Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:45][C:46]1[CH:53]=[CH:52][C:49]([NH:50][CH3:51])=[CH:48][CH:47]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([N:50]([C:49]3[CH:52]=[CH:53][C:46]([Cl:45])=[CH:47][CH:48]=3)[CH3:51])=[O:19])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: CNc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-tert-Butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (101 mg) was dissolved in dichloromethane (2 mL). To this solution, trichloroacetonitrile (74.0 μL) and triphenylphosphine (196 mg) in dichloromethane (1.5 mL) were sequentially added and the mixture was stirred at room temperature for 2 hours. This was followed by addition of triethylamine (0.18 mL) and 4-chloro-N-methylaniline (98.6 μL) and stirring at room temperature for additional 5.5 hours. The reaction mixture was then poured into aqueous citric acid (5 mL) and was extracted with ethyl acetate (3×10 mL). The ethyl acetate extracts were combined, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:hexane:ethyl acetate=2:1) to give 4-tert-butoxycarbonylamino-N-(4-chlorophenyl)-N-methylbicyclo[2.2.2]octane-1-carboxamide (91.4 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COCCN
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 444 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[C:16]([N:18]([CH3:20])[CH3:19])=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](/[CH:8]=[CH:16]/[N:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 72.4 %

Procedure:
A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50.0 mmol), DMA (11.9 g, 100 mmol) in DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected by filtration, washed with water, and dried to give (E)-2-(5-chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine (9.84 g, 72%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[Na+]>FC(F)(F)C(O)=O>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2]
Reactant: N#CCCC1CCc2ccccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#CCCC1CCc2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C

Procedure:
A solution of 7.7 g (41 mmol) of 2-cyanoethyl-3,4-dihydro-2H-1-benzopyran in 150 ml of trifluoroacetic acid is reacted for 15 min with 10.5 g (123 mmol) of sodium nitrate, and then the mixture is poured into ice water and the product is extracted with dichloromethane. The organic phase is then dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 30% ethyl acetate, 4.5 g of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[NH4+].[Cl-].[OH-].[NH4+].Cl>O>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
Ref.: WO 96/11917. A slurry of 2,6-dinitro phenol (20% in H2O, 5 g, 0.0271 mol), NH4Cl (14.30 g, 0.267 mol), and ammonium hydroxide solution (3 mL) was heated in a 70° C. bath. A warm solution of Na2S-9H2O (24.19 g, 0.1 mol) in H2O (23 mL) was added to the slurry and the resulting orange suspension was heated with stirring for 3 h, then allowed to cool to room temperature. The mixture was cooled in an ice bath and slowly acidified with 6 N HCl to pH 2. The mixture was filtered and the filtrate was extracted with CHCl3 (3×75 mL). The combined organic extracts were concentrated in vacuo and the crude material was adsorbed onto silica gel. Purification by silica gel chromatography, eluting with 25% hexane/CH2Cl2 then CH2Cl2, afforded the title compound (1.47 g) as a brick red powder. MS (ESI-POS): [M+H]+=155.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([NH:35][C:36](=[O:38])[CH3:37])[CH:13]=[C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[Si](C(C)C)(C(C)C)C(C)C)[CH:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:39][O-:40].[Na+]>CO>[NH:20]1[C:21]2[C:17](=[C:16]([C:14]3[CH:13]=[C:12]([NH:35][C:36](=[O:38])[CH3:37])[CH:11]=[C:10]([C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([O:40][CH3:39])[CH:7]=4)=[O:9])[CH:15]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: C[O-]
Reactant: CC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2cc(NC(C)=O)cc(-c3cccc4[nH]ccc34)c2)ccn1
Yield: 11.8 %

Procedure:
To N-[3-(2-Chloro-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide (Example 83, 0.120 g, 0.22 mmol) in 25 mL of anhydrous methanol was added 0.036 g (0.66 mmol) NaOMe. The reaction mixture was refluxed overnight. The methanol was removed under vacuum and water added to the reaction mixture. The aqueous phase was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The crude product was purifed on the preparative SFC to give 10 mg N-[3-(1H-indol-4-yl)-5-(2-methoxy-pyridine-4-carbonyl)-phenyl]-acetamide. 1H NMR (400 MHz, CD3COCD3): δ 10.46 (s, 1H), 9.50 (s, 1H), 8.41 (q, J=1.7 Hz, 1H), 8.37 (dd, J=5.1, 0.7 Hz, 1H), 8.11 (q, J=1.5 Hz, 1H), 7.82 (t, J=1.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.28 (dd, J=5.1, 1.4 Hz, 1H), 7.20 (m, 2H), 7.08 (t, J=1.1 Hz, 1H), 6.75-6.73 (m, 1H), 3.96 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[CH:22]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)([CH3:24])[CH3:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:9]3([CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:20][CH:19]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CN1CCN(CC2(c3ccc(O)cc3)CCOCC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCN(C)CC4)CCOCC3)cc2)CC1
Yield: 14 %

Procedure:
The title compound (72 mg, 14%) was prepared using 4-{4-[(4-methylpiperazin-1-yl)methyl]tetrahydro-2H-pyran-4-yl}phenol, 1-isopropyl-4-hydroxypiperidine (step 1 of intermediate 21), PPh3 and DIAD similarly to the procedure used for intermediate 55. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, 6H), 1.76-1.90 (m, 4H), 1.96-2.08 (m, 4H), 2.17-2.26 (m, 11H), 2.33-2.38 (m, 4H), 2.69-2.80 (m, 3H), 3.51 (t, 2H), 3.69-3.74 (m, 2H), 4.24 (m, 1H), 6.84 (d, 2H), 7.18 (d, 2H). HRMS ESI+ m/z 416.3268 [MH]+.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:3]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:31][CH3:32])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:30])([C:17](=[CH:26][CH2:27][O:28][CH3:29])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)C1C=CC=CC=1.CC(O)C>C(O)(C)(C)C>[CH2:31]([C:10]1[C:9]([OH:8])=[CH:25][C:24]2[CH2:23][CH2:22][CH:21]3[CH:13]([CH2:14][CH2:15][C:16]4([CH3:30])[CH:20]3[CH2:19][CH2:18][C:17]4=[CH:26][CH2:27][O:28][CH3:29])[C:12]=2[CH:11]=1)[CH3:32]
Reactant: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCOC)CCC12
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: CCc1cc2c(cc1O)CCC1C2CCC2(C)C(=CCOC)CCC12
Temperature: 25 °C

Procedure:
A solution of 3-benzyloxy-2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene (0.43 g, 1 mmol) in 50 ml tert-butanol was reflux and Na (0.46 g, 20 mmol) was added in small portions over a period of 6 hours. The mixture was refluxed for 18 h, cooled to room temperature and 2-propanol added to destroy excess sodium. The solvents were evaporated and the residual solid poured in water (20 ml). The organics were extracted with ethyl acetate and the organic layer was washed with water, brine, dried over MgSO4. The solvent was evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 15/1 to 8:1) to give 2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ol as a white powder, 230 mg (68%), mp=133-134° C.; 1H NMR (CDCl3, 270 MHz): 0.79 (s, 3H, CH3), 1.22 (t, J=7.4 Hz, 3H, CH3), 1.28-1.60 (m, 6H), 1.75-1.96 (m, 3H), 2.18 (m, 1H), 2.39 (m, 3H), 2.59 (q, J=7.4 Hz, 2H, CH2), 2.79 (m, 2H, H6), 3.35 (s, 3H, CH3O), 3.94 (m, 2H, CH2OMe), 5.11 (s, 1H, OH), 5.24 (m, 1H, CHCH2OH), 6.48 (s, 1H, ArH), 7.05 (s, 1H, ArH). 13C NMR (CDCl3, 400 MHz): 14.9 (CH3), 19.2, 23.5, 24.4, 26.7, 27.1, 28.1, 29.7, 36.4, 39.1, 44.4, 44.8, 53.5, 58.2, 70.2, 112.8, 115.7, 126.4, 127.5, 132.6, 135.5, 151.5, and 157.1. HPLC: 98%; HRMS (FAB+): found 340.24023 calcd. C23H32O2 340.24023.
Reaction SMILES: CI.[I-].CS[C:6]([NH2:18])=[NH+:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17].[I-].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.CSC(N)=[NH+]CCSCC1N=CNC=1C.CSC(N)=[NH+]CCSCC1N=CNC=1C.[NH2:60][CH2:61][CH2:62][CH2:63][C:64]1[N:65]=[CH:66][NH:67][CH:68]=1>CO.O>[CH3:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6]([NH:60][CH2:61][CH2:62][CH2:63][C:64]1[N:65]=[CH:66][NH:67][CH:68]=1)=[NH:18]
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Reactant: NCCCc1c[nH]cn1
Agent: O=S(=O)([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: O
Solvent: CI
Product: Cc1[nH]cnc1CSCCNC(=N)NCCCc1c[nH]cn1

Procedure:
i A solution of n-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affordng S-methyl-N -[2-((5-methyl-4-imidazolyl)methylthio)ethyl] thiouronium iodide (2.3 g), m.p. 128°-131°. The iodide was converted into the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form. ii. A solution of S-methyl-N-[2-((5-methyl-4-imidazolyl) methylthio)-ethyl] thiouronium sulphate (2.93 g) and 4-(3-aminopropyl) imidazole (1.25 g) in water (10 ml) was heated under reflux for 3 hours. Following concentration, the residue was converted to the free base with an ion-exchange resin (IRA 401) in the OH- form and then applied to a weakly acid cation exchange resin (CG 50 in the H+ form) and eluted with dilute hydrochloric acid. The eluate was concentraed to give the title compound which was isolated as the tripicrate (1.8 g) m.p. 183°-185° (from acetone-water). (Found: C, 37.8; H, 3.2; N,21.8% C14H23N7S.3 C6H3N3O7 requires: C, 38.1; H, 3.2; N,22.2%). The tripicrate was converted into the trihydrochloride salt by means of ion-exchange resin IRA 400 (Cl-). The tripcrate was converted into the free base by means of ion-exchange resin IRA 401 (OH-) and the free base was treated with oxalic acid in warm ethanol. The dioxalate crystallised on cooling and was recrystalised from aqueous etanol m.p. 125°-127°. (Found: C, 42.8; H, 5.4; N, 19.4; S, 6.3; C14H23N7S.2 C2H2O4 requires: C, 43.1; H, 5.4; N, 19.5; S, 6.4%)
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10]C2N[C:7](=O)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CI.[CH3:25][N:26]([CH3:29])[CH:27]=[O:28]>O>[Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10][C:25]2[N:26]([CH3:29])[C:27](=[O:28])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)n(C)c2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 5-bromo-6-(2,4-difluorophenoxy)-1,3-dihydro-2H-benzimidazol-2-one (0.106 g, 0.311 mmol) in N,N-dimethylformamide (2.2 mL) was treated with sodium hydride (0.0273 g, 0.684 mmol) and stirred at 20° C. for 30 min. The reaction mixture was treated with methyl iodide (0.0426 mL, 0.684 mmol) and stirred 20° C. for 30 min. The reaction mixture was diluted with water which resulted in the formation of a precipitate. The solid was filtered and washed with water to give the desired product (108 mg, 94%) which was used without further purification. LCMS calculated for C15H12BrF2N2O2 (M+H)+: m/z=369.0, 371.0. found: 368.9, 371.0.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: Cc1ncc[nH]1
Reactant: Fc1cc(CBr)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1ccc(Br)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step A (ca. 42 mmol) in 50 mL of dimethylformamide was added 2-methylimidazole (3.47 g, 82.1 mmol) and potassium carbonate (7.53 g, 54.6 mmol). After stirring for two hours, the mixture was poured into EtOAc and washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was taken up in 100 mL of EtOAc, and excess HCl gas was bubbled through the solution. The precipitate was removed by filtration, partitioned between dichloromethane and dilute NaHCO3 solution, and the water phase was extracted repeatedly with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the desired product as a pale yellow oil.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH2:7]([O:14][C:15](=[O:19])[C:16]([O-])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:19])[CH2:16][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])C(=O)OCc1ccccc1
Reactant: CCCC[Mg]Cl
Product: CCCCCC(=O)OCc1ccccc1

Procedure:
Alternatively, the compound of Example 3 was prepared by the Grignard reaction of n-butylmagnesium chloride with excess benzyloxalate to obtain desired product in 27% yield. 1H NMR (CDCl3, TMS) δ0.91 (t,3H), 1.35 (m,2H), 1.6 (m,2H), 2.85 (t,2H), 5.29 (s,2H), 7.4 (m,5H). Rf value is identical to Example 3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.CS(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:20]=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
To a solution of the objective compound (10.7 g, 37.5 mmol) of Step (1) and triethylamine (21.3 mL, 153 mmol) in dichloromethane (100 mL) was added a solution of sulfur trioxide-pyridine complex (23.9 g, 150 mmol) in dimethyl sulfoxide (DMSO) (100 mL) at -10° C. The obtained solution was stirred at 10-20° C. for 45 min and added to the saturated brine (400 mL). The mixture was extracted with ether. The extract was washed successively with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give N-benzyloxycarbonyl-L-phenylalaninal as a white solid (0.6 g, quantitatively).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:35]([NH:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])=[O:36])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4c(NC(=O)Nc5ccccc5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (50 mg, 0.144 mmol) and 2-fluorophenylisocyanate (20 mg, 0.144 mmol) were dissolved in THF (1 mL) then stirred at RT for 16 h. A precipitate formed in the mixture and was collected on a glass frit, washing with minimal THF then CH2Cl2 to give N-(6-((6,7-bis(methoxy)-4-quinolinyl)oxy)-1-naphthalenyl)-N′-(2-fluorophenyl)urea as an off-white solid. MS (ESI, pos. ion) m/z: 484.2 (M+1). Mass Calc'd for C28H22FN3O4: 483.50
Reaction SMILES: [CH3:1][C:2]1([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:6][C:5]2[C:7]([CH3:17])=[C:8]([NH:13][C:14](=O)[CH3:15])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]2[O:3][C:2]([CH3:1])([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH2:6][C:5]=2[C:7]=1[CH3:17])[CH3:15]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1c(C)c(C)c2c(c1C)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Yield: 64.7 %

Procedure:
To a solution of N-[2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]benzofuran-5-yl]acetamide (0.56 g) in tetrahydrofuran (8 mL) was added 0.11 g of lithium aluminum hydride in small portions under ice-cooling. The mixture was then refluxed for 30 hours. After this reaction mixture was cooled with ice, 0.42 g Hyflo Super-Cel (tradename) and ethyl acetate were added, further followed by addition of water (0.2 mL). The mixture was stirred vigorously and, then, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to provide 0.35 g of the title compound. Yield 63%.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([C:9]2[C:18]([CH2:19][OH:20])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc2ccccc2nc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (45 mg, 1.18 mmol) was added to a solution of 2-phenyl-quinoline-3-carbaldehyde (212 mg, 0.91 mmol) in MeOH (7 mL) and the reaction mixture was stirred at r.t. for 1 h. The reaction was quenched by the addition of glacial AcOH (0.1 mL) and the solvent was removed in vacuo. The residue was partitioned between EtOAc and 10% aqueous K2CO3 solution. The organic phase was dried (MgSO4) and the solvent removed in vacuo to give the title compound (quantitative) as a clear oil which crystallized on standing to a yellow solid. δH (CDCl3) 8.32 (s, 1H), 8.12-8.19 (m, 1H), 7.80-7.86 (m, 1H), 7.67-7.74 (m, 1H), 7.50-7.59 (m, 3H), 7.37-7.47 (m, 3H), 4.71 (s, 2H), 2.76 (br. s, 1H). LCMS (ES+) 236.1 (M+H)+, RT 3.04 minutes (Method 4).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=O.O.[NH2:15][NH2:16].Cl>C(O)C.O>[OH:13][N:11]1[C:3]2[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=2[N:16]=[N:15]1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: On1nnc2ccccc21

Procedure:
Referring to FIG. 1, 1-hydroxybenzotriazole-6-carboxylic acid is formed in two steps from 4-chloro-3-nitrobenzoic acid. In the first step, 4-chloro-3-nitrobenzoic acid and hydrazine monohydrate are heated at reflux in ethanol to yield a crude precipitate. In the second step, the crude precipitate is dissolved in water and acidified with HCl to pH 1 to yield 1-hydroxybenzotriazole, a peach colored precipitate. Confirmation of the compound can be conducted by NMR spectroscopy and high resolution mass spectroscopy (HRMS), as well as other detection methods determined by one of skill in the art.