Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:23][CH:24]=O.[CH:26]1([NH:32][C:33]2[C:38]3[N:39]=C(S(C)(=O)=O)[N:41]=[CH:42][C:37]=3[CH:36]=[CH:35][N:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][C:33]2[C:38]3[N:39]=[C:24]([NH:23][C:4]4[CH:5]=[CH:6][C:7]([C:9]5[CH:10]=[N:11][N:12]([CH2:14][CH2:15][N:16]6[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]6)[CH:13]=5)=[CH:8][C:3]=4[O:2][CH3:1])[N:41]=[CH:42][C:37]=3[CH:36]=[CH:35][N:34]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCCCC3)c2n1
Reactant: COc1cc(-c2cnn(CCN3CCN(C)CC3)c2)ccc1NC=O
Product: COc1cc(-c2cnn(CCN3CCN(C)CC3)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
Yield: 48 %

Procedure:
The title compound was prepared according to Example 40 above using N-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)formamide (Preparation 61) and N-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 44). The residue was purified by silica gel column chromatography eluting with 0 to 15% MeOH in DCM to give the title compound (51 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C
Reactant: CC(C)(C)N=C=O
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.5007 g of 6-(2,3-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 92 and 0.23 mL tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1); mp 326-330° C., MS(CI)
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:29][CH:26]2[CH2:27][CH2:28][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCNC(=O)c1ccc(OC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a mixture of 6-chloropyridazine-3-carboxylic acid pentylamide (0.530 g, 2.33 mmol) and 1-benzylpiperidin-4-ol (0.399 g, 2.33 mmol) in dioxane (20 mL) was added KOtBu (0.288 g, 2.56 mmol). The colourless reaction mixture turned to bright red upon the addition of KOtBu. The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography to afford the title compound in 28% yield (0.100 g). The solid material was triturated with ether give 22.7 mg of product as a colourless solid. M.p. 127-130° C. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=9.3 Hz, 1H), 7.91 (t, J=5.1 Hz, 1H), 7.31 (m, 5H), 7.02 (d, J=9.3 Hz, 1H), 5.34 (septet, J=4.5 Hz, 1H), 3.51 (s, 2H), 3.44 (q, J=6.9 Hz, 2H), 2.79-2.73 (m, 2H), 2.35-2.27 (m, 2H), 2.15-2.09 (m, 2H), 1.93-1.83 (m, 2H), 1.62-1.54 (m, 2H), 1.36-1.29 (m, 4H), 0.89-0.85 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 148.6, 138.4, 129.6, 129.1, 128.7, 128.3, 127.1, 118.6, 73.8, 62.9, 50.8, 39.5, 30.8, 29.2, 29.1, 22.4, 14.0. MS (ES+) m/z 363 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:23](O)[CH3:24]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20])=[CH:12][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCc1ccc(CCCc2ccccc2)s1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCCc1ccc(CCCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3 g of 5-[5-(3-phenylpropyl)-thien-2-yl]-valeric acid are dissolved in 10 ml of ethanol and the solution is saturated with HCl gas. The solution is stirred at room temperature for 24 hours and concentrated in vacuo. Purification by column chromatography (silica gel/hexane/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12]Br.[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[CH2:12][CH2:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: CSc1ccc(CCCBr)c(Br)c1
Reactant: Nc1ncccn1
Solvent: Cc1ccccc1C
Product: CSc1ccc(CCC[n+]2cccnc2N)c(Br)c1
Product: [Br-]
Yield: 98.4 %

Procedure:
To a solution of 154.0 g of 3-(2-bromo-4-methylthiophenyl)propyl bromide in 400 ml of dry xylene, is added a solution of 70.0 g of 2-aminopyrimidine in 300 ml of dry xylene and the mixture is heated under reflux for about 18 hours. The cooled xylene solution is decanted from the crystalline solid, the solid is triturated with 200 ml of 2-propanol and filtered to give 117.0 g of crude product. Recrystallization of the latter from 2-propanol gives about 98.0 g of 2-amino-1-[3-(2-bromo-4-methylthiophenyl)propyl]-pyrimidinium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: OC1CCc2cc(Cl)ccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a precooled (5–10° C.) solution of 5-chloro-indan-1-one (2.0 g, 12 mmoles) in 33 mL of anhydrous methanol was added sodium borohydride (0.43 g, 11 mmoles). The reaction mixture was stirred at 10° C. for 2 hrs and then at room temperature for 18 hrs. The reaction mixture was evaporated to afford a yellow residue. The residue was dissolved in 200 mL of diethyl ether and then washed with water (2×100 mL), with 0.10 N hydrochloric acid (2×100 mL), and then with brine (100 mL). The organic layer was separated, dried (sodium sulfate), filtered, and the filtrate was evaporated to provide the title compound in good purity. MS m/z 167 (M−1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(C=O)CCCCC1.[C:18]12([O:28][CH2:29][C:30]3[NH:34][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:41])=[N:32][C:31]=3[C:42](O)=[O:43])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.[CH3:45][O:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>>[CH2:4]([O:5][C:42]([C:31]1[N:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[NH:34][C:30]=1[CH2:29][O:28][C:18]12[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][CH:24]([CH2:26]3)[CH2:25]1)[CH2:27]2)=[O:43])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1.[CH3:45][O:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:54][C:42]([C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[NH:34][C:30]=2[CH2:29][O:28][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[O:43])[CH:49]=1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)[nH]c1COC12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)c1cccc(N)c1
Agent: O=CC1CCCCC1
Product: COC(=O)c1cccc(NC(=O)c2nc(-c3ccccc3Cl)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(OCc1ccccc1)c1nc(-c2ccccc2Cl)[nH]c1COC12CC3CC(CC(C3)C1)C2

Procedure:
5-(Adamantan-1-yloxymethyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 216, steps a, b, c and d with the modification that 2-chloro-benzaldehyde was used in step d instead of cyclohexanecarboxaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the resulting 5-(adamantan-1-yloxymethyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester according to the procedure of Example 20, step d to afford 3-{[5-(adamantan-1-yloxymethyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carbonyl]-amino}-benzoic acid methyl ester. The methyl ester was hydrolysed according to the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.82 (2H, br s), 9.96 (1H, s), 8.51 (1H, s), 7.94 (1H, d), 7.73 (1H, dd), 7.61 (2H, m), 7.45 (3H, m), 4.90 (2H, s), 2.11 (3H, s), 1.79 (6H, s), 1.59 (6H, s). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].O1CCCC1.CC(C)([O-])C.[K+]>O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-n2ccccc2=O)cc1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C/C=C/c1ccc(-n2ccccc2=O)cc1
Temperature: -50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
3.00 g of 4-(1,2-dihydro-2-oxo-1-pyridyl)benzaldehyde and 6.15 of β-carboxyethyltriphenyl phosphonium chloride were suspended into 30 ml of tetrahydrofuran, cooled to -50° C. and stirred. 20 ml of a tetrahydrofuran solution of 3.72 g of potassium-tert-butoxide was dropped and the temperature was gradually raised to 0° C. After 10 hours, iced water was added and the aqueous layer was washed with ether. The aqueous layer was adjusted to about pH 3 with concentrated hydrochloric acid, and deposited crystals were collected by filtration to obtain 2.96 g of the above-captioned compound as pale brown yellow powder (yield: 77%). Melting point (°C.): 218.5-221.5
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].Br[CH2:7][CH2:8]Cl.[Na].[SH:11][C:12]1[CH:13]=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([OH:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1>>[OH:24][C:15]1[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:12]([S:11][CH2:7][CH2:8][S:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:13][C:14]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CS
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Reactant: ClCCBr
Agent: [Na]
Product: O=C(O)CSCCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared according to the method of Example 13 from mercaptoacetic acid (2.3 g, 0.025 mole); 1-bromo-2-chloroethane (2.1 ml, 0.025 mole); sodium (1.8 g, 0.08 mole) and 5'-mercapto-[1,1':3',1"-terphenyl]-2'-ol (8.6 g, 0.03 mole), m.p. ca. 125° C.
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1>C(Cl)Cl>[C:10]([Si:7]([O:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1C=CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Pyridine (4.74 g, 60 mmol) and tert-butyldimethylsilyl chloride (4.83 g, 32 mmol) were added to a solution of cyclohex-2-enol (1.96 g, 20 mmol) in DCM (40 mL). The reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dispersed in EtOAc and water. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica flash chromatography eluting with EtOAc and petroleum ether (5-10% EtOAc) to give the title compound as an oil (4.1 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 0.06-0.09 (m, 6H), 0.92 (s, 9H), 1.50-1.57 (m, 2H), 1.74-1.89 (m, 2H), 1.93-2.03 (m, 2H), 4.21-4.23 (m, 1H), 5.61-5.64 (m, 1H), 5.72-5.76 (m, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]1[CH2:10]C=[CH:8][CH:7]=1.O>ClCCl.C(N(CC)CC)C>[CH:5]12[CH2:8][CH:7]([CH:6]=[CH:10]1)[CH2:4][CH:3]2[CH:2]=[O:1]
Reactant: C=C(C)C=O
Reactant: C1=CCC=C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1CC2C=CC1C2
Yield: 95 %

Procedure:
Diels-Alder reaction was conducted to a methacrolein wherein the scandium (III) pentafluorophenylbis(triflyl)methide obtained from Examples 13 and 14 was used as a Lewis acid catalyst (Chemical formula 39). Methacrolein (0.21 mL, 2.6 mmol) and cyclopentadiene (0.56 mL, 6.8 mmol) were reacted while stirring in 3 mL dichloromethane at −40° C. for 4 hours, under the presence of scandium (III) pentafluorophenylbis(triflyl)methide as 1 mol % of Lewis acid catalyst. Two to 3 drops of triethylamine was added to stop the reaction, 5 mL of water was added and the 5-norbornene-2-aldehyde produced was extracted with pentane. After concentration and drying, the crude product was analyzed with 1HNMR and it was found that the 5-norbornene-2-aldehyde showed a high yield of 95% (88% exo). The same reaction as mentioned above was conducted, except for the use of scandium (III) triflate [Sc(OTf)3] as a conventionally known Lewis acid catalyst, instead of the scandium (III) pentafluorophenylbis(triflyl)methide mentioned above. The 5-norbornene-2-aldehyde was hardly synthesized. Subsequently, 2 mol % of this scandium (III) triflate was used, and the yield of the 5-norbornene-2-aldehyde was 97% (89% exo). Based on these results, it was found out that the catalytic activity of the scandium (III) pentafluorophenylbis(triflyl)methide of the present invention is much more higher compared to that of the existing Lewis acid catalysts.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=1.[I:29]I>C1COCC1>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[C:17]([I:29])[CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To a solution of TMEDA (25.4 g, 219.3 mmol) in dry THF (300 mL) was added dropwise n-BuLi (87.7 mL, 219.3 mmol) at −78° C., the mixture was stirred for 0.5 h at this temperature. A solution of tert-butyl 6-chloropyridin-3-yl-carbamate (20 g, 87.7 mmol) in THF (170 mL) was added dropwise to the reaction mixture at −78° C. and the resulting mixture was continued to stir for 1 h at −78° C. Then a solution of I2 (26.7 g, 105.3 mmol) in dry THF (170 mL) was added dropwise at −78° C. After 1 h, the reaction was quenched with sat. aqueous NH4Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give tert-butyl 6-chloro-4-iodopyridin-3-ylcarbamate (10.0 g, 33%). 1H-NMR (CDCl3, 400 MHz) δ 8.95 (s, 1H), 7.73 (s, 1H), 6.64 (br s, 1H), 1.53 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH3:18][O:19][CH2:20][C:21](=N)OCC.C(=O)([O-])O.[Na+]>C(O)C>[CH3:18][O:19][CH2:20][C:21]1[NH:3][C:4]2=[CH:5][S:6][CH:7]=[C:8]2[N:9]=1
Reactant: CCOC(=N)COC
Reactant: Nc1cscc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 70 h
Yield: 58 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl 2-methoxyacetimidate monohydrochloride (Journal of Medicinal Chemistry, 1991, vol. 34, p 2468; 906 mg, 4.01 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-(methoxymethyl)-1H-thieno[3,4-d]imidazole (156 mg, 58%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31](Cl)(=O)C.C[Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[C:29]([CH3:31])[CH:30]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(=O)Cl
Agent: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344 mmol) was dissolved in THF (3.5 mL) cooled to 0° C. Acetyl chloride (0.0256 ml, 0.361 mmol) was added and the reaction was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412 mmol) was added. The reaction was stirred 1 hr. at 0° C. and then warmed to RT and quenched with saturated ammonium chloride and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium hydroxide, water, brine, and dried over sodium sulfate. The crude product was dissolved in isopropylacetate (4 mL) and heated to 50° C. before DDQ (0.117 g, 0.515 mmol) was added. After 30 minutes the reaction was cooled and diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, once with water, brine, and dried over sodium sulfate. The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and concentrated to afford the title compound, MS m/z: 451.3 (100%, M+1)).
Reaction SMILES: [O:1]([CH2:8][C:9]#[C:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[C:20]3[CH2:21][C:22]4[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[CH:26][C:27]=4[C:19]=3[NH:18][N:17]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.CN(C)C(=O)C>[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:28]([C:25]2[CH:24]=[N:23][C:22]3[CH2:21][C:20]4[C:16]([C:13]5[CH:12]=[C:11]([C:10]#[C:9][CH2:8][O:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[S:15][CH:14]=5)=[N:17][NH:18][C:19]=4[C:27]=3[CH:26]=2)=[O:29])[CH2:45][CH2:44]1
Reactant: O=C(O)c1cnc2c(c1)-c1[nH]nc(-c3csc(C#CCOc4ccccc4)c3)c1C2
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cnc3c(c2)-c2[nH]nc(-c4csc(C#CCOc5ccccc5)c4)c2C3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Example 1094D (68 mg, 0.16 mmol), N-cyclohexylcarbodiimide-N′-methyl polystyrene (1.0 g, 1.28 mmol) and 1-hydroxybenzotriazole hydrate (44 mg, 0.33 mmol) in (2:1) dichloromethane/N,N-dimethylacetamide (10 mL) was agitated for about 15 min. 1-Methylpiperazine (77 mg, 0.77 mmol) was added, the mixture was agitated at room temperature for about 18 h, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (100:8:0.1) as the mobile phase to provide the title compound. 1H NMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.39 (m, 4H), 3.40 (m, 2H), 3.63 (m, 2H), 3.97 (s, 2H), 5.09 (s, 2H), 7.03 (m, 3H), 7.38 (m, 2H), 7.80 (s, 1H), 8.01 (m, 2H), 8.41 (s, 1H), 13.41 (s, 1H).MS (ESI): m/z 496 (M+H)+.
Reaction SMILES: C([Mg]Br)=C.[Cl:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:12])(C)Cl.[CH2:13]1[CH2:17]OC[CH2:14]1>>[Cl:5][CH2:6][CH2:7][CH2:8][SiH2:9][CH:12]=[C:13]([CH3:17])[CH3:14]
Reactant: C1CCOC1
Reactant: C[Si](C)(Cl)CCCCl
Agent: C=C[Mg]Br
Product: CC(C)=C[SiH2]CCCCl
Reaction time: 2 h
Yield: 66.49 %

Procedure:
To a stirred solution of 1 M vinyl magnesium bromide in THF (9.1 L), 3-chloropropyl dimethylchlorosilane (1.5 Kg) was added over the period of 3 hr through an addition. The reaction mixture stirred further for 2 hr. Added D.M water (9.1 L) and separated the organic layer. The hazy aqueous layer was filtered through hyflo bed and extracted with dichloromethane (3.0 L). The dichloromethane extract was mixed with organic layer and evaporated to dryness to give yellow liquid which was distilled using a Vigreaux column to get pure colorless title product (0.986 Kg)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1>CN(C=O)C>[Si:11]([O:6][C@@H:3]([CH2:4][CH3:5])[CH2:2][NH2:1])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: CC[C@H](O)CN
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CN)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product from step (ii) (310 mg) in DMF (10 mL), tert-butylchlorodimethylsilane (734 mg) was added followed by imidazole (474 mg) and stirred at rt for 24 h. The mixture was washed with water and extracted with EtOAc, dried and the solvent removed to give the subtitle compound as a yellow oil, 610 mg.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])[CH:18]=[CH:17][CH:16]=1>CCO>[OH:14][C@@H:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: CCOC(=O)COc1cccc2cccnc12
Reactant: NC[C@@H](O)CN1Cc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@@H](O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 51 %

Procedure:
(R)-1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol) and ethyl 2-(quinolin-8-yloxy)acetate (120 mg, 0.52 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (100 mg, yield 51%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.95-8.85 (m, 1H), 8.44-8.34 (m, 1H), 7.69-7.54 (m, 3H), 7.33-7.27 (m, 1H), 7.18 (s, 4H), 4.79 (s, 2H), 4.09-4.03 (m, 1H), 3.99 (s, 4H), 3.61-3.53 (m, 1H), 3.47-3.38 (m, 1H), 2.91-2.85 (m, 1H), 2.84-2.77 (m, 1H).