Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Cl[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:13]([Si:10]([CH3:12])([CH3:11])[O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
1,3-Benzenediol (5 g, 45 mmol) in dichloromethane (150 mL) was treated with chloro(t-butyl)dimethylsilane (7.5 g, 50 mmol) and triethylamine (5 g, 50 mmol). The resulting mixture was stirred at rt for 16 h then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 6N NaOH, then concentrated in vacuo. The residue was purified by column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound (4.3 g, 42%). MS (ES+) m/e 225 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-chlorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.4 mg, 35.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.71 (apparent d, 1H, J=2.9 Hz), 6.69 (apparent t, 1H, J=2.9 Hz), 6.67 (apparent t, 1H, J=2.9 Hz), 6.65 (apparent d, 1H, J=2.9 Hz), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (apparent sept, partially hidden, 2H, J=7.1 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 491.1 (M+H)+.
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18].[CH3:19][O:20][CH2:21]Cl>O1CCCC1.[OH-].[Na+]>[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:19][O:20][CH3:21])=[CH:12][C:11]=1[CH3:18]
Reactant: COCCl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, hexane (50 mL) was added to sodium hydride (50% in oil, 12.6 g, 264 mmol). The mixture was stirred for 30 sec, and stood still, and the supernatant was removed. Tetrahydrofuran (460 mL) was added thereto, and the mixture was cooled to 0° C. A solution of 4-bromo-3,5-dimethylphenol (53.0 g, 264 mmol) in tetrahydrofuran (50 mL) was added slowly dropwise. After completion of the dropwise addition, and the mixture was stirred at 0° C. for 10 min, allowed to warm to room temperature, and was stirred for 20 min. Then, chloromethyl methyl ether (22.3 g, 277 mmol) was added slowly at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with 1 M aqueous sodium hydroxide solution (80 mL). Tetrahydrofuran was evaporated under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed successively with 2 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-10:90) to give the title compound (47.6 g, yield 74%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][CH:38]([F:41])[CH2:39]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:39][CH:38]([F:41])[F:37])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)CBr
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1cccc(OCC(F)F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-2-acetylamino-1-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (204 mg) and 2,2-difluoro-1-bromoethane (0.065 mL) and cesium carbonate (391 mg) in N,N-dimethylformamide (5 mL) and heat to 60° C. for 18 hours. Dilute with ethyl acetate, wash with saturated aqueous sodium chloride, dry and purify (silica gel chromatography, eluting with 1:1 ethyl acetate:dichloromethane), to give the desired compound (223 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C@@H:17]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH:28]1([C@H:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(OCc1ccccc1)[C@@H](OS(=O)(=O)C(F)(F)F)C1CCCCC1
Reaction time: 0.33 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (12.7 g, 45.2 mmol) in 40 mL CH2Cl2 was cooled in an ice bath. A solution of 2-(S)-hydroxy-2-(cyclohexyl)acetic acid, benzyl ester (10.7 g, 43 mmol, from Step A) and 2,6-lutidine (4.6 g, 43 mmol) in 40 mL CH2Cl2 was added dropwise over 25 min and the mixture was stirred for an additional 20 min. The mixture was washed with water and sat'd NaCl then the organic layer was dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 0→15% EtOAc/hexanes) gave the desired product. 1H NMR (500 MHz, CDCl3) δ1.09-1.33 (m, 5H), 1.66-1.73 (m, 2H), 1.75-1.83 (m, 2H), 2.01-2.08 (m, 1H), 4.98 (d, 1H), 5.27 (d, 1H), 5.29 (d, 1H), 7.35-7.4 (m, 5H).
Reaction SMILES: C([N:8]1[CH:13]2[CH:14]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH2:15][C:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:43]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:43].[F:31][C:29]([F:30])([F:32])[C:27]1[CH:28]=[C:23]([CH2:22][O:21][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:15][C@H:14]3[N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=1
Reactant: FC(F)(F)c1cc(COC2CCC3C(n4cnnn4)CC2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3n2cnnn2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(1H-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane. (Example 116; 154 mg, 0.26 mmol) was dissolved in methanol (30 ml) and 2N hydrochloric acid (0.5 ml) and 10% palladium hydroxide (40 mg, 10%) added. The mixture was hydrogenated at 35 psi for 1 hour. The reaction mixture was then filtered and concentrated in vacuo and the oil partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were collected, dried (MgSO4) and concentrated in vacuo to give an orange foam which was purified by flash column chromatography [7.5% methanol in dichloromethane] then further isolated by thin layer chromatography [7.5% methanol in dichloromethane] to give a clear oil. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60° C. (25 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[C-]#N.[Na+].[C:16]1([C:22]#[C:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:24][C:23]#[C:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(CC#N)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1OCC#Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetonitrile (17.4 g) and sodium cyanide (6.6 g) in dimethylformamide (250 ml) is stirred under an atmosphere of nitrogen for 3 hours at +120° C. The mixture is then cooled to +60° C. and toluene-4-sulfonic acid 3-phenyl-prop-2-ynyl ester (39 g) in dimethylformamid (50 ml)is added during 5 minutes. It is stirred at +65° C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2×500 ml). The organic phases are washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:3) and recrystallised from ethyl acetate/hexane. [3-Methoxy-4-(3-phenyl-prop-2-ynyloxy)-phenyl]-acetonitrile is obtained, m.p. 74-75° C.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:11]=[C:9]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(/C=C/C(=O)O)cc1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: N#Cc1ccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)cc1

Procedure:
150 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-cyanocinnamic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[NH:17][C:16]2[C:39]([CH3:43])=[CH:40][CH:41]=[N:42][C:15]1=2)[CH3:13]>C(Cl)Cl>[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N+:31]([O-:9])=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[NH:17][C:16]2[C:39]([CH3:43])=[CH:40][CH:41]=[N:42][C:15]1=2)[CH3:13]
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)Nc2c(C)ccnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)Nc2c(C)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Solid mCPBA (163 mg, 0.75 mmol) was added to a solution of 5,11-dihydro-11-ethyl-4-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (144 mg, 0.34 mmol) in CH2Cl2 (7.5 mL). The solution was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2 (125 mL), washed successively with aqueous 10% Na2S2O3 (2×25 mL), aqueous saturated NaHCO3 (2×25 mL) and brine (25 mL), then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:MeOH, 10:1) to give the title compound (102 mg, 68% yield) as a white solid: MS (ESI) m/z 442 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cn1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-amino-5-bromopyridine (6.92 g, 40 mmol) and 6.22 g (48 mmol) of diisopropylethylamine in 50 mL of chloroform was added dropwise to a solution of 8.19 g (48 mmol) of benzyl chloroformate in 20 mL of chloroform at about 0° C., with stirring. A voluminous white precipitate formed. After about 15 minutes, the mixture was filtered and the precipitate was washed three times with chloroform and dried to give 2.70 g of the title product, mp 184° C. (dec) (recrystallization solvent=2-propanol). 1H nmr (dimethylsulfoxide-d6): δ=10.48 (br s, 1 H), 8.37 (d, 1 H), 7.98 (d of d, 1 H), 7.81 (d, 1 H), 7.40 (m, 5 H), 5.17 (s, 2 H); ms (NH3Cl): m/z=307, 309 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.[CH3:27][CH2:28][O:29][C:30]1[C:34](=O)[C:32](=[O:33])[C:31]=1[O:36]CC.O>C(O)C>[CH2:28]([O:29][C:30]1[C:31](=[O:36])[C:32](=[O:33])[C:34]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1)[CH3:27]
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O

Procedure:
2 g of the compound of Example 1 (6.15 mmol) and 0.9 ml of diethyl squarate are stirred at ambient temperature for 2 hours in 15 ml of ethanol. After adding water, the crystals obtained are filtered off and dried in a desiccator to yield the title product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(CBr)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(COc2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture of 0.6 g (0.0016 mole) of N-(4-chloro-2-fluoro-5-bromomethylphenyl)-3,4,5,6-tetrahydrophthalimide and 0.22 g (0.0016 mole) of potassium carbonate in acetone was added 0.15 g (0.0016 mole) of phenol. The mixture was stirred overnight at room temperature and then was heated at 50° C. for approximately 24 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with water, dried, and the solvent was evaporated under reduced pressure, leaving a residue weighing 0.7 g. Preparative thin layer chromatography was used to separate the components of this residue, eluting with ethyl acetate/heptane (3/7). The product, 0.18 g of N-(4-chloro-2-fluoro-5-phenoxymethylphenyl)-3,4,5,6-tetrahydrophthalimide, was isolated as an oil. The nmr and ir were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][C:21]([O:37]C)=[C:22]([NH:24][C:25]4[N:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:23]=3)[C:13]=2[CH3:39])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.Cl.[OH-].[Na+]>O>[C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[C:21](=[O:37])[NH:20][CH:19]=3)[C:13]=2[CH3:39])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1Nc1ccc(N2CCOCC2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1c[nH]c(=O)c(Nc2ccc(N3CCOCC3)nn2)c1
Yield: 41.3 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4-tert-butyl-N-(3-(6-methoxy-5-(6-morpholinopyridazin-3-ylamino)pyridin-3-yl)-2-methylphenyl)benzamide (7) (0.10 g, 0.18 mmol), dioxane (3 mL), H2O (1 mL), and conc. HCl (0.3 mL). After the reaction mixture was refluxed for 2 h, it was basified with 10 N NaOH (1 mL). The mixture was then diluted with water (5 mL), extracted with dichloromethane (3×5 mL), washed with H2O (5 mL) and brine (5 mL), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane, to afford 0.040 g (41%) of 4-tert-butyl-N-(2-methyl-3-(5-(6-morpholinopyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)benzamide (8) as a solid: LCMS m/z 552.2342 (M+).
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C@@H:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C@@H:7]12.I[CH3:20].O>O1CCCC1>[CH3:20][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C@H:6]2[CH2:5][C:4]3[C:15]([C@@H:7]12)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: c1ccc2c(c1)C[C@@H]1c3ccccc3N[C@H]21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1c2ccccc2[C@H]2Cc3ccccc3[C@H]21
Reaction time: 1 h

Procedure:
A flame dried flask was charged with sodium hydride (60 mg, 2.5 mmol), and tetrahydrofuran (THF) (5 cm3) protected under an atmosphere of nitrogen. To the stirring suspension was added cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (500 mg, 2.4 mmol) in THF (5 cm3) dropwise. The reaction was stirred for 1 hour, a pink colour developing. Iodomethane (0.2 cm3) was added, and the solution was stirred overnight. Water (5 cm3) was added, and the THF removed in vacuo. The colourless solid thus obtained was filtered, and dried in a vacuum desiccator. The product was dissolved in 5% ethyl acetate petrol (60°-80° C.) and filtered through a pad of flash silica. After evaporation of the solvent in vacuo, the title compound was obtained as a colourless solid. Yield: 450 mg (85%). M.p. 76°-77° C. 1H NMR (CDCl3) δ: 3.0 (3H, s,), 3.1 (1H, dd,), 3.4 (1H, dd,), 4.1 (1H, ddd,), 4.9 (1H, d,), 6.4 (1H, d,), 6.7 (1H, dd,), 7.1-7.5 (6H, m,).
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[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=O)[CH2:29]1)(=[O:27])[CH3:26].CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([NH:64][C:57]2[CH:56]=[C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:49]=3[CH:48]=[CH:47][NH:46]4)[CH:63]=[C:62]3[C:58]=2[CH:59]=[N:60][NH:61]3)=[O:36])[CH2:29]1)(=[O:27])[CH3:26]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(=O)N1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of HATU (0.107 g, 0.28 mmol) in dry DMF (3 ml) was added 4-acetyl-2-morpholinecarboxylic acid (0.05 g, 0.282 mmol). DIPEA (0.098 ml, 0.56 mmol) was added and the mixture was left to stand for 10 min. 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.04 g, 0.14 mmol), dissolved in dry DMF (3 ml) was added and the solution was left to stand at room temperature for 20 hr. DMF was removed by blow down under a stream of nitrogen, then the residue was dissolved and purified by Mass Directed AutoPrep Method B. The solvent was removed in vacuo and product dried in a vacuum oven at 50° C. overnight to give the title compound as a brown oil (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][NH:33][O:34][CH3:35].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]([O:34][CH3:35])[CH3:32])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNOC
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of 1 g of the 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide (2.04 mmol, 1 equiv.), 1.2 g of N,O-Dimethylhydroxylamine hydrochloride (12.25 mmol, 9 equiv.), and 1.5 g of sodium bicarbonate (18.38 mmol, 9 equiv.) in DMF (10 ml) was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the crude product was filtered. After flash chromatography (ethyl acetate:methanol:triethylamine 40:4:1), 0.486 g of the title compound was isolated (50.7% yield); mp 210-217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Solvent: CO
Product: Nc1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Yield: 91.6 %

Procedure:
The enantiomer (S)-(+)-5′nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (6.85 g, 26.2 mmol) treated in the same way as described in example 8A in ammoniated methanol provided the title compound (5.55 g, 24 mmol, 92%): electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).