Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23]([O-:28])(=O)[C:24]([O-])=O.[Sn+2]>O>[C:23]([O:3][CH2:2][CH2:1][O:4][C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:28])[CH2:24][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: O=C([O-])C(=O)[O-]
Reactant: OCCO
Agent: [Sn+2]
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
90 g ethylene glycol (Fluka), 571 g palmitic acid (Edenol C16 98-100, Cognis-Oleochemicals) and 0.3 g tin (II) oxalate Goldschmidt) were heated under nitrogen. The esterization reaction starts at approx. 170° C. with the formation of water. After 3 hrs the reaction water is drawn off again by applying a vacuum and the vacuum within 4 hrs reduced to approx. 15 mbar. The final temperature was 230° C. at an acid value <6 the reaction was ended. It was cooled to 90° C. and filtered. Yield 568 g, acid value=3.9, dew point 70.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.[Cl:25]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:25][C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:18])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:5]=2[CH:14]=1
Reactant: ClCl
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccn2)c2cc(Cl)ccc2O1

Procedure:
1 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 20 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 10 ml of a 0.42M solution of chlorine in carbon tetrachloride were added. After 30 minutes the mixture was washed with sodium bicarbonate solution, the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 1% (v/v) methanol/dichloromethane and then 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 200 mg of 6-chloro-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 124°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH2:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(P(=O)(OCC)[O:33][CH2:34]C)#N.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([N:29]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:34]=[O:33])[CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(N(C=O)Cc2cccc3ccccc23)c1

Procedure:
A solution of 3-[(tert-butoxy)carbonylamino]benzoic acid (250 mg, 1.05 mmol), 1-naphthylmethylamine (170 mg, 1.05 mmol), diethyl cyanophosphonate (260 mg, 1.6 mmol), and triethylamine (0.22 ml, 1.6 mmol) in acetonitrile was stirred overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N HCl. The layers were separated, and the organic phase was washed twice more with 1N HCl, then 3 times each with water and brine. The solvent was removed in vacuo, and the crude product was purified on a silica gel column, eluting with 20% ethyl acetate in hexane, to deliver 270 mg of the amide.
Reaction SMILES: [C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:5](=[O:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[CH3:37][I:38]>>[I-:38].[C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=1[CH3:37])[C:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:13]=1)=[O:29])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)N(Cc2ccccn2)C(C)=O)cc1
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1
Product: [I-]
Temperature: 100 °C
Yield: 93.7 %

Procedure:
A mixture of 1.37 g of product from Example 96 and 19.55 g of methyl iodide is heated in a sealed tube at 100° C. for 5 hours. The reaction is concentrated in vacuo and the residue recrystallized from methyl alcohol to give 1.65 g of the desired product.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19]N=2)CCCCC1.O([CH3:27])[Na]>C1COCC1>[C:20]1([CH:21]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:19]=[CH:27][CH:17]=[CH:24][CH:23]=1
Reactant: CO[Na]
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 43.5 %

Procedure:
1.72 g (12.6 mmol) of 2-hydroxyacetophenone, 2.0 g of 6-(piperidin-1-yl)nicotinaldehyde (10.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.41 g (43.5%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 13.10 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.93-7.89 (m, 2H), 7.80 (d, d, J=2.4, 9.0 Hz), 7.51-7.42 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.71-3.67 (m, 4H), 1.75-1.67 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[CH:20][N:21]([CH3:23])[CH3:22]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To 13.2 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in 100 mL of DMF was added 23.8 g of N,N-dimethyformamide dimethyl acetal. The mixture was stirred at 75° C. for 16 hours. The solution was then concentrated and used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.Cl.[N:13](OCCCC)=[O:14]>C(O)C>[N:13](=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1)[OH:14]
Reactant: Cc1cnnc2ccccc12
Reactant: CCCCON=O
Agent: Cl
Solvent: CCO
Product: ON=Cc1cnnc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g of 27A in 3 ml of absolute ethanol was added drop-by-drop over 3 minutes to 3.4 ml of stirred absolute ethanol containing 0.9 g of anhydrous hydrogen chloride, at 0° C. The resulting mixture was stirred for 30 minutes, then a solution of 1.03 g of butyl nitrite in 2 ml of absolute ethanol was added drop-by-drop over 3 minutes at 0° C. The mixture was stirred for 30 minutes at 0° C., for 4 hours at room temperature, then stored in a refrigerator overnight. A precipitated solid was collected, washed with a small amount of water, mixed with a saturated potassium bicarbonate solution, and filtered. Recrystallization from water gave 4-(hydroximinomethyl)cinnoline (27B), as a solid, m.p.: 223° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([S:48]([CH3:51])(=[O:50])=[O:49])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([S:48]([CH3:51])(=[O:49])=[O:50])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN)S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CCN)c1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl 3-{N-[(1R)-2-(4-(2-[(2-aminoethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step f) (294.8 mg, 0.4 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white solid (224 mg). MS (ESI, pos. ion) m/z: 638 (M+1); (ESI, neg. ion) m/z: 636 (M−1). Calc'd for C33H40ClN5O4S: 637.25. Anal. Calcd for C33H40ClN5O4S.2.5C2H3O2: C, 49.43; H, 4.64; N, 7.41. Found: C, 49.39; H, 4.78; N, 7.58.
Reaction SMILES: [C:1]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21].Cl>C(Cl)(Cl)Cl>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:22][CH2:18][CH2:19][CH2:20][S:21]2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reactant: SCCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7 g of 1,3-propanedithiol are treated with hydrogen chloride up to saturation while stirring. After 3 hours at room temperature, the solution is evaporated to 50 ml and diluted with ether. The resulting solution is extracted three times with 5% sodium carbonate. The basic phases are combined and made acidic with concentrated hydrochloric acid. The precipitated product is extracted with ether/methylene chloride (1:3). The organic extracts are dried and evaporated. The residue is recrystallized from ethanol, there being obtained 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid of melting point 134°-135° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CCCOc1ccc(CN2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
The title compound was prepared from 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 1-methylpiperazine, following the procedure of Example 84, and was obtained as a colourless solid (36%), m.p. 149-150° C. Found: C,65.68; H,7.33; N,19.10. C24H34N6O2 requires C,65.73; H,7.81; N,19.16%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(N(C(C)C)CC)(C)C.Cl.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C(#N)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COCCCCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 90 h
Yield: 66.6 %

Procedure:
To a solution of 1,3-difluoro-2-nitrobenzene (3.00 g) and diisopropylethylamine (7 μl) in acetonitrile (30 ml) was added a solution of 4-methoxybutan-1-amine hydrochloride (2.51 g) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 90 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:98-25:75) was concentrated under reduced pressure to give the object product (2.90 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a mixture of 4-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 4-(4-nitrophenyl)pyridine as a solid (342 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3C(OC(C)(C)C)=O)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc2c(N)ncnn12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: Nc1ncnn2c(C3CCCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12

Procedure:
Following the procedure described in Steps 3-5 (bromination, coupling, deprotection) of Example 1, the title compound was prepared using tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and Intermediate C. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1 H), 7.85 (s, 1 H), 7.81 (d, 1 H), 7.64 (s, 1 H), 7.27-7.41 (m, 5 H), 7.22 (dd, 1 H), 6.73 (s, 1 H), 5.65 (s, 2 H), 4.27 (dd, 1 H), 3.08-3.18 (m, 1 H), 2.79-2.90 (m, 1 H), 1.51-2.14 (m, 6 H); ES-MS m/z 424.42 [M+H]+, HPLC RT (min) 2.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2[S:24][C:23]([CH:25]=O)=[CH:22][C:20]=2[N:21]=1.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:15][C:16]1[N:17]=[C:18]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:19]2[S:24][C:23]([CH2:25][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:14])[CH2:13][CH2:12]3)=[CH:22][C:20]=2[N:21]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(4-chlorophenyl)-4-hydroxypiperidine (368 mg, 1.74 mmol) in dichloroethane was added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (400 mg, 1.41 mmol) and trimethylorthoformate. After stirring for 1 hour at room temperature, sodium triacetoxyborohydride was added and the reaction mixture stirred overnight. The mixture was quenched with saturated aqueous Na2CO3. Chloroform/brine extraction gave crude material which was then triturated with hot ethyl acetate to give 1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol. (272 mg, 0.56 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([Cl:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:26][C:24]1[CH:25]=[C:2]([Cl:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:22]([Cl:29])[CH:23]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2,6-dichloro-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (454 mg, 0.99 mmol) in a mixture of ethanol (10 mL) and EtOAc (20 mL) was added catalyst 10% Pd/C (100 mg). The mixture was hydrogenated under 45 psi at RT for 2 h. The mixture was filtered through Celite and concentrated to give the title compound of Step C (405 mg) as a solid. The title product of Step C was used in the next step without further purification. MS (APCl−) Calc.: 427.0, Found: 426.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][N:11]1[C@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:35]
Reactant: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Yield: 108.8 %

Procedure:
Deprotection of (R)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (410 mg, 0.86 mmol, 1 equiv) was accomplished in 3 hours in the presence of 4M hydrogen chloride solution in dioxane at ambient temperature. The resulting mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a white solid (355 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.83 (d, 2H, J=14.0 Hz), 2.66-2.74 (m, 2H); 3.44-3.51 (m, 4H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.4 Hz); 4.84 (d, 1H, J=4.8 Hz); 5.93 (s, 1H); 6.85 (t, 1H, J=7.2 and 7.6 Hz); 6.95 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.39-7.45 (m, 4H); 7.53 (s, 1H); 8.97-9.04 (m, 2H); MS for C22H25N3O3 m/z 380.03 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18](Cl)=[C:13]3[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]=O>[N:29]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=4)[N:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=23)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(Cl)c12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3ccnc3)c12
Yield: 81.4 %

Procedure:
A solution of compound (36a) (0.196 g), potassium carbonate (0.145 g), copper(II) oxide (nanopowder) (0.021 g), and imidazole (0.042 g) in DMF (2.0 mL) was stirred at 120° C. for 20 hr. The reaction solution was diluted with chloroform, and insoluble matters were filtered through celite. The solvent was distilled away, and ethyl acetate and ether were added to the residue. The precipitate was collected by filtration to obtain compound (36b) (0.173 g, 81%) as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][SH:11])=[CH:5][CH:4]=1.Cl[C:13]1[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]2[C:13]([S:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:20])=[CH:23][CH:24]=1
Reactant: SCCc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of 60% sodium hydride (35 mg, 0.88 mmol) in N,N-dimethylformamide (1 mL), a solution of 4-pyridineethanethiol (104 mg, 0.75 mmol) in N,N-dimethylformamide (1.5 mL) and a solution of 2-chloro-N-(4-chlorophenyl)pyridine-3-carboxamide (200 mg, 0.75 mmol, Reference compound No. 2-1) in N,N-dimethylformamide (1.5 mL) were added under ice-cooling successively. The reaction mixture was stirred at room temperature for 2 hours, and then ethyl acetate (40 mL) was added thereto. The ethyl acetate layer was washed with water (40 mL) and brine (40 mL) and dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The precipitated solid was filtered off and washed with diethyl ether :ethyl acetate (3:1). The solid was dried under reduced pressure to give 240 mg of the target compound as a white solid. (Yield 88%)
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@@H:11]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[C:1]1([CH3:38])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][C@H:13]3[CH2:12][C@@H:11]2[CH2:26][N:46]3[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of 2697 g (4.653 moles) of (2R, 4S)-1-(4-toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)pyrrolidine and 1640 g (15.304 moles) of benzylamine in 15 L of toluene was heated under reflux. Ater 6 hours 100 g of benzylamine were added and the reflux continued for 3 hours. The mixture was cooled, filtered and the residue was washed with 5 L of toluene. The combined organic layers were evaporated to dryness and the resulting solid was taken up with 2 L of isopropanol. After cooling the product was filtered, washed with cold isopropanol and dried under reduced pressure to give 1434 g of the titled compound. (90%). M.P.=124° C.