Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:19]1[CH2:23]OC[CH2:20]1.C([Mg]Cl)C=C.[NH4+].[Cl-]>C(Cl)Cl>[F:18][C:2]([F:1])([F:17])[C:3]([OH:16])([CH2:23][CH:19]=[CH2:20])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)[Si](C#CC(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: C=CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC(O)(C#C[Si](C(C)C)(C(C)C)C(C)C)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 1,1,1-trifluoro-4-(triisopropylsilyl)but-3-yn-2-one (3.00 g, 10.8 mmol) in CH2Cl2 (80 mL) at 0° C., was added a THF solution of allylmagnesium chloride (2.0 M, 8.08 mL, 16.2 mmol). After 1 h, a saturated solution of NH4Cl was added. The aqueous layer was extracted with CHCl3 (3×), and the combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated under vacuum at 30° C. affording the title compound (3.63 g). 1H NMR (400 MHz, acetone-d6): 6.02 (m, 2H), 5.20-5.27 (m, 2H), 2.62 (m, 2H), 1.10 (m, 21H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)Cl>CC(C)=O>[CH2:21]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[C:3]([O:13][CH3:14])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(CCC(=O)O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc(CCC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Yield: 180.5 %

Procedure:
A mixture of 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid (5.1 g, 25.99 mmol), anhydrous K2CO3 (25 g, 180.88 mmol) and benzyl bromide (7.5 ml, 63.14 mmol) in anhydrous acetone (100 ml) was stirred at reflux for 7.5 h under nitrogen. After cooling, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (CH2Cl2) gave the title compound (8.83 g, 23.45 mmol, 90%).
Reaction SMILES: CS[CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])[CH:12]=[CH:11][C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5]>[Zn].C(O)(=O)C>[O:21]=[C:19]1[NH:18][C:17](=[O:22])[C:16](=[CH:15][C:13]2[CH:12]=[CH:11][C:10]([O:23][CH3:24])=[C:9]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=2)[S:20]1
Reactant: CCOC(=O)C(SC)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(C=C2SC(=O)NC2=O)ccc1OC
Yield: 50.2 %

Procedure:
Ethyl 2-methylthio-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetate (6.18 g, 16.8 mmol) and acetic acid (100 mL) were mixed, and zinc powder (46.0 g, 706 mmol) was added under stirring, which was stirred for 24 hours at room temperature. Zinc was collected by filtration. washed with acetic acid, and the filtrate was concentrated. The residue was dissolved into ethyl acetate, washed with water and brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol to obtain 2.71 g (50%) of the title compound as yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([O-])=O.O.NN>COCCO>[NH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:33]=[CH:34][CH:35]=[C:4]([NH2:1])[CH:5]=3)=[CH:9][CH:10]=2)([CH3:15])[CH3:16])=[CH:22][CH:21]=1
Reactant: CC(C)(c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: NN
Solvent: O
Solvent: COCCO
Product: CC(C)(c1ccc(Oc2cccc(N)c2)cc1)c1ccc(Oc2cccc(N)c2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In the second step, a 500 ml glass reaction vessel was charged with 100 grams (0.21 mol) of 2,2-bis[4-(3-nitrophenoxy)phenyl]propane, 10 grams of active carbon, 1 gram of ferric chloride hexa-hydrate and 300 ml of ethyleneglycol monomethylether. The mixture was refluxed with stirring for 30 minutes, followed by dropping 42 grams (0.84 mol) of hydrazine hydrate at 70°-80° C. during 2 hours, and stirred for further 5 hours at 70°-80° C. The resultant reaction mixture was cooled, filtered to remove the catalyst and 150 ml of ethyleneglycol monomethylether was distilled off. To the residual matter, 270 grams of 20% aqueous hydrogen chloride solution and 30 grams of sodium chloride were added, and cooled to 20°-25° C. with stirring. The separated crystals were filtered, dissolved into 30% aqueous IPA solution and neutralized with aqueous ammonia to separate crystals. The crystals were filtered, washed with water, dried and recrystallized from a mixture of benezene and n-hexane. Colorless crystals of 2,2-bis[4-(3-aminophenoxy)phenyl]propane thus obtained were 69.2 grams (75% yield) and had a melting point of 106°-108° C. and their analytical results were as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][CH2:14][C@@H:13]([CH3:17])[N:12]1[CH2:18][CH2:19][CH3:20].Cl>>[Cl:9][C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][C@@H:13]([CH3:17])[N:12]([CH2:18][CH2:19][CH3:20])[C@@H:11]([CH3:10])[CH2:16]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Reactant: Clc1ccc(Br)cc1Cl
Agent: Cl
Product: CCCN1[C@H](C)CN(c2ccc(Cl)c(Cl)c2)C[C@@H]1C

Procedure:
Beginning with 4-bromo-1,2-dichlorobenzene and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 225° C. (HCl), MS m/z (rel. intensity, 70 eV)) 301 (M+, 24), 271 (64), 112 (bp), 70 (47), 56 (53).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1.F[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[N:21][CH:22]=1
Reactant: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)c[nH]1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(-n2cc(C#Cc3cccc(C(F)(F)F)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=342.1 (M+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(3-trifluoromethyl-phenylethynyl)-1H-imidazole and 2-fluoro-5-methylpyridine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([Br:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[CH:50]=[C:49]([Br:48])[CH:57]=[C:56]([Br:58])[CH:55]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3cc(Br)cc(Br)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dibromobenzoic acid (10 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([O:12]C(=O)C)[CH:4]=1.[NH2:16][C@H:17]1[CH2:22][C:21]2[C:23]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:23]2[C:21]3[CH2:22][C@H:17]([NH:16][C:7](=[O:9])[C:6]4[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[OH:12])[CH2:18][O:19][C:20]=3[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: COc1ccc(C(=O)O)c(OC(C)=O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.2 %

Procedure:
A solution of 4-methoxy-2-acetoxybenzoic acid (232 mg, 1.10 mmol; described in: Schonhofer, F. Ber Deutsch Chem Ges 1951, 84, 13) in thionyl chloride (5 mL) was heated at 55° C. for 30 min. The excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (248 mg, 1.00 mmol) and triethylamine (210 μL, 1.50 mmol) in anhydrous methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 2.5 h after which the mixture was washed with a saturated NaHCO3 solution, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in absolute ethanol (20 mL), and conc. NH3 (5 mL) was added. The mixture was stirred overnight. The solvent was removed in vacuo, and the remains was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 120 mg (33% yield) of the title compound as a white solid: mp sinters >80° C.; [α]21D−92° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 397 (27, M+).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:31](=[O:33])[NH2:32])([NH:16][C:17](=O)/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([N:16]=[C:17](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[NH:32][C:31]2=[O:33])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)/C=C/c2cccc(C(F)(F)F)c2)(C(N)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(/C=C/c1cccc(C(F)(F)F)c1)NC2=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.5 %

Procedure:
A 6 N aqueous sodium hydroxide solution was added to a solution of 4-carbamoyl-4-[(E)-3-(3-trifluoromethyl-phenyl)-acryloylamino]-piperidine-1-carboxylic acid tert-butyl ester (961 mg, 2.27 mmol) in ethanol (20 ml), and the mixture was stirred at room temperature for 22 hours. The reaction solution was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-oxo-2-[(E)-2-(3-trifluoromethyl-phenyl)-vinyl]-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (706 mg, 73%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH2:72])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[NH:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH:72][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:15])([F:14])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:67][CH2:66]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc-hexahydro azepine 4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-2.05 (m, 16 H) 2.88 (d, J=3.28 Hz, 1 H) 3.01 (br. s., 2 H) 3.31 (s, 3 H) 3.34 (br. s., 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.26 Hz, 3 H) 4.46 (m, 1 H) 7.47 (d, J=8.1 Hz, 1 H) 7.50 (s, 1 H) 7.91 (s, 1 H) 8.21 (s, 1 H) 8.23-8.30 (m, 2 H). [M+H] calculated for C28H37F2N7O3, 558; found 558.
Reaction SMILES: [O:1]1[C@@H:3]([C:4]([O:6]CC)=[O:5])[C@@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[K+]>>[CH2:12]([O:11][C:9]([C@@H:2]1[O:1][C@H:3]1[C:4]([OH:6])=[O:5])=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)O
Yield: 73.2 %

Procedure:
Followed general procedure for 4 using the following quantities: 3b (15.2 g, 81 mmol): KOH (4.53 g, 81 mmol, in EtOH [50 ml]); yielded 5 as a colorless oil (9.5 g, 73.5%). 1H NMR (CDCl3, 400 MHz): δ 7.57 (br, 1H); 4.35-4.24 (m, 2H); 3.73 (s, 1H); 3.72 (s, 1H); 1.36-1.32 (t 3H). 13C NMR (CDCl3, 100 MHz): 171.61, 166.40, 62.45, 52.20, 51.45, 13.89.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([CH:3]=1)[CH:20]=[O:21]
Reactant: COc1cc(Br)cnc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cnc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromo-2,3-dimethoxy-pyridine (43 g) in THF (500 ml) at −78° C. was added n-butyllithium (191 mmol). After stirring for 30 minutes at −78° C. DMF (28.8 g) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with NH4Cl (saturated in water, 500 ml). The aqueous layer was extracted with ethyl acetate, the organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica eluting with heptane with increasing amounts of ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:22])=[O:17])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CN(CCCCC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
1.97 g (7.43 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are dissolved in 30 ml of dichloromethane, and 4.9 ml (67.3 mmol) of thionyl chloride are added. The mixture is heated under reflux for 1 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 2 g (95% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.O1CCCC1>[Na].[Hg].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(Cl)cc3)ccc2o1
Agent: [Hg]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1Cc2cc(-c3ccc(Cl)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
61.5 g of 2.5% sodium amalgam was added in portions to a mixture of 6.7 g of 18A, 270 ml of tetrahydrofuran and 90 ml of ethanol. The mixture was stirred for 20 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in 1 liter of hot water containing 4 ml of saturated sodium hydroxide solution. The mixture was filtered, the filtrate was cooled with an ice bath, and acidified to pH=2. The mixture was stirred for 30 minutes, the resulting solid was collected, washed with water and dried (reduced pressure, P2O5, refluxing acetone) to give 2,3-dihydro-5-(4-chlorophenyl)-2-benzofurancarboxylic acid (18B), mp: 147°-149° C.
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]=3[CH3:36])[CH2:23][CH2:22]2)[O:20]CC1>>[CH3:36][C:28]1[NH:29][C:30]2[C:35]([C:27]=1[CH:24]1[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1)=[CH:34][CH:33]=[CH:32][CH:31]=2
Reactant: Cc1[nH]c2ccccc2c1C1CCC2(CC1)OCCO2
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: Cc1[nH]c2ccccc2c1C1CCC(=O)CC1
Yield: 87.9 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-2-methyl-1H-indole (2.2 g) to afford 1.62 g (88%) of the title compound as a yellow thick oil: MS EI m/e 227 (M+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[F:6][C:7]([F:35])([CH2:30][CH2:31][C:32](Cl)=[O:33])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].COC>CC(C)=O>[F:6][C:7]([F:35])([CH2:30][CH2:31][C:32]([N:1]=[N+:2]=[N-:3])=[O:33])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:25])([F:24])[C:11]([F:22])([F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: COC
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
Sodium azide (6.0 g) was put in a 250 mL round-bottom flask (2-neck) equipped with a thermometer. H2O (20 mL) was added to dissolve sodium azide. It was cooled on an ice-water bath. A solution of 3-(perfluorooctyl)propionyl chloride (12.9 g) in acetone (25 mL) was added dropwise to keep the temperature below 12° C. The mixture was vigorously stirred for 2 h. Dimethyl ether (100 mL) and water (100 mL) are added, and the mixture was vigorously stirred for 1 min. After the separation of two layers, the aqueous layer was extracted with ether (2×50 mL). The ether layers were combined, and are washed with water (3×100 mL) and brine. After drying over MgSO4, the solvent was removed under vacuum to give a mixture of white solid and liquid (12.0 g) that was immediately used for the next reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[CH2:17]([O:20][CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:18]=[CH2:19].C1OCCOCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:20][CH2:21][CH2:22][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])[C:15]#[N:16])[CH:18]=[CH2:19]
Reactant: N#CCc1ccccc1F
Reactant: C=CCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOCCC(C#N)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
Potassium tert-butoxide (9.93 g) was added to a solution of 2-fluorophenylacetonitrile (10 g), toluene-4-sulfonic acid 2-allyloxyethyl ester (19 g) and 18-crown-6 (3.91 g) in tetrahydrofuran (400 mL) under ice-cooling. The reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was warmed to room temperature and further stirred for four hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.9 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.NC1C=CC=CC=1>C(Cl)Cl.CCN(C(C)C)C(C)C>[C:32]1([NH:34][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:15])[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 121 %

Procedure:
A mixture of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (1.0 g, 4.7 mmol), CDI (1.3 g, 7.0 mmol) and HOBT (0.5 g) in CH2Cl2 (20 mL) and Hunig's base (2.0 mL) was cooled to 0° C. and stirred for 15 minutes. Then aniline (520 mg, 5.6 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated and purified by SiO2 chromatography (eluent: 1:1 EtOAc:petroleum ether) to afford the title compound (1.3 g) as an oil. 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 2.10 (m, 2H), 3.0 (m, 1H), 3.7-4 (m, 4H), 4.2 (m, 1H), 7.21 (m, 1H), 7.40 (m, 2H), 7.51 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@@H:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=2[O:4][CH2:5]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccc(F)cc2NC1=O
Yield: 85.5 %

Procedure:
1.96 g (6.24 mmol) (S)-3-(2-Amino-4-fluoro-phenoxy)-2-tert-butoxycarbonylamino-propionic acid and 1.20 g (6.24 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride in 25 ml dimethylformamide were stirred overnight at room temperature. Extraction with water/ethylacetate and removal of the solvent by distillation yielded 1.58 g (86%) ((S)-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester, MS m/e (%): 314 (M+NH4+, 13), 297 (M+H+, 40), 241 (100), 197 (63).