Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([O:12][C:13]2[CH:21]=[CH:20][C:19]3[N:18]4[CH2:22][CH2:23][CH2:24][C:17]4=[CH:16][C:15]=3[CH:14]=2)[CH2:11][CH2:10]1>C(#N)C>[CH:9]1([O:12][C:13]2[CH:21]=[CH:20][C:19]3[N:18]4[CH2:22][CH2:23][CH2:24][C:17]4=[C:16]([I:1])[C:15]=3[CH:14]=2)[CH2:11][CH2:10]1
Reactant: c1cc2c(cc1OC1CC1)cc1n2CCC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Ic1c2n(c3ccc(OC4CC4)cc13)CCC2
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
18.5 g N-iodosuccinimide at 0° C. was added to a solution of 17.55 g 6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene in acetonitrile and the mixture was stirred at this temperature for 15 min. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 20.1 g 6-cyclopropoxy-8-iodo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene as beige crystals melting at 104-105° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:33])[CH2:22][N:23]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[N:24]3)[CH2:17][CH2:16]2)[S:13][CH:14]=1)#[CH:9].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:9]#[C:8][C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:33])[CH2:22][N:23]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:30])([F:32])[F:31])=[N:24]3)[CH2:17][CH2:16]2)[S:13][CH:14]=1
Reactant: COc1ccccc1I
Reactant: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (25 mg), copper(I) iodide (7 mg) and triethylamine (48 mg) are added to a solution of 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (I-86, 150 mg) and 1-iodo-2-methoxybenzene (101 mg) in degassed N,N-dimethylformamide (1.5 ml). After 2 hours of stirring at 85° C., the reaction mixture is then diluted with water and extracted with ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives 1-(4-{4-[(2-methoxyphenyl)ethynyl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (100 mg).
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:40]([CH3:41])=[CH:39][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.CO.[OH-].[Na+]>C1COCC1>[NH:38]1[C:34]([C:30]2[CH:29]=[C:28]([C:24]3[CH:23]=[C:22]([C:20]4[S:21][C:17]5[C:16]([C:42]6[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=6)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:40]([CH3:41])=[CH:39][C:18]=5[N:19]=4)[CH:27]=[CH:26][N:25]=3)[CH:33]=[CH:32][CH:31]=2)=[N:35][N:36]=[N:37]1
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of crude (S)-2-(2-(2-(3-(1H-tetrazol-5-yl)phenyl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate from the previous reaction (assume 0.027 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added NaOH (0.4 mL of a 2N solution). The reaction mixture was heated at 40° C. for 2 h, cooled, quenched with NH4Cl (sat. aq.), and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was used without further purification. LCMS-ESI+: calc'd for C32H30ClN6O2S: 597.2 (M+H+); Found: 597.0 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28](=[CH:34]N(C)C)[C:29](OCC)=[O:30]>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28]1[CH:34]=[N:2][N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[C:29]=1[OH:30]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.39 (m, 4 H) 1.68 (d, J=12.9 Hz, 2 H) 3.20-3.37 (m, 6 H) 3.63 (s, 1 H) 3.92 (dd, J=11.2, 2.7 Hz, 2 H) 7.90 (d, J=8.1 Hz, 1 H) 8.15 (s, 1 H) 8.49 (d, J=3.8 Hz, 2 H) 8.73-8.87 (m, 1 H) 8.98 (s, 1 H). MS m/z [M+H]+ 438.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([OH:21])=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[ClH:26].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>ClCCl>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([NH:53][CH2:52][CH2:51][O:50][CH3:49])=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: COCCN
Reactant: O=C(O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 22.5 %

Procedure:
A mixture of 33 mg (0.088 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine-1-acetic acid, 30 mg (0.157 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 16 mg (0.105 mmol) of 1-hydroxybenzotriazole hydrate and 14 mg (0.187 mmol) of 2-methoxyethylamine was stirred in 3 ml of dichloromethane for 3 hours. The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed three times on silica gel using dichloromethane/methanol (94:6), dichloromethane/methanol 92:8) and ethyl acetate/methanol (9:1) for the elutions. The product was dissolved in a solution of hydrogen chloride in ethyl acetate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 5 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-N-(2-methoxyethyl)-1H-1,4-benzodiazepin-1-acetamide dihydrochloride as a red solid. MS: m/e 431.9 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C:18]2(OCC[O:32]2)[CH:17]=[CH:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C:18](=[O:32])[CH:17]=[CH:16]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 97.3 %

Procedure:
2.6 g of 7α-(11-hydroxyundecyl)-17,17-ethylenedioxy-1,3,5(10),15-estratetraen-3-ol is stirred in 57 ml of acetone and 6.6 ml of water at 25° with 164 mg of p-toluenesulfonic acid for 2.5 hours. Then the mixture is concentrated to one-third, precipitated with ice/aqueous sodium chloride solution, filtered off, taken up in dichloromethane, washed neutral, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 2.3 g of crude 7α-(11-hydroxyundecyl)-1,3,5(10),15-estratetraen-3-ol-17-one, [α]D =-14.0°, as an oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][CH:6]=1.O1CCCC1.O.O.[OH-].[Li+]>CO>[C:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]2([CH3:32])[CH3:31])#[CH:24]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
A solution of [4-(2,2,4,4-tetramethyl-8-trimethylsilanylethynyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 38, 0.13 g, 0.28 mmol) in a mixture of methanol (3 mL), tetrahydrofuran (3 mL) and water (1.5 mL) was treated with lithium hydroxide monohydrate (0.13 g, 3.1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2.5 h. The volatiles were distilled off in vacuo and the residue was diluted with water and saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a white solid (0.078 g, 74%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14](O)=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3].B.CO.Cl>C1COCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][C@@H:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[N+:25]([O-:27])=[O:26])[CH2:17][S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(N[C@H](CCO)CSc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of Example 122E (206 mg, 0.50 mmol) and 1M borane in THF (20 mL) was stirred for 16 hours, treated sequentially with methanol (5.0 mL) and 1N HCl (2.0 mL), diluted with ethyl acetate (50 mL), washed with water (2 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/dichloromethane to provide the desired product. MS (ESI(+)) m/e 398 (M+H)+.
Reaction SMILES: [C:1]([C@:4](CO)([OH:25])[C@:5](C(=O)C)([OH:21])[C@:6](C(=O)C)([OH:17])[C@@:7](C(=O)C)([OH:13])[C:8]([CH2:10][CH:11]=[CH2:12])=[O:9])(=[O:3])C>[OH-].[Na+]>[CH2:10]([C:8]([C@@H:7]([C@H:6]([C@H:5]([C@@H:4]([CH2:1][OH:3])[OH:25])[OH:21])[OH:17])[OH:13])=[O:9])[CH:11]=[CH2:12]
Reactant: C=CCC(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(CO)C(C)=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 2 h

Procedure:
Compound 1 (23 g) was dissolved in 4N NaOH solution (100 mL) and stirred for 2 hr. The reaction mixture was extracted with ether. The aqueous layer was acidified with Dowex-H resin. The resin was removed by filtration and the filtrate was lyophilized to give the deprotected derivative 2 as a white powder. This was recrystallized in ethyl acetate-methanol (7:3) to give crystals (7.0 g). 1H NMR (CD3OD): 6 8.2-8.90, m, 1H, CH2CH=CH2 ; 5.12-5.09, dd, 2H, CH2CH=CH2 ; 3.99-4.01, m, 1H, H-1; 3.80-3.84, m, 1H, H-2; 3.87-3.62, mm, 3H, H,4,5,6: 13C NMR (CD3OD): 136.73, 116.86, 75.66, 74.02, 71.91, 70.11, 70.00, 61.97, 31.03: [α]D =+106.45 (c 1.03, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1>COCCOC.[Pd].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
2-[2-(4-Fluorophenyl)ethenyl]benzonitrile (8.10 g, 36.3 mmol) was dissolved in ethylene glycol dimethyl ether (200 mL). Palladium on charcoal (10% Pd; 0.81 g) in H2O (1.0 mL) was added, and the reaction mixture was shaken under 60 psig H2 for 1 h. The reaction mixture was then filtered through Celite®, and the filtrate was rotary evaporated (75° C.). This provided 8.03 g (98.3%) of the product as an orange oil which crystallized on standing.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.C(Cl)Cl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:7]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)+-2-methylpiperazine (10 g) was dissolved in acetonitrile (140 ml) and cooled to 5-10° C. whereupon triethylamine (35 ml) was added, followed by drop wise addition of a solution of trityl chloride 27.9 (g) in DCM (80 ml). The reaction was stirred for 1 h at room temperature. The resulting slurry was cooled to approximately 0° C. then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography (silica, 1-4% MeOH/DCM as eluent) to give the sub-title compound (29 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C([Li])CCC.C=O.N1C=CC=CC=1.[C:24]([O:27][C:28](=O)C)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:27][CH2:28][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:26])[CH3:25]
Reactant: C#CCOc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A 0.5-L reactor (#1) was equipped with a thermometer, an addition funnel, an overhead stirrer, and a nitrogen inlet. 150 mL of THF was charged followed by 27.5 g (0.21 mole) of phenyl propargyl ether. The solution was cooled to −20° C. 100 mL (0.25 mole) of n-butyllithium in hexanes was charged into an addition funnel. This solution was added to the reactor at a temperature between −25 and −35° C. The temperature was controlled by the rate of addition and the mixture was stirred for 1 h at −25 to −35° C. A second 1-L reactor (#2) was equipped with a thermometer, an overhead stirrer and a cannulation device. 120 mL of THF was charged followed by 9.4 g (0.42 mol) of paraformaldehyde as a solid in one portion. The resulting suspension was stirred for 5 min. and cooled to 5–10° C. The contents of reactor #1 were cannulated into reactor #2 maintaining temperature in reactor #2 between 5 and 15° C. The temperature in reactor #1 was maintained below −15° C. The cooling bath from reactor #2 was removed and the reaction mixture was allowed to warm up slowly to 20–25° C. Stirring was continued for 16 h at ambient temperature. 200 mL of water was added to the reaction mixture and the mixture was stirred for 15–30 min at ambient temperature. The reaction mixture was extracted twice with 200 mL and then 100 mL of ethyl acetate. The combined organic solution was washed with 200 mL of water. The organic solution was dried with 50 g of anhydrous sodium sulfate. The drying agent was filtered off and rinsed with 50 mL of ethyl acetate. The filtrate was transferred into a 1-L reactor fitted with an overhead stirrer. Pyridine (67 mL, 0.83 mol) was charged followed by acetic anhydride (39 mL, 0.42 mol). The solution was stirred overnight at ambient temperature. The solution was washed sequentially with water (200 mL), sodium bicarbonate solution (2×150 mL) until pH=7–8, hydrochloric acid solution (2×150 mL) until pH=1–3, and brine (1×150 mL). The solution was dried with anhydrous sodium sulfate (50 g). The drying agent was filtered off, and the filtrate was concentrated in vacuo at a temperature that did not exceed 60° C. to yield 37 g (87% yield, HPLC strength 65%) of product as a dark-red slightly viscous fluid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[O:41][CH3:40])(=[O:50])=[O:49])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3OC)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added 2-methoxybenzenesulfonyl chloride (98 mg, 0.474 mmol). After stirring for ˜10 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then was stirred for 4 hours at room temperature under nitrogen. During this time, some solvent had evaporated. Additional methylene chloride was added. The reaction mixture was diluted with water (˜25 mL) and extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. Silica gel chromatography (20-33% ethyl acetate/hexanes) afforded {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (64 mg, 55%). MS cald. for C26H29FNO5S [(M+H)+]: 486, obsd. 486.2.
Reaction SMILES: CC(C)(CC=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14](C(C)C)[NH2:15])C=NO.C1(NN)C=CC=CC=1.[CH3:28][C:29]([CH3:45])([CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[CH:30]=[O:31].CC(C)(CC=CCCC=CCC(C(C)C)N)C=NNC(N)=O>>[CH3:28][C:29]([CH3:45])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH:42]([CH3:43])[CH3:44])[NH2:41])[CH:30]=[O:31].[CH2:14]([NH2:15])[C:13]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=O
Agent: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NNC(N)=O
Solvent: NNc1ccccc1
Product: CC(C)C(N)CCCCCCCCC(C)(C)C=O
Product: NCc1ccccc1
Yield: 76 %

Procedure:
When the above example is repeated using, in place of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime, 34.1 g (0.1 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal phenylhydrazine (prepared according to Example 24), 42 g (0.084 mol) of di-(2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal) hydrazone (prepared according to Example 25), 26.5 g (0.086 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal semicarbazone (prepared according to Example 26) or . . . 2,2-dimethyl-11-isopropyl-11-amino-undecanal-benzylamine (prepared according to Example 27), 1-isopropyl-10,10-dimethyl-1,11-diamino-undecaneis obtained in a yield of 76% of theory, 60.6% of theory, 62.6% of theory and 72% of theory respectively.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:31])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:31])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Reaction time: 1.5 h

Procedure:
5 ml of triethylamine are added to a solution of 12 g of 2-[(4R)-4-(benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 500 ml of methylene chloride and the mixture is allowed to stand at room temperature for 90 minutes. The reaction mixture is washed with 5% aqueous citric acid solution, dried over sodium sulphate and freed of solvent in vacuo. The residue is purified by chromatography over silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the title compound, which after recrystallisation from diethyl ether/pentane has a melting point of 63°-66°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:25][CH:24]1[CH2:22][CH2:23]1)=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(Br)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-benzoic acid (2.5518 g, 12.7 mmol) and HATU (5.2230 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.644 mL, 26.7 mmol) was added, and the mixture was allowed to stir at room temperature for 15 minutes. Then cyclopropylamine (0.88 mL, 12.7 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:24]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccccc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1-c1cccc(CN2CCN(c3ccccc3OC)CC2)c1

Procedure:
103 mg of the target compound (0.27 mmol, 56.4%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 2′-methoxybiphenyl-3-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.