reduced under an atmosphere of Hydrogen gas over 16 hrs. The reaction mixture was filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 3:1 ethyl acetate : hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate(89 mg, 81%). H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.58 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.09 (b, 2H), 3.68 (m, 2H), 3.88 (m, 4H), 4.16 (m, 1H), 4.24 (b, 1H), 4.81 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.66 (d, 2H), 7.23 (m, 5H), 7.56 (d, 2H). MS(ESI): 612(M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][C@H:47]1[CH:52]2[CH2:53][CH2:54][N:49]([CH2:50][CH2:51]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:49]12[CH2:54][CH2:53][CH:52]([CH2:51][CH2:50]1)[C@H:47]([NH:46][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[O:20][CH3:21])=[N:12][C:11]=13)=[O:18])[CH2:48]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A mixture of 2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxylic acid (95 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol), 1-hydroxybenzotriazole (76 mg, 0.62 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (78 mg, 0.39 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide (69 mg, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.59 (d, J=7.0 Hz, 1H), 8.19 (dd, J=7.8, 1.0 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.2, 1.0 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 4.40-4.22 (m, 1H), 4.02 (s, 3H), 3.55-3.50 (m, 1H), 3.20-2.75 (m, 5H), 2.23-2.19 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.60-1.50 (m, 1H); MS (ESI+) m/z 412 (M+H); HPLC>99% (AUC), tR=13.78 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][N:11]([CH3:18])[C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:14]2[CH:13]=[C:12]([N:11]([CH3:18])[CH3:10])[NH:16][N:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CN(C)c1cc(N)n[nH]1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)c1cc(Nc2nc(Cl)ncc2F)n[nH]1
Yield: 39 %

Procedure:
2,4-dichloro-5-fluoropyrimidine (166 mg, 1 mmol), N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 34, 150 mg, 1.2 mmol), and DIEA (0.35 ml, 2 mmol) in ethanol (3 ml) was heated at 55° C. overnight. Solvent was removed, and the residue was purified by silica gel chromatography (by ISCO Combiflash with a gradient of 0-5% methanol in methylene chloride with 1% NH4OH). 100 mg product was obtained as a white solid (40%). MS: 257 (M+1); NMR (DMSO-d6, 400 MHz, 80° C.) δ11.60 (br, 1H), 10.26 (br, 1H), 8.23 (s, 1H), 5.73 (s, 1H), 2.76 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8](Br)=[CH:7][C:4]=1[CH:5]=[O:6].[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[F-].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([C:8]2[CH:7]=[C:4]([CH:5]=[O:6])[C:3]([O:2][CH3:1])=[CH:10][C:9]=2[O:11][CH3:12])[CH:23]=[N:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Product: COc1cc(OC)c(-c2cnn(C(=O)OC(C)(C)C)c2)cc1C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Ex-74B: To a mixture of 2,4-dimethoxy-5-bromo-benzaldehye (0.28 g, 1.13 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Ex-76A, 0.61 g, 1.70 mmol), bis(tri-tert-butylphosphine)palladium (43 mg, 0.085 mmol) and potassium fluoride (0.24 g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60° C. for one day. Additional potassium fluoride (0.24 g, 4.08 mmol) and water (20 μL) were added. The reaction mixture continued to stir at 60° C. for another 8 hours. The reaction was then quenched by water. The aqueous solution was extracted with ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) afforded 4-(5-formyl-2,4-dimethoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (0.15 g, 40%) as white solid. 1H NMR (CDCl3) δ 10.35 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 6.52 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z=333 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12].CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:21](=[O:22])[C:20]([C:18]([OH:19])=[O:17])=[CH:7]2
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
3-(Trifluoromethoxy)salicylaldehyde (0.250 g, 1.21 mmol) and Meldrum's acid (0.200 g, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 0.197 g of 8-(trifluoromethoxy)-3-carboxy-coumarin in a 60% yield: LCMS (ESI) m/z 275 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[C:3]#N.[C:13](O)(=[O:15])C.S(=O)(=O)(O)[OH:18]>O>[CH3:13][O:15][C:3](=[O:18])[C:2]([CH3:5])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH3:1]
Reactant: CC(=O)O
Reactant: CC(C)(C#N)c1cccc(Br)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(C)(C)c1cccc(Br)c1
Yield: 36 %

Procedure:
2-Methyl-2-[3-bromophenyl]propionitrile (0.56 g, 2.5 mmol) was refluxed in sulfuric acid (2 ml), water (3 ml) and acetic acid (2.5 ml) overnight. The reaction mixture was poured in water, then extracted with Et2O. The combined organic extracts were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 10% EtOAc, 1% HOAc) to give the title compound as a white solid (0.2 g, 36%), which was converted to the methyl ester with diazo methane in Et2O and was used in the next reaction without further purification.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=[C:27]1[CH2:28][CH2:29][CH2:30][C:25]1=[O:9]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Agent: Cl
Product: COc1ccc(C=C2CCCC2=O)c(OC)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 2,4-dimethoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 71.2%.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:8]=1CO.N1C(C)=CC=CC=1C.[CH2:25](Cl)[Cl:26]>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:11]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:25][Cl:26]
Reactant: COc1cccc(CO)c1OC
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(CCl)cc1OC
Reaction time: 0.5 h

Procedure:
Thionyl chloride (288 g) is added over 1.5 hour to a stirred solution of 2,3-dimethoxybenzyl alcohol (400 g) and 2,6-lutidine in methylene chloride (2 l). The reaction mixture is then stirred for 30 minutes after which it is washed with 2 N hydrochloric acid (7×1 l) and then with water. The organic layer is separated, dried (MgSO4) and evaporated to give a residue, which upon distillation yields 3,4-dimethoxybenzyl chloride (375 g), b.p. 145°-150° C. at 20-25 nm (waterpump vacuum). The material solidifies on standing.
Reaction SMILES: [C:1]1([CH:14]=O)[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N:16]1[C:25]2[CH:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]1([CH2:14][N:26]([CH:24]2[C:25]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22][CH2:23]2)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Reactant: O=Cc1nccc2c1[nH]c1ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCCN(Cc1nccc2c1[nH]c1ccccc12)C1CCCc2cccnc21
Yield: 24 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of 9H-pyrido[3,4-b]indole-1-carbaldehyde, 2, (0.20 g, 1.02 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (0.36 g, 1.12 mmol), sodium triacetoxyborohydride (0.43 g, 2.04 mmol), 4 A molecular sieves and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction mixture was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.12 g (24% yield) of desired product 4: 1H NMR (400 MHz, CDCl3) δ 13.43 (bs, 1H), 8.67 (d, J=3.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.54 (dt, J=1.2, 7.4 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.21 (dt, J=0.8, 7.2 Hz, 1H), 7.14 (dd, J=4.8, 7.6 Hz, 1H), 4.28-4.02 (m, 4H), 2.90-2.60 (m, 5H), 2.44-2.26 (m, 2H), 2.12-2.04 (m, 1H), 1.96-1.84 (m, 1H), 1.80-1.65 (m, 1H), 1.44-1.25 (m, 1H), 1.33 (s, 9H), 1.22-1.12 (m, 1H); ESI+ MS: m/z (rel intensity) 500.2 (100, [M+H]+).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1)#[N:16].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([C:15]#[N:16])[CH:22]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: N#Cc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(C#N)c1
Reaction time: 16 h

Procedure:
A 1.5 g (20 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 3.57 g (30 mmol) of 3-cyanophenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 30 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel, eluting with 100:0-85:15 hexane:ethyl acetate to give 2.71 g of the title compound. MS: 303 (M+H)+, 320 (M+NH4)+. NMR (CDCl3) δ: 1.48 (s, 9H), 1.84-2.05 (m, 4H), 3.35-3.45 (br, 2H), 3.75-3.95 (m, 1H), 4.05-4.18 (br, 2H), 7.25-7.40 (m, 4H).