Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:37][NH2:38])=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:38]3)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)=[CH:32][C:33]#[N:34])=[CH:27][C:26]=1[O:45][CH3:46])(C)(C)C.CCOCC>C1COCC1>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([C:31]([C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[C:26]([O:45][CH3:46])[CH:27]=2)=[CH:32][C:33]#[N:34])[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(O)c(OC)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 5.55 ml, 5.55 mmol) was added at rt to a stirred solution of 3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile (1.97 g, 4.63 mmol) in THF (35 ml). The colorless clear solution immediately turned into brown/red wine color. The reaction should be done within one hour. Ice water (15 ml) was poured into the reddish solution, followed by addition of ether (80 ml). The mixture was washed with water (2×100 ml), dried over MgSO4, filtered and concentrated to a yellow oil, which was lyophilized to give 3-(3,5-dimethoxy-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-acrylonitrile as a white gummy solid (1.26 g, 88%): mp, 120-122° C.; 1HNMR (DMSO-d6) δ 9.68 (s, 1H, OH group of one isomer), 9.60 (s, 1H, OH group of the other isomer), 7.11-6.61 (m, 8H, Ar), 6.49-6.46 (m, 4H, Ar), 6.23 (s, 1H, double bond proton of one isomer), 6.11 (s, 1H, double bond proton of the other isomer), 3.78-3.74 (multiple singlets, 18H, 6OCH3), isomer ratio based on 1HNMR was 49%:51%; 13C NMR (CDCl3) δ 163.0, 162.9, 160.9, 160.8, 148.2, 147.7, 146.6, 146.3, 141.6, 139.2, 130.9, 128.9, 124.2, 122.9, 118.5, 118.2, 114.6, 114.5, 112.3, 110.6, 107.9, 107.2, 102.3, 102.2, 93.7, 93.1, 56.4, 56.2, 55.7, 55.6; Anal. Calcd. For C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.24; H, 5.38; N, 4.27.
Reaction SMILES: C[O-].[Na+].C[Si](C)(C)[N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13].[CH3:16]S(OC)(=O)=O>COCCOC>[CH3:16][N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13]
Reactant: COS(C)(=O)=O
Reactant: C[Si](C)(C)N1CCCCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.4 g (0.1 mol) of sodium methylate and 18.5 g (0.1 mol) of N-trimethylsilylcaprolactam are introduced successively into 150 ml of 1,2-dimethoxyethane, and the mixture is stirred at room temperature for 30 minutes. Then 11 g (0.1 mol) of methyl methanesulfonate are added dropwise. After the reaction mixture has been stirred at 50° C. for a further one hour, it is cooled, the sodium mesylate is removed by filtration with suction, and the filtrate is evaporated. The oily residue is distilled in vacuo.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:5]1[CH:6]=[CH:7][C:8]([C:16](O)=[O:17])=[N:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.Cl.[NH2:27][C:28]([CH2:35][CH3:36])([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[C:28]([NH:27][C:16]([C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][C:2]([F:1])([F:25])[F:24])[CH2:19][C:20]([F:22])([F:21])[F:23])=[C:10]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[N:9]=1)=[O:17])([CH2:35][CH3:36])[CH2:33][CH3:34]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 162 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=500.1 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([N:16]2[CH2:21][CH2:20][C:19]3([O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]4[C:31](/[CH:34]=[N:35]\O)=[CH:32][CH:33]=[C:22]34)[CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[O:39][CH3:40])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([N:16]2[CH2:17][CH2:18][C:19]3([O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]4[C:31]([C:34]#[N:35])=[CH:32][CH:33]=[C:22]34)[CH2:20][CH2:21]2)=[O:15])=[CH:12][C:11]=1[O:39][CH3:40])[CH3:9]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(/C=N\O)ccc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C#N)ccc23)cc1OC
Temperature: 140 °C
Yield: 116.1 %

Procedure:
Acetic anhydride (4.0 mL, 42 mmol) was added to (Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde oxime (847 mg from previous step). The reaction mixture was heated at 140° C. for 3.5 h then cooled to room temperature and poured onto ice. Dichloromethane (30 mL) was added followed by sodium bicarbonate (0.7 g). The organic phase was then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried, filtered, and concentrated to give a yellow oil. The crude material was purified by column chromatography (silica gel: 5-45% EtOAc in hexanes) to give 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile (944 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.0 Hz, 1H), 7.22-7.16 (m, 1H), 7.15-7.08 (m, J=7.6 Hz, 3H), 7.00 (d, J=4.0 Hz, 1H), 6.93-6.87 (m, 2H), 6.08 (d, J=4.0 Hz, 1H), 4.64 (s, 1H), 3.83 (s, 3H), 3.65-3.14 (m, 3H), 2.62 (q, J=7.5 Hz, 2H), 2.27-1.67 (m, 4H), 1.16 (t, J=7.5 Hz, 3H). ESI-MS m/z calc. 427.5. found 428.5 (M+1)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: Br[CH:2]([CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][N:30]([CH2:19][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(Br)COc1ccc(OCc2ccccc2)cc1
Product: OC1(Cc2ccccc2)CCN(CCCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=432.6 (M+H+), was prepared from 1-(2-bromopropoxy)-4-(benzyloxy)-benzene and 4-benzyl-piperidin-4-ol.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH2:14][OH:15])[CH:12]=[C:11]([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[O:9]1)=O)(C)(C)C.[ClH:26]>CO>[ClH:26].[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:10]2[O:9][NH:8][CH:13]([CH2:14][OH:15])[CH:12]=[C:11]2[CH3:16])=[CH:22][CH:21]=1)[CH3:25]
Reactant: CCOc1ccc(C2ON(C(=O)OC(C)(C)C)C(CO)C=C2C)cc1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C2ONC(CO)C=C2C)cc1

Procedure:
A solution of 2-t-butyloxycarbonyl-3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine (2.02 g, 5.78 mmol) in methanol (10 ml) saturated with hydrogen chloride gas was stirred at room temperature for 2 h. The solvent was evaporated and the residue crystallised from methanol-diethyl ether to give 3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine hydrochloride as a crystalline product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].C(=O)(O)[O-].[Na+]>C1COCC1>[F:13][C:14]1[C:19]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cnccc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(C)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A THF (1 mL) solution of diisopropylamine (160 μL; WAKO) was cooled to −78° C. under a nitrogen atmosphere followed by the dropwise addition of normal butyllithium (2.6 M, 430 μL; KANTO). The resulting mixture was stirred as it was for 30 minutes followed by the dropwise addition of a THF (1 mL) solution of 4-fluoro-3-methylpyridine (111 mg) and the resulting mixture was further stirred for 1 hour. Then tri-n-butyltin chloride (330 μL; TCI) was added and the resulting mixture was slowly raised to room temperature and then stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture solution, to the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4]1.Br[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[ClH:1].[OH:8][CH2:6][C:3]1([N:2]2[CH2:12][C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH:16]=[CH:15][C:14]=3[CH2:23]2)[CH2:4][CH2:5]1
Reactant: BrCc1ccc2ccccc2c1CBr
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: OCC1(N2Cc3ccc4ccccc4c3C2)CC1
Yield: 22.1 %

Procedure:
Ethyl 1-aminocyclopropanecarboxylate hydrochloride (16 g) in chloroform (50 ml) was added to 1,2-bis(bromomethyl)naphthalene (40 g) and potassium carbonate (40 g) in chloroform (200 ml) kept at 60°. The reaction mixture was refluxed for a further 6 hr and then filtered; the filtrate was evaporated to dryness and the residue [i.e. crude 2-(1'-carbethoxycyclopropyl)benz[e]isoindoline] was dissolved in THF (150 ml) and added to lithium aluminium hydride (10 g) in THF (100 ml) over 0.5 h. Water was then added and the resultant slurry was filtered and the filtrate was evaporated to dryness; the residue was partitioned between ether and water and the ether layer was extracted with concentrated hydrochloric acid. The acidic extract was evaporated to dryness to give a residue which was recrystallised from iso-propanol/ethyl acetate to give the title compound (5.9 g. m.p.192°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2ncccc2c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 6-aminoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (52 mg, 25% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.84 (1H, br), 9.02 (2H, m), 8.825 (1H, m), 8.81 (1H, m), 8.34 (1H, m), 8.32 (1H, m), 8.04 (1H, m), 7.97 (1H, m), 7.51 (1H, m). MS m/z: 475.18, 477.09 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:31])([CH3:30])[CH3:14])[CH2:21]1)[CH2:12]2)([O-:11])=[O:10]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1CC2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene (40.9 g, 132 mmol, described in Intermediate 2) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (31.5 g, 119 mmol, described in Intermediate 1) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:16]([O:24][CH2:25][C:26]#[CH:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:16]([O:24][CH2:25][C:26]#[C:27][C:6](=[O:7])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCOC(=O)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(OCC#CC(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A solution of 2-thiophenecarbonyl chloride (549 mg, 3.75 mmol) in anhydrous dioxane (15 mL) was bubbled with argon for 10 minutes. Triethylamine (1.31 mL, 9.36 mmol) was added and the bubbling was maintained for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.12 mmol), copper iodide (48 mg, 0.25 mmol) and propargyl benzoate (0.45 mL, 3.12 mmol) were added, and the reaction mixture was stirred for 1 hour at room temperature, under argon atmosphere. The solution was filtered and water (20 mL) was added to the filtrate. Layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5) to provide 4-oxo-4-(thiophen-2-yl)but-2-yn-1-yl benzoate (3a) (333 mg, 1.23 mmol, 39%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12]1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)COC(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2-Pyridyl)piperazine (106 m) was dissolved in chloroform (2 mL), and neopentyl chloroformate (0.10 mL) and triethylamine (0.135 mL) were added thereto and stirred at room temperature for 5 hours, and the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 177 mg of the entitled compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.Cl>ClCCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1)=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: N#CC1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#CC1(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (100 mg, 0.205 mmol) in DCE (10.0 mL) at RT was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) (58.9 mg, 0.307 mmol), 1-amino-1-cyclopropanecarbonitrile hydrochloride (24.3 mg, 0.296 mmol), DMAP (catalytic) and TEA (22.79 mg, 0.225 mmol). The resulting reaction mixture was stirred at RT for 18 h. To the reaction mixture was added EtOAc (50 mL) and 0.1N HCl (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with aq NaHCO3 (1×), dried (MgSO4), filtered and concentrated under reduce pressure to give an oil. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 35% EtOAc in hexanes) afforded the title compound as a white solid (13 mg, 11.5%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[C:11]([OH:18])=[CH:10][C:7]=1[C:8]#[N:9])=[O:5].[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].CN(C)C=O.O>C(OCC)(=O)C>[CH2:25]([O:24][C:23]([O:18][C:11]1[C:12]([OH:17])=[C:13]([N+:14]([O-:16])=[O:15])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[F:1])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:27])[CH3:26]
Reactant: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1F
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Oc1cc(C#N)c(C(=O)c2ccccc2F)c([N+](=O)[O-])c1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of 2-(2-fluorobenzoyl)-4,5-dihydroxy-3-nitrobenzonitrile (compound 1-29) (70 mg), ethyl chloro-carbonate (30 mg) and N,N-dimethylforamide (1 mL) was stirred at 50° C. for 3 hours. Water and ethyl acetate were added to the mixture. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50-100% ethyl acetate/hexane, gradient elution) to give the title compound (60 mg). The structural formula was illustrated in table 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[C:24]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)CCNCC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2CC1

Procedure:
To a stirred solution of 42.6 g. (0.206 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 1 l. of toluene were added 35.7 ml. of triethylamine (0.256 mole) and 24.5 ml. of ethyl chloroformate (0.256 mole), at room temperature, and the mixture was refluxed for 12 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The solid residue (57 g.) was recrystallized from ethyl acetate to give 3-carboethoxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 91°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].N1C(C)=CC=CC=1C.N1C=CC(C)=CC=1C.N1C=CC=C(C)C=1C.N1C=CC(C)=C(C)C=1.N1C=C(C)C=CC=1C.N1C=C(C)C=C(C)C=1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: Cc1ccc(C)nc1
Agent: Cc1cccnc1C
Agent: Cc1cncc(C)c1
Solvent: Cc1ccnc(C)c1
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccncc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
Reacting pure N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI) with n-valeryl chloride in the presence of a heterocyclic amine base selected from 2,6-lutidine, 2,4-lutidine, 2,3-lutidine, 3,4-lutidine, 2,5-lutidine, 3,5-lutidine to produce pure N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) substantially free from alkene impurity of formula (VIIa).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3ccccc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
(3-Hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (213 mg), 4-chloro-6,7-dimethoxyquinoline (223 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (89 mg, yield 22%).