Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.C(N(CC)CC)C>CC#N>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Fc1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1cccnc1Cl)N1CCc2cc(F)ccc21
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
2-Chloronicotinoyl chloride (200 mg, 1.14 mmol) was dissolved in CH3CN (5.6 mL). 5-Fluoroindoline (171 mg, 1.25 mmol) was added followed by triethylamine (0.24 mL, 1.71 mmol) and the reaction mixture was stirred at 23° C. for 16 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 (10 mL) and sat. aq. NaHCO3 solution (10 mL). The organic phase was removed and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography (40 g SiO2, 2% CH3OH—CH2Cl2) afforded the desired product as an off-white solid (247.8 mg, 79%). 1H NMR (DMSO-d6) δ 3.14 (t, 2H, J=8.39 Hz), 3.82 (t, 2H, J=8.39 Hz), 7.09 (dt, 1H, J=9.03, 2.80 Hz,), 7.20 (dd, 1H, J=8.39, 2.80 Hz), 7.60 (dd, 1H, J=7.38, 4.83 Hz), 8.10 (dd, 1H, J=7.63, 2.03 Hz), 8.15 (dd, 1H, J=8.90, 4.83 Hz), 8.55 (dd, 1H, J=4.83, 1.78 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][S:24][CH3:25])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.I([O-])(=O)(=O)=[O:27].[Na+]>CO.O>[CH3:25][S:24]([CH2:23][O:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)=[O:27]
Reactant: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OCSC)CC3)cc2)C(=O)O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OCS(C)=O)CC3)cc2)C(=O)O1
Reaction time: 19 h

Procedure:
10.7 g (29.28 mmol) of (R)-5-methoxymethyl-3-[4-(trans-4-methylsulfanylmethoxy-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 500 ml of methanol, cooled to 0° and treated dropwise while stirring during 90 minutes with a solution of 4.7 g (22.0 mmol) of sodium periodate in 150 ml of water. The reaction mixture was stirred in a cold storage chamber at 4°-5° for 19 hours. Thereafter, it was diluted with 1 l of water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and filtered. The filtrate was filtered through a 400 g silica gel 60 pad and washed in succession and separately with ethyl acetate (800 ml), methanol (1 l) and tetrahydrofuran (800 ml). 3.16 g of educt remained behind after evaporation of the ethyl acetate eluate. After evaporation the methanol and tetrahydrofuran eluates gave 8.11 g of (R)-3-[4-(trans-4-methanesulfinylmethoxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one (S-oxide R:S=1:1 diastereomer mixture) as a yellow oil, b.p. 205°/0.02 mbar, [α]D =-32.2° (c=1.0%, DMSO).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:12])=[C:6]([Cl:5])[CH:11]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
53.2 gm. (400 mmol) of aluminum chloride was carefully added in portions to a mixture of 26.2 gm (200 mmol) of 1-chloro-2-fluorobenzene and 31.2 gm of acetyl chloride at 50° C. After all the Lewis acid had been added, the reaction temperature was raised to 100° C. and maintained at that temperature for 3 hours. The hot reaction mixture was carefully poured onto ice and the resulting light-red oil twice extracted with ether. The combined ether extraacts were washed with saturated sodium chloride solution, dried and evaporated in vacuo to yield a crude brown oil. The oil was distilled to yield 26.47 gm of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](OC)=[S:9].C[O-:14].[Na+]>C1(C)C=CC=CC=1>[O:14]=[C:5]1[CH2:6][CH2:7][CH2:8][S:9][CH:4]1[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CCCCC(=S)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1SCCCC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A 250-mL round bottomed flask was charged with methyl 4-(2-methoxy-2-oxo-ethyl)thiobutanoate (26 g, 126 mmol, 1 eq.), sodium methoxide (30 g, 25 w % in methanol, 139 mmol, 1.1 eq.) and toluene (100 ml). The resulting mixture was stirred at 80° C. overnight and then methanol was removed by distillation until the temperature of the reaction mixture rose to 106° C. After cooling to room temperature, the mixture was poured into a mixture of ice (100 g) and 12N HCl (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 ml) and the combined organic layers were dried over Na2SO4. Removal of solvent under reduced pressure gave the title compound as an oil (19.3 g, 88% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[Cl:16][C:14]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 4-bromo-N,N-dimethylbenzenesulfonamide and THF as solvent. Yield (0.068 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.0 mg, 0.309 mmol), β-dimethylaminoethyl chloride hydrochloride (49.0 mg, 0.340 mmol) and cesium carbonate (0.302 g, 0.928 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then filtered and concentrated under reduced pressure to give the desired product (60 mg, 88%). LCMS calculated for C13H25BN3O2 (M+H)+: m/z=266.2. Found: 266.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (2.00 g, 11.5 mmol) in DMF (20 mL) was added NBS (2.15 g, 12.1 mmol) and the reaction mixture was stirred at 25° C. for 4 hours. The resulting mixture was diluted with EtOAc (300 mL), washed with H2O (100 mL×5) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE/EtOAc=20/1) to give the product (2.10 g, yield 72%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH3:14][O:15][C:16]1[C:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1c(/C=C/c2nc3ccccn3c(=O)c2Br)cccc1OC

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.501 g, 6.271 mmol) and 3-methoxy-2-(hexyloxy)benzaldehyde (1.642 g, 6.942 mmol) in the presence of sodium ethoxide (0.642 g, 9.401 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 986 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.84-0.90 (m, 3H), 1.30-1.38 (m, 4H), 1.52-1.58 (m, 2H), 1.88 (t, J=6.9 Hz, 2H) 3.87 (s, 3H), 4.01 (t, J=6.9 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 7.04-7.10 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.59-7.70 (m, 3H), 8.38 (d, J=15.6 Hz, 1H), 8.94 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:2].[CH:24](OCC)(OCC)OCC.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.O>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH:24]=[N:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc2ocnc2c1)NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of crude 3-(3-amino-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid ethyl ester (0.89 g, 2.74 mmol) in toluene (20 mL) was added triethyl orthoformate (0.57 mL, 3.36 mmol) and the mixture was heated to 75° C. under an atmosphere of argon for 3 hours at which time all starting material had been consumed. The reaction mixture was concentrated in vacuo to a black waxy solid which was dissolved in acetonitrile (25 mL) and di-tert-butyldicarbonate (0.80 g, 3.67 mmol) added. The mixture was stired at ambient temperature under an atmosphere of argon for 16 hours then poured into water (100 mL), diluted with brine (50 mL) and extracted with ethyl acetae (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to a black viscous oil. Purification by chromatography over silica gel eluted with 35% ethyl acetate/65% hexanes gave (S)-3-benzooxazol-5-yl-2-tert-butoxycarbonylamino-propionic acid ethyl ester as a colorless solid (0.54 g, 59%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2]([CH:22]=[CH2:23])[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 60.4 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (1.03 g, 3.0 mmol), tributyl-(vinyl)-stannane (0.98 g, 3 mmol) and tetrakis-(triphenylphosphine)-palladium (0.07 g, 0.06 mmol) in toluene (30 ml) was heated under reflux conditions for 3 h, evaporated and purified by chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (526 mg, 60%). MS (ISP): m/e=291.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.C(O)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[CH:27][S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:14][CH2:15]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3ncsc3NC(=O)OC(C)(C)C)cnn2C)CC1
Yield: 75 %

Procedure:
A solution of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.15 g, 0.244 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a clear gum (98 mg, 96%). This gum (97 mg, 0.182 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to give 283 as an off-white solid (39 mg, 84%). 1H NMR (400 MHz, d4-MeOD) δ 7.97 (s, 1H), 7.44 (s, 1H), 3.71 (s, 3H), 3.21-3.07 (m, 4H), 2.65 (d, J=6.6 Hz, 2H), 1.83 (d, J=12.5 Hz, 2H), 1.60-1.47 (m, 1H), 1.43-1.30 (m, 2H). LCMS (ES+) m/z 336 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]3[NH:24][CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]3[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(C=O)cnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Yield: 41.7 %

Procedure:
rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (118 mg, 0.338 mmol) in N,N-dimethylformamide (3 mL) was cooled to 0° C. and stirred with sodium hydride (55 wt % dispersion in mineral oil, 126 mg, 0.586 mmol) for 30 minutes and then with [2-(chloromethoxy)ethyl]trimethylsilane (104 μL. 0.586 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a brown oil (67.5 mg, yield 42%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 3-[4-[4-(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (100 mg) in chloroform (1.5 ml) was added trifluoroacetic acid (0.45 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (70 mg).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[N:23]=[C:22](OC)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1>CS(C)=O>[CH3:12][O:13][C:14]1[N:23]=[C:22]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc2nc(OC)nc(OC)c2c1
Solvent: CS(C)=O
Product: COc1ccc2nc(OC)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 1 h
Yield: 17.8 %

Procedure:
3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfoxide (15 ml). The obtained mixture was stirred under heating at 150° to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compound as a pale-yellow crystal. molecular formula; C18H17 N3O4
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide (example A149) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CS([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:28]([C:44]([F:47])([F:46])[F:45])=[CH:27][N:26]=1)(=O)=O.C(O)(C(F)(F)F)=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(O)C(F)(F)F>[CH3:43][O:42][C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][C:29]1[C:28]([C:44]([F:47])([F:45])[F:46])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (I88) (50 mg, 0.18 mmol) and methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I67) (72 mg, 0.18 mmol) were heated in trifluoroethanol (1.2 mL) and TFA (0.12 mL) under microwave irradiation (100° C./20 minutes). The mixture was concentrated, evaporated from toluene and loaded onto a 5 g SCX cartridge in methanol (1 mL). The cartridge was washed with methanol (50 mL), and then eluted with 1% methylamine/methanol (50 mL). The basic eluent was concentrated, and taken up in dichloromethane (5 mL). Boc anhydride (0.062 mL, 0.27 mmol) was added, and the mixture stirred at room temperature for 18 hours. The mixture was evaporated onto silica gel, and chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I89) (46 mg, 42% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) 8.55 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.47 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.29-7.18 (m, overlaps with CHCl3), 4.41 (d, J=8.4 Hz, 1H), 4.08 (m, 3H), 3.76 (s, 2H), 3.73-3.64 (m, 4H), 3.16-2.98 (m, 5H), 2.85 (s, 1H), 1.51-1.47 (m, 9H). LCMS Method C: rt 6.88 min; m/z 601.1 [M+H]+, 545.1 [M−tBu+2H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:19][S:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: OC(CS)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
3-Mercapto-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (230 mg) (prepared as in the previous Example), potassium carbonate (138 mg, 2.7 equivalents), and methyl iodide (200 mg, 1.9 equivalents) were stirred together in acetone (15 ml) at room temperature for two hours. The acetone was then evaporated under reduced pressure, and the residue triturated with water to give the crude title compound as a solid, 220 mg. This was crystallized from isopropanol to yield the pure title compound, yield 190 mg, m.p. 117°-119° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1)=[O:21]
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccco1
Product: O=C(c1ccco1)N1CCC2(CC1)Cc1ccccc1O2

Procedure:
A sample of 5.8 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, is treated with 4.8 g of 2-furoyl chloride according to the procedure of Example 18 to provide an off-white solid. This solid is purified by three recrystallizations from hexane to provide the product, 2,3-dihydro-1'-(2-furoyl)spiro[benzofuran-2,4'-piperidine], mo 102°-103° C.