Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[O:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20](OC)=[O:21])[CH2:11][CH2:10]1>C1COCC1>[O:21]=[C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][CH2:15][CH:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)[CH:18]=1)[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCOCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(OCC2CCOCC2)c1
Reaction time: 0.5 h

Procedure:
The solution of CH3CN (0.37 g, 8.9 mmol) in THF (40 mL) was added to n-BuLi (1.6 M in hexanes, 0.58 g, 8.9 mmol) at −78° C. and the reaction mixture was stirred for 30 min. Solution of ester (12) (1.5 g, 5.9 mmol) in THF (10 mL) was added to the reaction mixture and the resulting solution was further stirred for 30 min. The reaction mixture was quenched by addition of aq.NH4Cl (200 mL) and extracted with EtOAc (100 mL). Drying over anhydrous Na2SO4 and concentration under reduced pressure gave 3-oxo-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propanenitrile (13). Yield (1.5 g, 96%); 1H NMR (400 MHz, DMSO-d6) δ 7.43-7.37 (m, 3H), 7.26-7.21 (m, 1H), 4.75 (bs, 2H), 3.89-3.83 (m, 4H), 3.32 (t, J=11.6 Hz, 2H), 2.03-1.98 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH:14]=[N:15]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=CC1C2CN(Cc3ccccc3)CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1C2CN(Cc3ccccc3)CC12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde oxime (1.57 g, 7.27 mmol) in THF (75 ml) was cooled to 0° C. under N2 and LiAlH4 (965 mg, 25.44 mmol) was added. The reaction was heated to 60° C. for 16 h and then cooled to 0° C. It was quenched with a mixture of H2O (3 ml) and sat. aq. sodium potassium tartrate (1 ml) and the resulting suspension stirred for 30 min. MgSO4 was added and the mixture filtered through celite. The filtrate was then concentrated in vacuo to give the title compound as a light yellow oil (1.35 g, 93%). LCMS purity 80%, m/z 203 [M+H]+, 1H NMR (300 MHz, CDCl3) δ: 1.21 (4H, m), 1.41 (1H, m), 2.36 (2H, d, J=8.7 Hz), 2.52 (2H, d, J=7.2 Hz), 2.97 (2H, d, J=8.7 Hz), 3.54 (2H, s), 7.20-7.36 (5H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH2:21]2)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1CCCC12CCNC2
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of 1.42 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 1.0 g of 1-methyl-1,7-diazaspiro[4,4]nonane and 1.48 g of potassium carbonate in 10 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The yellow oily residue is purified on silica, with an elution gradient with dichloromethane/methanol (100/0 then 90/10), so as to obtain 160 mg of 1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of an orangey-coloured oil.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>ClCCl>[C:22]([CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)([OH:24])=[O:23]
Reactant: O=C(O)CCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: O=C(O)CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.7 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (305 mg) was dissolved in dichloromethane (10 ml) and 3-mercaptopropionic acid (0.09 ml) was added. The solution was stirred at room temperature for 3 days, during which time a yellow precipitate was formed. This precipitate was filtered off and recrystallised from absolute ethanol to give 10-(carboxyethylthio)-1,8-dihydroxy-9-anthrone (240 mg, 72.7%) as pale yellow needles, melting point 152°-153° C. (Found: C 61.5, H 4.3, S 9.8%; M=330.0548; C17H14O5S requires C 61.8, H 4.3, S 9.7%; M=330.0562).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1([OH:39])[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)#[CH:25]>>[OH:39][C:26]1([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC1(O)c2ccccc2-c2ccccc21
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(O)c3ccccc3-c3ccccc31)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 9-ethynyl-9H-fluoren-9-ol. MS (+ESI) m/z: 477.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[C:4]([NH2:29])[N:3]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]([CH:9]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC(=O)c1ccc(CCCC(c2c(N)nc(N)nc2N)C(OC)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)C(CCCc1ccc(C(=O)O)cc1)c1c(N)nc(N)nc1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The product of Example 13 (403 mg) was suspended in a mixed solution of tetrahydrofuran-water (5:1, 8.0 ml), 1N aqueous solution of sodium hydroxide (2.0 ml) was added thereto and the mixture was stirred at 40° C. overnight. After neutralizing the mixture by adding 1N hydrochloric acid (2.0 ml), solvent was removed by distillation under reduced pressure and the residue was dried to give crude 4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoic acid. The total amount of the crude product and diethyl glutamate hydrochloride (360 mg) were suspended in dimethylformamide (4.0 ml), a solution (4.0 ml) of diethyl phosphorocyanidate (171 mg) in dimethylformamide was added thereto at 0° C. and the mixture was stirred. Subsequently, a solution (4.0 ml) of triethylamine (303 mg) in dimethylformamide was added dropwise thereto at the same temperature and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours, followed by removing solvent by distillation under reduced pressure. The resulting residue was purified by flash column chromatography (15 g of silica gel; dichloromethane-methano 30:1→75:1) to give the subject compound (417 mg).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:14]=[C:13]([CH3:15])[C:9]([C:10](O)=[O:11])=[C:8]([F:16])[CH:7]=1)([CH3:5])[CH3:4])#[N:2].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]([C:3]([CH3:5])([CH3:4])[C:6]1[CH:14]=[C:13]([CH3:15])[C:9]([C:10]([NH2:19])=[O:11])=[C:8]([F:16])[CH:7]=1)#[N:2]
Reactant: Cc1cc(C(C)(C)C#N)cc(F)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C#N)cc(F)c1C(N)=O
Reaction time: 2.5 h

Procedure:
4-(2-cyanopropan-2-yl)-2-fluoro-6-methylbenzoic acid (14 g, 35 mmol, 75% pure) was taken up in dry tetrahydrofuran (100 ml). To this was added 1,1′-carbonyldiimidazole (11.2 g, 69.1 mmol) in four equal portions over 15 minutes. The mixture was stirred for 2.5 hours and then a 28% aqueous solution of ammonium hydroxide (20.4 ml) was added via drop-wise addition. The material was stirred for 4 hours and then concentrated under reduced pressure to remove 90% of the volatiles. The residue was taken up in water (80 ml) and dichloromethane (80 ml) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with dichloromethane (3×60 ml). The combined organic phase was dried (magnesium sulfate), filtered and concentrated in vacuo and the resultant semisolid was purified via trituration from hot dichloromethane/hexanes to provide the desired product as a slightly-impure off-white solid (10.71 g, 80% purity). (M+H)+=221 m/e.
Reaction SMILES: [CH:1]([C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>>[CH2:1]([C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCC=Cc1cc(Br)cs1
Product: CCCCCCc1cc(Br)cs1

Procedure:
From said spectra it was determined that 2-(n-hex-1-enyl)-4-bromothiophene was still present in the reaction product. The reaction product was again treated with Wilkenson's Catalyst and hydrogen, overnight. The re-treated reaction mixture was passed through a silica gel plug and eluted with hexane to yield 2.1 gms of a clear, colorless liquid having the following NMR spectra: 7.01 (s, 1H), 6.71 (s, 1H), 2.77 (t=7 Hz, 2H), 1.65 (m, 2H), 1.29-1.35 (m, 6H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1
Reactant: CC1(C)OB(c2cncc(O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1-c1cncc(O)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.31 mmol) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol (102 mg, 0.46 mmol), (1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 25 mg, 0.03 mmol) and a 2M aqueous solution of cesium carbonate in dioxane (462 μl). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 56 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:18])[NH:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=O.C([O-])(O)=O.[Na+].Cl>>[CH3:1][N:2]1[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][NH:4][C:3]1=[S:18]
Reactant: CNC(=S)NNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2ccc3ccccc3c2)n[nH]c1=S

Procedure:
4-Methyl-1-(2-naphthoyl)thiosemicarbazide (12.9 g, 4.97×10-2 mole) and 1 molar aqueous NaHCO3 (480 ml, 4.80×10-1 mole) were stirred and warmed to reflux. After refluxing overnight, the reaction was cooled in an ice bath before being acidified by the dropwise addition of concentrated hydrochloric acid (40 ml, 4.8×10-1 mole). The resulting product was collected by filtration and dried by suction. Crystallization from ethanol afforded beige needles, Mp 223°-225° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[CH:5]2.[OH:14][C@:15]1([C:22]2[CH:23]=[C:24]([SH:27])[S:25][CH:26]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1>>[OH:14][C@:15]1([C:22]2[CH:23]=[C:24]([S:27][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[CH:5]4)[S:25][CH:26]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Reactant: Cn1c(=O)ccc2cc(I)ccc21
Product: C[C@H]1C[C@@](O)(c2csc(Sc3ccc4c(ccc(=O)n4C)c3)c2)CCO1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2-dihydroquinolin-2-one (European Patent Application No. 0420511, Example 1 thereof) was reacted with (2S,4R)-4-hydroxy-4(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 65% yield as a foam;
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:19][CH:15]([NH:16][C:17]2=[O:18])[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[CH3:20]I>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:19][CH:15]([N:16]([CH3:20])[C:17]2=[O:18])[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: COc1cccc(C23CCCC(C2)NC3=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
0.36 g of 69% sodium hydride is added to 40 ml of dimethylsulfoxide, The mixture is heated at 70°C for 30 minutes in a nitrogen atmosphere. 2 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-7-one are added to the mixture at 10° to 15°C. Then, the mixture is stirred at room temperature for 1 hour. 2.1 G of methyl iodide are added to the mixture, and the mixture is further stirred at room temperature for 2 hours. The reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from n-hexane. 2 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one are obtained. M.p. 68° - 70°C.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:37]=[CH:36][C:23]2[C:24]3[CH:25]([CH2:34][Cl:35])[CH2:26][NH:27][C:28]=3[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:39][N:40]([CH3:56])[CH2:41][CH2:42][O:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53](O)=[O:54])=[CH:47]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[P:1]([O:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:37]=[CH:36][C:23]2[C:24]3[CH:25]([CH2:34][Cl:35])[CH2:26][N:27]([C:53]([C:48]4[NH:49][C:50]5[C:46]([CH:47]=4)=[CH:45][C:44]([O:43][CH2:42][CH2:41][N:40]([CH3:56])[CH3:39])=[CH:52][CH:51]=5)=[O:54])[C:28]=3[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OP(=O)(OCCNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
A mixture of 227 (351 mg, 0.61 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (225 mg, 0.79 mmol), EDCI (466 mg, 2.4 mmol) and TsOH (21 mg, 0.12 mmol) in DMA (3 mL) was stirred at room temperature for 3.5 h and then cooled to 0° C. Ice-cold aqueous NaHCO3 was added, and the resulting precipitate was filtered off, washed with aqueous NaHCO3 and water, and dried. Trituration with acetone gave di(tert-butyl) 2-({[1-(chloromethyl)-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}amino)ethyl phosphate (229) (433 mg, 88%) as a yellow solid: mp 220-225° C. (dec.); 1H NMR [(CD3)2SO] δ 11.73 (s, 1H), 9.30 (s, 1H), 8.87 (d, J=1.7 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.16 (br s, 1H), 8.02 (dd, J=8.9, 1.7 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.96 (dd, J=−8.9, 2.4 Hz, 1H), 5.00-4.94 (m, 1H), 4.73 (dd, J=11.0, 2.4 Hz, 1H), 4.68-4.62 (m, 1H), 4.19-4.11 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.87-3.80 (m, 2H), 3.08-3.03 (m, 2H), 2.66 (t, J=5.9 Hz, 2H), 2.24 (s, 6H), 1.36 (s, 18H. Anal. (C36H47ClN5O10PS.½H2O) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.Cl>CN(C=O)C>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(F)(F)F)cc(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylate (100 mg) was suspended in DMF (1.5 ml). Cesium carbonate (268 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (83 μl) were sequentially added and the mixture was stirred at room temperature for three hours. A 1 N aqueous hydrochloric acid solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->40:1 (v/v)] to give 159 mg of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:17][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: COc1cccc(-c2ccc(C)c(F)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2ccc(CBr)c(F)c2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 3-fluoro-3′-methoxy-4-methyl-bipheny (0.5 g, 1.7 mmol, 1.0 eq) in chloroform (30 mL), was added N-bromo succinimide (0.3 g, 1.7 mmol followed by catalytic amount of dibenzoyl peroxide. The reaction mixture was refluxed by irradiating with a tungsten lamp for 3 hours. After the reaction was completed, it was cooled to room temperature and washed with water. The combined organic layers were dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.45 g, 89%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCOCc1ccc2ccccc2c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc3ccccc3c2)CC1
Yield: 95.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.00 g) as starting compound and 5-(2-naphthylmethoxy)-pentyl chloride (1.88 g) were reacted and treated in the same manner as in Example 168 to give 1.45 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethoxy)pentyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1CO>O1CCCC1>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:1][Cl:5]
Reactant: COCOc1ccccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccccc1CCl
Yield: 57 %

Procedure:
16.4 ml of carbon tetrachloride, followed by 44.5 g of triphenylphosphine were added, whilst ice-cooling, to a solution of 23.8 g of 2-methoxymethoxybenzyl alcohol in 240 ml of tetrahydrofuran, and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the mixture was cooled, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 15.5 g (yield 57%) of the title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)c(CBr)c1

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of methyl 4-bromo-3-methylbenzoate (10 g, 43.65 mmol, 1.00 equiv) in CCl4 (150 ml), NBS (8.12 g, 45.62 mmol, 1.05 equiv). The resulting solution was heated to reflux overnight under 100 w incandescent bulb. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 6 g (47%) of methyl 4-bromo-3-(bromomethyl)benzoate as a off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=O)[C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[NH2:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:25])[C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1cccc(Cl)c1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Into a flame dried flask, N-(1-benzyl-piperidin-4-yl)-2-chloro-6-nitro-benzamide (1.67 g, 4.47 mmol) and lithium aluminium hydride (0.51 g, 13.43 mmol) were combined. To this was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly brought to reflux and stirred for 16 h. The reaction mixture was cooled to 0° C. and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction.