Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:29]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCOCC(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCOCC(O)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
1.23 g of N,N'-dicyclohexylcarbodiimide was added, with ice cooling, to a solution of 1.08 g of 2-(2-aminoethoxy)-1-phenylethanol, 730 mg of nicotinic acid, 810 mg of 1-hydroxybenzotriazole and 0.83 ml of triethylamine dissolved in 5 ml of tetrahydrofuran. The resulting mixture was stirred at the same temperature for 5 minutes and further at room temperature for 1 hour. To the reaction mixture was added 11 ml of ethyl acetate. The insolubles were removed by filtration. To the filtrate was added 5 ml of water and the mixture wa adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 5 ml of water. The extract was combined with the previously separated aqueous layer. The combined aqueous layer was mixed with 20 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=15/1) to obtain 400 mg of oily 2-(2-nicotinoylaminoethoxy)-1-phenylethanol (compound No. 216).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH3:23]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH2:21][CH2:22][CH3:23])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: CCCBr
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccncc1)c1csc2cc(Cl)ccc12
Product: Cl
Temperature: 0 °C
Yield: 128.1 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (4.2 g, 16.1 mmol) was added portionwise as a powder to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, 20 mmol, washed with heptane) in 25 mL of dimethylformamide. After the anion formation was completed, 1-bromopropane (2 g, 16.3 mmol) was added. After one hour the reaction mixture was poured into ice-water and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to a brown oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography yielded 3.5 g of an amber oil. Conversion to the hydrochloride salt in 10% methanol in ether afforded 3.7 g of a pale yellow powder, mp 276-277° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:12][C:11]2[C@@H:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[C@H:9]([OH:20])[C:8]([CH3:22])([CH3:21])[O:7][C:6]=2[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C@@H:9]1[C:8]([CH3:22])([CH3:21])[O:7][C:6]2[CH:5]=[C:4]([Br:3])[S:12][C:11]=2[C@H:10]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.47 g, 11.7 mmol) was added to a solution of trans-2-bromo-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno-[3,2-b]pyran (4.0 g, 11.1 mmol) in DMF (50 mL) at 0° C. and stirred at rt for 30 min. Benzylbromide (1.45 mL, 12.2 mmol) was added to the resultant solution and stirred at rt for 2 h. The solution was poured into water (200 mL) and extracted into dichloromethane. The organic phase was washed several times with water and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 2% methanol in dichloromethane as the eluant. The product was recrystallized from dichloromethane/hexane to give a colorless solid, 3.87 g (77%); mp 146°-147° C.; IR(KBr): 1634 and 1570 cm-1 ; MS: m/z 450 (MH+); 1H NMR(CDCl 3): 1.32 (s, 3H), 1.50 (s, 3H), 1.53-1.77 (m, 4H), 2.37-2.45 (m, 2H), 2.87 (m, 1H), 3.08 (m, 1H), 3.69 (d, J=8.6 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.73 (d, J=11.8 Hz, 1H), 5.90 (bs, 1H), 6.54 (s, 1H) and 7.26-7.37 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([OH:14])=[O:13].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([O:14][CH3:19])=[O:13]
Reactant: O=C(O)c1cccc2cc(Cl)ncc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(Cl)ncc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 20 mL microwave vial was charged with 3-chloroisoquinoline-8-carboxylic acid (1 g, 4.82 mmol) in 5 mL of MeOH and then was added with thionyl chloride (0.703 mL, 9.63 mmol). Stirred at 65° C. overnight and then concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded Methyl 3-chloroisoquinoline-8-carboxylate (27-1).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH2:7]([C@:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.C(N([CH:35]([CH3:37])[CH3:36])CC)(C)C>ClCCl.C(OCC)(=O)C>[C:35]([O:22][C:21](=[O:23])[CH2:20][C@@:14]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15]1)([CH3:37])([CH3:1])[CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H]1CC[C@@](CC(=O)O)(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@](CC(=O)OC(C)(C)C)(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Oxalyl chloride (4.14 mL, 47 mmol) was added dropwise to a stirring solution of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (10 g, 43 mmol) in dichloromethane under argon at room temperature. The reaction mixture was cooled to 5° C., dimethylformamide (1 mL) was carefully added, and the mixture was allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed in vacuo and the residue diluted with dichloromethane (60 mL). 1,1-Dimethylethanol (15 mL) was carefully added to the reaction mixture under argon followed by diisopropylethylamine (11.5 mL, 65 mmol). The mixture was stirred for 17 hours and then taken up in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate (2×200 mL), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 9:1 heptane:ethyl acetate) to give 10.92 g (88%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid tert-butyl ester;
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:20][CH2:21][CH3:22])[C:9]([O:18][CH3:19])([O:16][CH3:17])[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]([CH2:20][CH2:21][CH3:22])[C:9]([O:18][CH3:19])([O:16][CH3:17])[C:10]([NH:12][CH:13]1[CH2:14][CH2:15]1)=[O:11]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(OC)(OC)C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(N)C(OC)(OC)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl(1-(cyclopropylamino)-2,2-dimethoxy-1-oxohexan-3-yl)carbamate (prepared from product of Example 19 by saponification and amidation using the conditions described in example 22 and 23) (25 mg, 0.075 mmol) in DCM (1 mL) was added a catalytic amount of TFA and the mixture was stirred for 1 h. The acid was neutralized with solid NaHCO3 and precipitates were filtered off. The solvent was removed under reduced pressure to give 20 mg of the amine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O.NN.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C1(C)C=CC=CC=1>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[NH2:3][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2 H), 1.50 (s, 9 H), 1.50-1.64 (m, 6 H), 3.22 (m, 1 H), 3.83 (br s, 1 H), 6.02 (s, 2 H), 6.86 (d, J=7.5 Hz, 1 H), 7.68 (br s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2.C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])[NH:7]2
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2[nH]c(C(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2.65 g of 4-methoxyindole-2-carboxylic acid are dissolved in 15 ml of DMF, 2.11 g of DBU are added and the mixture is then stirred at RT for 1 hour. 2.61 g of benzyl bromide are added dropwise at RT and this mixture is stirred for 5 hours at RT. The mixture is concentrated under vacuum and the residue is taken up in EtOAc, washed with water, with saturated Na2CO3 solution, with sulphate buffer and then with saturated aqueous NaCl. This solution is dried over Na2SO4 and concentrated. 3.57 g of the expected compound are obtained, which product crystallizes from pentane: m.p.=162-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)=[O:24].N1C=C(C2C(C3C=CC=CC=3)=NOC=2C(F)(F)F)N=C1.FC1C=CC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:28]4[CH:29]=[CH:30][C:25]([C:23](=[O:24])[CH3:22])=[CH:26][CH:27]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: Fc1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 50 %

Procedure:
As described for Example 4, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol) and 4-fluoroacetophenone, instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole and 4-fluorobenzotrifluoride, was converted to the title compound (70 mg, 50%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][CH2:11][C:12]3=[O:17])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1>>[O:17]=[C:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]4[N:26]=[C:27]5[C:22]([CH2:21][CH2:20][C:19](=[O:18])[NH:28]5)=[CH:23][CH:24]=4)[CH2:5][CH2:6]3)=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: O=C1CCCc2c1cccc2N1CCNCC1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4CCCC5=O)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 169–170° C. MS: APCI: M+1: 449.2 (Exact Mass: 448.25).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.19 g (6.83 mmol) of 2-(3,5-dimethylphenyl)- 3-[2-[4-(pyridin-4-yl)butylamino] ethyl]-1H-indole-5-carboxylic acid ethyl ester in 25 mL of dry methylene chloride was stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath as 2.38 mL (1.76 g, 13.7 mmol) of N,N-diisopropylethylamine was added, followed by gradual addition of 3.4 mL (4.06 g; 23.7 mmol) of benzyl chloroformate by syringe, in portions. After about 2.5 hours, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% potassium bisulfate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) afforded a quantitative yield of the product as a yellow foam. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e=604.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][NH:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.[F:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][N:15]([C:31]4[N:32]=[CH:33][C:28]([F:27])=[CH:29][N:30]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1
Reactant: Nc1ccc(F)c(C23CNCC2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(F)c(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Yield: 66.6 %

Procedure:
A solution of N-[7a-(5-amino-2-fluoro-phenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (705 mg, 1.90 mmol), 5-fluoro-2-chloropyrimidine (1.01 g, 7.61 mmol), and diisopropylethylamine (1.66 mL, 9.52 mmol) are heated in 1,4-dioxane (20 mL) to reflux for 4 hours under nitrogen. The reaction is cooled, diluted with water, and extracted with ethyl acetate (3×). The organic layers are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo to give crude product. The crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (590 mg, 66%). ES/MS (m/e): 467 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(OCC)(=O)C>CN(C=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1[nH]cnc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1[nH]cnc1CO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
4-(Hydroxymethyl)-5-methyl-1H-imidazole (4 g, 26.9 mmol) was dissolved in DMF (80 mL). Triethylamine (13.5 mL, 96.9 mmol) and tert-butyl(dimethyl)silyl chloride (4.68 g, 31.0 mmol) were added, followed by stirring for three hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, dichloromethane/methanol=92/8) to obtain 4.67 g of the title compound (77%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)[CH3:53]>>[NH3:3].[CH3:51][N:52]([CH3:53])[CH:54]1[CH2:59][CH2:58][N:57]([C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:4]4[N:3]([CH3:2])[C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH:13]=3)[CH2:19]2)=[O:25])[CH2:56][CH2:55]1
Reactant: Cn1c(-c2cccc(N3CCC[C@@H](C(=O)O)C3)c2)nc2ccccc21
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)C1CCN(C(=O)[C@@H]2CCCN(c3cccc(-c4nc5ccccc5n4C)c3)C2)CC1
Product: N
Temperature: 35 °C
Yield: 74.8 %

Procedure:
Method N—Step a To a mixture of (R)-1-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 1, step d) (0.01 g, 0.30 mmol) (obtained as described in method A, step d) in dcm (2.5 mL), HATU (0.12 g, 0.33 mmol), TEA (0.09 mL, 0.63 mmol) and 4-(N,N-dimethylamino)piperidine (0.04 g, 0.35 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature, washed with ammonium chloride solution (3 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column (eluent: first dcm:MeOH/1:1 then NH3 in MeOH (2N)) and flash chromatography (eluent: gradient from EtOAc:NH3 in MeOH (2N)/10:0 to 9:1) to obtain 0.05 g of the title compound (37%).
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]1[C:13]2[C:8]3=[C:9]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[CH2:6][CH2:5]1)[C:10]([CH3:14])=[CH:11][CH:12]=2.[H-].[Na+]>O1CCCC1>[CH3:14][C:10]1[C:9]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[C:8]=2[C:13]([CH:4]([O:3][CH3:1])[CH2:5][CH2:6]3)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3OC
Temperature: 25 °C
Yield: 58.8 %

Procedure:
Methyl iodide (0.55 g, 3.86 mmol) was added dropwise to a mixture of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (0.50 g, 1.93 mmol), 60% sodium hydride (0.08 g, 1.93 mmol) and tetrahydrofuran (20 ml) with stirring at room temperature, and the resulting mixture was stirred at room temperature for another 2 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/95) to obtain 0.31 g of ethyl 5,6-dihydro-9-methyl-6-methoxy-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH:25]=O)[CH:2]=[CH2:3].C(OC(=O)[NH:34][C@H:35]([C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH2:36][SH:37])(C)(C)C.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:23])([CH3:24])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:37][CH2:36][C@H:35]([NH2:34])[C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Reactant: Cc1noc([C@H](CS)NC(=O)OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 13.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid allyl ester in 38 ml of trifluoroacetic acid, cooled to 0° C., were added within 15 min a solution of 13.7 g of (R)-2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethylcarbamic acid tert-butyl ester and 6.2 g of triethylsilane in 38 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water; saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue Was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 14.1 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester as a pale yellow oil.