Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8](Cl)[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[Mg].[S:19](Cl)(Cl)=[O:20]>C1COCC1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([S:19]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:7]=2)=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(Cl)cc1OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(S(=O)c2ccc(OC(C)(C)C)c(OC(C)(C)C)c2)cc1OC(C)(C)C
Yield: 64 %

Procedure:
A Grignard reagent was conventionally prepared using 3,4-di-tert-butoxyphenyl chloride, magnesium, and THF and further reacted with thionyl chloride, obtaining bis(3,4-di-tert-butoxyphenyl) sulfoxide in a yield of 64%. Then 58.9 g (0.12 mol) of bis(3,4-di-tert-butoxyphenyl) sulfoxide was dissolved in 120 g of THF and cooled in an ice water bath. Then 12.1 g (0.12 mol) of triethylamine was added thereto and 68.3 g (0.31 mol) of trimethylsilyl triflate was added dropwise in a controlled manner at less 10° C. To this solution, a Grignard reagent which was conventionally prepared using 61.6 g (0.24 mol) of 1,2-di-tert-butoxy-4-chlorobenzene, 5.8 g (0.24 mol) of magnesium, and 100 g of THF was added dropwise in a controlled manner at less 10° C. With the reaction temperature controlled at 0° to 10° C., reaction ripening was carried out for 30 minutes. A 20% ammonium chloride aqueous solution, 700 g, was added to the reaction solution to terminate reaction, followed by separation. 300 g of chloroform was added to the organic layer. The organic layer was washed twice using 300 g of water and then evaporated, obtaining an oily residue. The oily residue was worked up by column chromatography (silica gel, eluent: chloroform/methanol), obtaining tris(3,4-di-tert-butoxyphenyl)sulfonium trifluoromethanesulfonate of 99% purity in a yield of 20%. The final percent yield of this two-steps synthesis process was 13%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[CH3:18][O:10][C:9](=[O:11])[C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:12]
Reactant: O=C([O-])O
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1

Procedure:
A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid (19.98 g) in methanol (250 ml) containing concentrated sulphuric acid (1 ml) was heated under reflux for 6.5 h. The solution was cooled, neutralised with aqueous sodium bicarbonate solution, and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried, and evaporated to give the title compound (21.13 g) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])=[CH:7][N:6]2[C:19]=1[CH3:20])[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:19]([CH3:20])=[C:3]([CH2:1][CH3:2])[N:4]=4)[CH:7]=3)[C:12](=[O:18])[CH:13]=2)[CH:23]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 26.9 %

Procedure:
To a solution of 1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (165 mg) and tributylphosphine (340 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (424 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (60 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:17])[NH2:16])=[CH:9][CH:8]=1.[OH:23][CH:24]=[C:25]([CH2:30][CH3:31])[C:26](OC)=O.C([O-])(=O)C.[K+]>C1COCC1>[CH2:30]([C:25]1[C:24](=[O:23])[N:17]=[C:15]([CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=3)=[CH:12][CH:11]=2)[NH:16][CH:26]=1)[CH3:31]
Reactant: N=C(N)CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CCC(=CO)C(=O)OC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c[nH]c(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)nc1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a solution of 3-(4-(3-(trifluoromethyl)phenoxy)phenyl)propanimidamide (200 mg, 0.580 mmol) in THF (4 mL) were added methyl 2-(hydroxymethylene)butanoate (151 mg, 0.580 mmol) and potassium acetate (171 mg, 1.740 mmol). The mixture was stirred with a microwave condition at 100° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature; the solvent was removed in vacuo. The residue was purified MDAP to afford the title compound (36.7 mg, 16.29% yield) as a white solid. LCMS: rt=1.67 min, [M+H+]=389.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccnc(Cl)n2)C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A flask was charged with a solution of 2,4-dichloropyrimidine (300 mg, 2.0 mmol) in N,N′-dimethylformamide (10 mL). tert-Butyl 3-hydroxyazetidine-1-carboxylate (349 mg, 2.0 mmol) and cesium carbonate (1.11 g, 3.42 mmol) were added and the resulting mixture was heated to 80° C. for 2 h. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-80% ethyl acetate in hexanes) afforded tert-butyl 3-[(2-chloropyrimidin-4-yl)oxy]azetidine-1-carboxylate (550 mg, 1.9 mmol, 96%). MS EST: [M+H]+ m/z 286.1.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Na+].C1COCC1>CO>[CH3:23][C:17]1[C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(C)nc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(COc2ccc3c(CC(=O)O)coc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzofuran-3-yl)acetate (430 mg), 1N NaOH (5 mL), THF (5 mL) and MeOH (5 mL) was stirred at room temperature for 1 h. The mixture was washed with Et2O. Water and 1N HCl (5 mL) were added to the water layer to be pH=4. The precipitate was collected by filtration and washed with water and Et2O respectively to give crystals. The crystals were recrystallized from acetone-hexane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(O[CH:25](N(C)C)[N:26]([CH3:28])[CH3:27])(C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]([C:15](=[CH:25][N:26]([CH3:28])[CH3:27])[C:16]([O:18][CH3:19])=[O:17])[CH3:14])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)cs1
Product: COC(=O)C(=CN(C)C)N(C)c1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
17 g (0.04982 mol) of methyl N-[4-(4-bromophenyl)-2-thiazolyl]-N-methylamino-acetate and 17.4 g (0.1078 mol) of t-butoxy-bis-(dimethylamino)-methane are stirred for 6 hours at 100° C., the mixture is cooled, treated with ice-water and stirred for a few hours at room temperature, and precipitated crystals are filtered off with suction and dried. 17.5 g (89% of theory) of methyl 2-{N-[4-(4-bromophenyl)-2-thiazolyl]-N-methylamino}-3-dimethylaminoacrylate of melting point 184°-185° C. are obtained.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:12][CH:11]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.Cl>CO.O1CCOCC1>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:10][CH:11]([NH:13][C@H:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)[CH2:12]2)=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC2CN(C(=O)c3ccc(-c4ccccc4)cc3)C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CC(N[C@H]2CCNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 3e (2.5 g, 5.92 mmol) in MeOH (7 mL) was added an HCl solution in dioxane (4M, 12 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (30 mL) was added to the residue. The off-white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 3f was used in the next reaction without further purification. MS m/z (M+H+) 322.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[C:18]1([CH2:21][O:20][CH2:19]1)[C:5]12[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:6]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:28])([CH3:27])[C:18]2([CH2:21][O:20][CH2:19]2)[C:5]23[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[N:6]2)=[O:37])=[N:34][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A mixture of tert-butyl (6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (878 mg, 2.25 mmol), 5-chloro-2-pyridinecarboxylic acid (476 mg, 2.93 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (562 mg, 2.93 mmol), 1-hydroxybenzotriazole (396 mg, 2.93 mmol), N,N-diisopropylethylamine (0.502 mL, 2.93 mmol) and CH2Cl2 (8.78 mL) was stirred for 1.5 hours at ambient temperature. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl (6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (976 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[C:25]([CH3:24])=[N:26][O:27][C:28]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: CC(=O)N(C)C
Product: Cc1noc(C)c1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 72.5 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (160 mg, 0.52 mmol), N,N-dimethylacetamide (3.2 mL) and 3,5-dimethylisoxazole-4-carbonyl chloride (99 mg, 0.62 mmol) and in the same manner as in Example 120, the title compound (163 mg, 73%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Mg]Br)[CH2:21][CH:22]=[CH2:23]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH2:23][CH2:22][CH:21]=[CH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (8.88 g, 33.0 mmol) in THF (40 mL, 0.8 M) was cooled to 0° C. and treated with a 0.5 M solution of 3-butenylmagnesium bromide (51 mmol, 102 mL) in a dropwise manner. After stirring for 4 h the reaction was quenched with 1 N HCl (24 mL), neutralized with 5% aqueous sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica (2-20% methanol in dichloromethane) to afford the desired product (4.95 g, 57%). Rf 0.22 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.21 (m, 5H), 5.82-5.76 (m, 1H), 5.15-4.95 (m, 2H), 3.50 (s, 2H), 2.91 (d, J=11.2 Hz, 2H), 2.54 (t, J=7.3 Hz, 2H), 2.39-2.23 (m, 3H), 2.06-1.97 (m, 2H), 1.82-1.61 (m, 4H). ESI MS found for C17H23NO m/z [258.2 (M+1)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]3[CH2:24][O:23]C4(CCCCC4)[O:21]3)[N:16]=2)=[N:12][CH:13]=1.[ClH:39].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]([OH:21])[CH2:24][OH:23])[N:16]=2)=[N:12][CH:13]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 75 °C
Yield: 68.8 %

Procedure:
A flask was charged with (S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.38 g, 2.40 mmol), ethanol (50 mL), and 3M HCl (1.67 ml, 5.00 mmol) and heated to 75° C. for 1 hour. The reaction was cooled to ambient temperature, and saturated aqueous sodium bicarbonate was added slowly. The mixture was extracted with ethyl acetate and dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (50 to 100% ethyl acetate in hexanes followed 5% methanol in ethyl acetate). The product was dissolved in 10% methanol in dichloromethane and 5 mL 2M HCl in ether was added. The solution was concentrated and dried in a vacuum oven to afford (S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.958 g, 1.65 mmol, 65.9% yield) as yellow solid. Mass Spectrum (apci) m/z=472.1 (M+H−HCl).
Reaction SMILES: [C:1]([C@@:18]1(C(O)=O)[CH2:22][C@@H:21]([NH2:23])[CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2]>C(#N)C.N1CCCC1>[NH2:23][CH:21]1[CH2:20][N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:18]([C:1]([OH:3])=[O:2])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@]1(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC(N)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2 dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) δ 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79 (m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). LC-MS (retention time: 1.707 min.), MS m/z 358 (MH+). Step 2:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: OCCCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 81 %

Procedure:
Compound 11-1 (9.53 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (13.3 g) and N-bromosuccinimide (8.97 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (200 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (10.1 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=4)[CH2:21][C:16]3=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>CS(C)=O.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35](=[O:36])[O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N:20]2[CH2:21][C:16]3[C:17](=[CH:18][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]4)=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[C:19]2=[O:29])[CH:23]=1
Reactant: O=C1c2cc(CN3CCC(F)(F)CC3)c3cccnc3c2CN1c1cccc(O)c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1cccc(N2Cc3c(cc(CN4CCC(F)(F)CC4)c4cccnc34)C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-[(4,4-difluoropiperidin-1-yl)methyl]-8-(3-hydroxyphenyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (0.070 g, 0.17 mmol) in 3 mL of dimethylsulfoxide was added sodium hydride (0.034 g, 0.86 mmol). After 5 min, dimethyl carbamyl chloride (0.047 mL, 0.51 mmol) was added. The mixture was stirred at ambient temperature for 15 hr, diluted with ethyl acetate, washed 3× with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 481.2066 for [M+H]+ [Calc'd for C26H27F2N4O3, [M+H]+=481.2046].
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:27])[O:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]([O:4][C:3]([N:2]([CH3:1])[CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[O:27])[CH2:14][CH2:15]1)=[O:9])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A solution of tert-butyl methyl(piperidin-4-yl)carbamate (1.25 g, 5.83 mmol), 3,5-dichlorobenzyl carbonochloridate (1.537 g, 6.42 mmol) and sat. sodium bicarbonate (0.583 ml, 5.83 mmol) in DCM (15 ml) was stirred at RT for 72 hrs. The resulting mixture was extracted with DCM and the combined organic extracts were dried over MgSO4, filtered and concentrated under pressure to afford the title compound which was used without further purification.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorophenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[Br:12][CH2:13][CH2:14][CH2:15]Br>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: BrCCCn1ccc2ccccc21
Reaction time: 72 h
Yield: 30.9 %

Procedure:
To a solution of 23.4 g of indole in 200 ml of DMF, cooled to 10° C., were added 22.4 g of potassium hydroxide and 101 g of 1,3-dibromopropane. The mixture was stirred under nitrogen for 3 days. The solid formed was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel with 5% diethyl ether in petroleum ether to give 14.7 g of 1-(3-bromopropyl)indole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1[OH:10])=[O:4].[CH2:15](I)[CH3:16]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:12])[F:13])=[CH:8][C:9]=1[O:10][CH2:15][CH3:16])=[O:4]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)sc1C(=O)OC

Procedure:
The 3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (mp.: 93.6° C.) was prepared from the known adduct 3-hydroxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (Synthesis 2000, No. 8, 1078-1080) by alkylation with ethyl iodide in the presence of cesium carbonate in DMF as solvent.