Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@@:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23][OH:24])([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7].CC(C)([O-])C.[K+].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[N+:40]([O-:42])=[O:41]>C1COCC1>[ClH:32].[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23][O:24][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[N+:40]([O-:42])=[O:41])([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[OH:7]
Reactant: CN(C)CCC[C@](O)(c1ccc(F)cc1)c1ccc(C#N)cc1CO
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCCC(O)(c1ccc(F)cc1)c1ccc(C#N)cc1COc1ccc(Cl)cc1[N+](=O)[O-]
Product: Cl
Reaction time: 0.17 h

Procedure:
To a solution of 5.6 gm of (S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile in 85 ml THF was added 2.02 gm of potassium tertiary butoxide at 0-10° C. and stirred for 10 min. 3.14 gm of 2,5-dichloronitrobenzene was added to the reaction mixture at 0-10° C. and stirred for 10-15 hrs at RT (30-35° C.), solvent distilled under vacuum and 40 ml of water was added, and extracted with toluene, toluene layer was washed with water and 10% sodium hydroxide solution and distilled to get an oily product, which is purified by column chromatography using silica gel and ethylacetate, Wt: 500 mg. The above oily product was dissolved in 10 ml of isopropanol (IPA) at 30° C. and 2.0 ml of IPA-HCl was added, stirred and solvent distilled under vacuum and crystallized in IPA to get (−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)-benzonitrile hydrochloride whose structure was confirmed by IR, NMR and Mass spectral data.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:23])[C:11]([OH:22])([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[C:24]([NH:31][CH2:32][CH2:33][CH2:34][Br:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[Br-:35].[C:27]([O:26][C:24]([NH:31][CH2:32][CH2:33][CH2:34][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:23])[C:11]([OH:22])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:2]2)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)c1cccs1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Product: [Br-]
Temperature: 60 °C

Procedure:
Hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (0.758 g, 2.17 mmol) and 3(BOC-amino) propylbromide (0.775 g, 3.25 mmol) are dissolved in DMF (7 ml) and heated at 60° C. for 2.5 hours. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the titled compound as an oil.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[H][H].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CN(C=O)C.[I-].[Na+]>[S:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[S:3][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]
Reactant: [H][H]
Reactant: OCC(O)CCl
Reactant: Sc1nc2ccccc2s1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC(O)CSc1nc2ccccc2s1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
1.80 g (60 mmol) of an 80% strength NaH/oil dispersion were added (with cooling) to a solution of 10.04 g (60 mmol) of 2-mercaptobenzothiazole in 100 ml of absolute DMF at about 40° C., and the mixture was stirred for 15 minutes at 40° C., after which the evolution of hydrogen was complete. 6.63 g (5.02 ml, 60 mmol) of 1-chloro-2,3-dihydroxypropane and 0.30 g (2 mmol) of powdered sodium iodide were added, the mixture was stirred for 3 hours at 87° C., and the DMF was subsequently substantially removed by distillation in vacuo in a rotary evaporator. The oily residue was taken up in 300 ml of CH2Cl2, and the solution was successively shaken twice with 80 ml of 0.2N NaOH in each case and twice with water, dried, filtered and evaporated in vacuo. The residue remaining, 12.5 g of a viscous oil, was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.0 cm, height 38 cm) by elution with CH2Cl2 and CH2Cl2 /ethanol 100:5-100:3 (v/v) mixtures. The fractions which were unary according to TLC were combined and evaporated vigorously in an oil-pump vacuum. 9.0 g (62.2% of theory) of 1-(benzothiazol-2-ylthio)-2,3-dihydroxypropane, a compound of the formula VIII (Z=S, L, m and p=0), were obtained as a highly viscous oil,
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5](I)[C:3]=1[NH2:4].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>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.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:3]=1[NH2:4]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1cc(Cl)c(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(S(C)(=O)=O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 1308.5 %

Procedure:
To the suspension of 2-chloro-6-iodo-4-methanesulfonylaniline (886.9 mg, 2.7 mmol.), Pd(PPh3)2Cl2 (94.5 mg, 0.13 mmol), and CuI (24.3 mg, 0.13 mmol.) was added triethyl amine (2 mL), and the suspension was slowly treated with (trimethylsilyl)acetylene (0.22 mL, 0.16 mmol.) at 0° C. The reaction mixture was stirred at room temperature for ˜16 h. Solvent was removed under vacuum. The residue was diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with saturated NaCl, water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using 20% ethyl acetate-hexane to give 2-chloro-4-methanesulfonyl-6-trimethylsilanylethynyl-phenylamine (632 mg, 78%). The 1H NMR (500 MHz, CDCl3) spectrum was: 0.27 (s, 9H), 3.01 (s, 3H), 5.17 (s, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([O:28]C(=O)C)[C:25](=[O:27])[CH3:26])[CH:17]=3)[C:12]2=[O:32])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(O)(C)C.O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([OH:28])[C:25](=[O:27])[CH3:26])[CH:17]=3)[C:12]2=[O:32])=[CH:4][CH:3]=1
Reactant: CC(=O)ON(CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O)C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: CC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
2-[3-(4-Fluorophenyl)-propyl]-6-[2-(N-acetyloxy-N-acetylamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (2.0 g) is dissolved in 40 ml of an isopropanol/water mixture (1:1) and treated with 0.94 g (25 mmol) of lithium hydroxide monohydrate for 30 minutes at room temperature. The mixture is diluted with ether and the organic phase is removed. The aqueous layer is brought to pH of approximately 3 with 2N HCl, and extracted with ether. The combined acidic extracts are dried (MgSO4) and evaporated to dryness to yield 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxy-N-acetylamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[N:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>O>[CH3:14][N:15]([CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: C=Cc1cccc(C)n1
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(CCN(C)Cc2ccccc2)n1

Procedure:
0.5 ml of glacial acetic acid was added to a solution of 10.0 g (84.0 mmol) of 6-methyl-2-vinylpyridine and 10.2 g (84 mmol) of N-methylbenzylamine in 100 ml of a mixture of methanol with water (1:1) and the mixture thus obtained was refluxed for 8 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3). A fraction containing the intended compound was concentrated to give the compound in the form of an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=4[CH3:7])[CH:31]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred ad the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 50 mg of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:18][C:17]2[C:16](=[O:19])[N:14]([CH3:15])[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH:24]([C:28](Cl)=[O:29])[C:25](Cl)=[O:26])C>O1CCOCC1.C(#N)C>[CH2:1]([N:8]1[C:9]2=[N:10][C:11]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH3:15])[C:16](=[O:19])[C:17]=3[N:18]2[C:28]([OH:29])=[CH:24][C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: Cn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(C)c1=O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Temperature: 25 °C

Procedure:
Add 8-benzylaminotheophylline (30 g) and ethyl malonyl chloride (35.1 gm) to 600 ml of 1:1 dioxan/acetonitrile. Heat the reaction mixture to reflux under a nitrogen atmosphere until the 8-benzylaminotheophylline is consumed (ca. 3.5 hrs.). Cool the reaction mixture to room temperature and pour the solution into 800 ml of ether. Filter off the precipitate. Wash the precipitate with ether and dry the product to obtain the title compound, mp 205.5°-209° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1.O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][I:29])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
The compound (178 mg, 0.42 mmol) prepared in Example 70 was dissolved in tetrahydrofuran (10 ml). Iodine (161 mg, 0.63 mmol), triphenylphosphine (166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (120 mg, Yield 54%).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:5]=12.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:6]2([OH:10])[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCn2cncc21
Product: OC1(c2ccccc2)CCCn2cncc21

Procedure:
In analogy to Example 3a 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and phenylmagnesium bromide solution [100-58-3] (1M in tetrahydrofuran) are reacted. The title compound is obtained as a beige solid. Rt=4.10 (Gradient 1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenyl isocyanate (40.5 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 415 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)(=[O:25])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][C:33](=O)[CH2:34][CH2:35][CH3:36].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([N:26]5[CH2:27][CH2:28][N:29]([CH:34]([CH2:35][CH3:36])[CH2:33][CH3:32])[CH2:30][CH2:31]5)(=[O:24])=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCCC(C)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCNCC3)ccc1OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(CC)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Reaction time: 20 h
Yield: 24.3 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperazine-1-sulfonyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.08 mmol), pentanone (25 μL, 0.24 mmol), AcOH (9 μL, 0.16 mmol) and 4 Å molecular sieves in DCE (2 mL) was stirred at RT for 1 h before the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol). The resulting mixture was stirred for 16 h before further pentanone (100 μL, 0.92 mmol) and sodium triacetoxyborohydride (198 mg, 0.96 mmol) were added. The mixture was stirred for 20 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) to afford 134 (10 mg, 25%) as a white solid. LCMS: RT 3.13 min [M+H]+ 514.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.36 Hz), 7.88 (1H, s), 7.70 (1H, s), 7.65 (1H, dd, J=8.59, 2.37 Hz), 7.17 (1H, d, J=8.60 Hz), 5.94-5.85 (1H, m), 4.59-4.58 (2H, m), 4.52-4.51 (2H, m), 3.05 (4H, s), 2.61 (4H, s), 2.13-2.10 (1H, m), 1.60 (6H, d, J=6.64 Hz), 1.46-1.35 (2H, m), 1.29-1.27 (2H, m), 0.83 (6H, t, J=7.36 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]([OH:17])[C:15]#[CH:16].[CH2:18]=O.O>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:18][C:16]#[C:15][CH2:14][OH:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: C=O
Reactant: C#CCO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cl
Product: OCC#CCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorophenyl)-piperazine (19.7 g; 0.10 mole) is weighed to propargyl alcohol (11.8 ml; 0.20 mole), copper(II) acetate monohydrate (1.0 g; 5.2 mmoles) is added to it, and 37% aqueous formaline (50 ml) is pipetted to the reaction mixture under stirring. The green suspension is refluxed for 2 hours. Then it is cooled, water and chloroform are added to it and the pale green substance insoluble in both phases are filtered off. The aqueous phase is extracted twice with chloroform, the combined organic phases are dried over sodium sulfate and evaporated. The residual brown oil is dissolved in ethyl acetate, and a solution of 2 molar equivalents of hydrogen chloride in ethyl acetate is dropped to it under stirring. The separated white salt is filtered, digested while hot with isopropanol, cooled and filtered.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH3:13][OH:14]>>[CH3:13][O:14][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: COc1cc(N)nc(N)n1
Reaction time: 44 h

Procedure:
To a solution of 9.2 g (0.40 mol) sodium in 320 ml methanol were added 28.9 g (0.20 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 44 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue in 300 ml ethanol was heated to boiling and filtered hot. The product precipitated out of the filtrate on standing overnight. Recrystallization of the mother liquor likewise afforded product. After drying, 6-methoxy-2,4-diaminopyrimidine was obtained as a white solid (58.8 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[C:20]([O:19][C:18]([NH:17][CH:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:24])([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C1(c2ccc(O)cc2)CCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2(C(CC(C)C)NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of phenol 67 (0.5 g, 0.0015 mole) in 25 mL of anhydrous DMF was added cesium carbonate (Cs2CO3). The resulting mixture was heated at 70° C. for 12 hours. The reaction mixture was cooled to room temperature and added ethyl bromoacetate. The reaction mixture was further stirred at 70° C. for 8 hours and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL×2), dried over anhydrous sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluent to give the pure ester 69 as colorless liquid in 61% (0.38 g) yield. MS (ESI): m/z=420.00 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C(O[CH:21]=[N:22][C:23]1[S:24][C:25]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])=[C:26]([CH3:33])[C:27]=1[C:28](OCC)=[O:29])C>C(O)C>[CH3:33][C:26]1[C:27]2[C:28](=[O:29])[N:1]([CH2:2][CH2:3][N:4]3[CH2:5][CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:16][CH3:17])[CH2:8][CH2:9]3)[CH:21]=[N:22][C:23]=2[S:24][C:25]=1[C:34](=[O:38])[N:35]([CH3:37])[CH3:36]
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCOC=Nc1sc(C(=O)N(C)C)c(C)c1C(=O)OCC
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2cnc3sc(C(=O)N(C)C)c(C)c3c2=O)CC1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
1.9 g (8.0 mM [sic]) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine were added to 2.4 g (7.8 mM [sic]) of 2-ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoyl thiophene in 30 ml of ethanol and refluxed for 2 h. The product crystallized out after standing overnight and was filtered off with suction and washed with a little ethanol. 2.2 g (62%) of product were isolated with melting point 188-190° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:15])=[CH:3]1.[O:16]1CCC[CH2:17]1.[BH4-].[Na+].[OH-].[Na+].[C:25](O)(=O)[CH3:26]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:14][CH2:25][CH3:26])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)[C:4]([CH3:15])=[CH:3]1
Reactant: CC1=CN(C)CCC1(C)c1ccccc1
Reactant: CC(=O)O
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCCC1(c2cccc(OC)c2)CCN(C)C=C1C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 50 g. of 1,3,4-trimethyl-4-phenyl-1,4,5,6-tetrahydropyridine in 2600 cc. of tetrahydrofuran containing 38 g. of sodium borohydride was stirred and cooled to 5° C. in an ice-water bath. To the reaction mixture was added 578 cc. of glacial acetic acid at a rate such as to maintain the temperature of the reaction mixture between 5° C. and 10° C. After the addition was complete, the reaction mixture was stirred at 10° C. for 1/2 hour and then heated at reflux for 1 hour. The reaction mixture was cooled to about 25° C. and 25 percent aqueous sodium hydroxide was added to adjust the pH to 11.5. The alkaline reaction mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over sodium sulfate. After filtering the drying agent, the solvent was evaporated under reduced pressure to provide 47 g. of essentially pure trans-1,3,4-trimethyl-4-phenylpiperidine. B.P. 90°-92° C. at 0.15 mm/Hg.