Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[C:6]([O:12][CH3:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:14].CCN(CC)CC.[C:22](Cl)(=O)[CH2:23][CH3:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C@@H:3]([OH:14])[C@H:2]([NH:1][CH2:22][CH2:23][CH3:24])[CH2:11]2
Reactant: COc1cccc2c1C[C@@H](O)[C@H](N)C2
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN[C@@H]1Cc2cccc(OC)c2C[C@H]1O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Compound 13A (1.50 g) was suspended in THF (15 mL) and Et3N (1.80 mL) and propionyl chloride (0.60 mL) were added. The solution was stirred for 20 minutes. LAH (1M in THF, 10 mL) was added drop-wise under stirring at rt and the reaction mixture were heated to 90° C. for 1200 sec. in a sealed microwave process vial. The reaction was quenched with wet Na2SO4. The mixture was diluted with THF (50 mL), filtered over dry Na2SO4 and concentrated in vacuo. Yield: 1.21 g of compound 14A as an oil. LC/MS (method 350): RT 0.40 min, ELSD 100%, UV 100%. MH+: 235.9. 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 3H), 1.43-1.52 (m, 2H), 2.37-2.51 (m, 3H), 2.61-2.68 (m, 1H), 2.74-2.80 (m, 1H), 3.14 (dd, J=4.93, J=16.0, 1H), 3.22-3.29 (dd, J=16.9, J=5.9, 1H), 3.56-3.63 (m, 1H), 3.73 (s, 1H), 6.60 (d, J=8.05, 1H), 6.62 (d, J=7.89, 1H), 7.03 (t, J=7.86, 1H). 13C NMR (500 MHz, CDCl3) δ: 157.7 136.4, 127.0, 123.8, 121.2, 107.7, 71.0, 59.8, 55.7, 49.5, 35.7, 32.1, 24.1, 12.2.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].C([O-])=[O:7].[NH4+].[CH:10]([OH:12])=[O:11]>C(O)(=O)C>[C:1](=[O:3])([O-:7])[O-:4].[NH4+:5].[NH4+:5].[C:10]([OH:12])(=[O:11])[CH2:1][CH3:2]
Reactant: O=C[O-]
Reactant: O=CO
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCC(=O)O
Product: O=C([O-])[O-]

Procedure:
A compound of the formula (XX) reported by Harry H. Wasserman, Tetrahedron Letter, Vol. 33, No. 40, pp. 6003-6006, 1992 and the like is reacted with a compound of the formula (XXI) in the presence of an ammonium salt such as ammonium lower alkanecarboxylate (e.g., ammonium acetate, ammonium formate and the like) and an ammonium salt of inorganic acid (e.g., ammonium carbonate and the like), in an acidic solution of lower alkanecarboxylic acid such as formic acid, acetic acid, propionic acid and the like to give a compound of the formula (XIX) (Step 12).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C[S-:13].[Na+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]>CN(C)C(=O)C.C(O)C>[CH3:19][O:18][CH:17]([O:20][CH3:21])[CH2:16][S:13][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Brc1ccc2ncccc2c1
Reactant: COC(CBr)OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: COC(CSc1ccc2ncccc2c1)OC
Temperature: 150 °C

Procedure:
To a solution of 6-bromoquinoline (0.832 g, 4.0 mmol) in N,N-dimethylacetamide (4.0 mL) was added sodium methyl mercaptide (0.841 g, 12.0 mmol). The reaction mixture was heated at 150° C. for 2 h. After cooling, 2-bromo-1,1-dimethoxyethane (1.41 mL, 12.0 mol) was then added, and the reaction mixture was diluted with ethanol (5 mL), and heated at 80° C. for 1 h. After the precipitated salt was isolated by filtration, the mother liquor was evaporated under reduced pressure. The residue was diluted with diethyl ether (50 mL), washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was directly used in the next reaction step without further purification. LCMS: (M+H)=249.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].CS(C)=O.[CH2:26]1[O:34][CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[C:28]1([CH:27]([OH:34])[CH2:26][O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: c1ccc(C2CO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: OC(COCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer was separated and mixed with 10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxy]ethanol (compound No. 144).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#N.ClCCl.C[OH:26]>C1(C)C=CC=CC=1>[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:26]
Reactant: N#Cc1cccc(I)c1
Reactant: Cc1ccccc1N
Reactant: CO
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL 3-neck round bottom flask was added o-toluidine (3.60 g, 33.6 mmol) and 150 mL toluene. The solution was cooled in an ice bath under nitrogen. Trimethylaluminum (2.0 M in toluene, 23.51 ml, 47.0 mmol) was added dropwise via dropping funnel. The reaction mixture was stirred at room temperature for 2 hours. Next, 3-iodobenzonitrile (10 g, 43.7 mmol) in 50 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid. The solid was triturated with hexane, filtered, washed with hexane (7.77 g, 69%).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:3][C:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]=2)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: OC1(c2cnccn2)CN2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: ClC1(c2cnccn2)CN2CCC1C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Thionyl chloride (1.5 g, 12.6 mmol) was added to a rapidly stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[ 2.2.1]heptan-3-ol (0.5 g, 2.6 mmol) in dichloromethane (30 ml) at room temperature. The solution was stirred for 1 h, heated at 60° C. for 0.5 h, and then cooled to room temperature, before adding water (20 ml) and basifying with potassium carbonate. Extraction into dichloromethane (3×75 mls), drying (Na2SO4) and chromatography of the residue remaining after removal of solvent through alumina, using ethyl acetate as eluant, gave 3-chloro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane as a pale yellow oil (0.18 g); m/e 209 (M+ of free base); δ (360 MHz,CDCl3) 0.84-0.92(1H,m,CH of CH2); 1.58-1.67(1H,m,CH of CH2); 2.42-2.48(1H,m,CH of CH2 --N); 2.69-2.72(1H,m,CH of CH2 --N); 2.78-2.86(1H,m,CH of CH2 --N); 3.22-3.24(1H,d, J=4.5 Hz, CH-bridgehead); 3.42-3.49(2H,m,2×CH of CH2 --N); 4.13(1H,dd J=3 and 14 Hz, CH of CH2); 8.48(2H,s,pyrazine-H); 8.91(1H,s,pyrazine-H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([C:1](=[O:3])[CH3:2])[CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc(Cl)c2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis(trifluoromethyl)benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-9-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0° C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=2)=[O:8])=[CH:5][C:4]=1[O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:34][CH2:33]1.[C:46]1([CH:52](Cl)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:46]1([CH:52]([NH:2][C:3]2[CH:27]=[CH:26][C:6]([C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=3)=[O:8])=[CH:5][C:4]=2[O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH2:34][CH2:33]2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NC(c3ccccc3)c3ccccc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Ethyl 4-{3-{4-amino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride (2.0 g) was dissolved in N,N-dimethylformamide (10 ml), and diphenylmethyl chloride (1.2 ml) and potassium carbonate (1.3 g) were added to the solution. The mixture was stirred at 90° C. for five hours. The reaction mixture was cooled and diluted with ethyl acetate (200 ml). The resultant mixture was sequentially washed with water and saturated brine, and dried and evaporated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 1.13 g of ethyl 4-{3-{4-diphenylmethylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C@H:10]([CH:21]=O)[CH2:9]1)C1C=CC=CC=1.[O:23]([C:28]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])[C:24]([CH3:27])([CH3:26])[CH3:25].[C:50]1([CH3:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:56]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C@H:10](/[CH:21]=[CH:30]/[C:28]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:29])[CH2:9]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc([C@@H]2CN(Cc3ccccc3)C[C@H]2C=O)c1
Product: COc1cccc([C@@H]2CN(Cc3ccccc3)C[C@H]2/C=C/C(=O)OC(C)(C)C)c1

Procedure:
A mixture of Example 261C (1.86 g, 6.3 mmol) and t-butoxylcarbonylmethylenetriphenylphosphorane (2.37 g, 6.3 mmol) in toluene (15 mL) was heated at 110° C. for 1 hour. The volatiles were removed and the crude material was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (3:1) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (m, 4H), 7.25 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.85 (m, 2H), 6.76 (d, J=15.3 Hz, 1H), 5.69-5.61 (m, 1H), 3.73 (s, 3H), 3.70 (d, J=15.0 Hz, 1H), 3.59 (d, J=15.0 Hz, 1H), 3.13 (m, 1H), 2.98 (m, 3H), 2.62 (m, 1H), 2.53 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:16][N:15]=[C:14]([Cl:21])[C:13]1[CH:17]=[CH:18][C:10]([O:9][C:8]2[CH:19]=[CH:20][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CC(C)Oc1ccc(Oc2ccc(C=NO)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ccc(C(Cl)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of Example 17C (1.48 g, 5.56 mmol) in N,N-dimethyl formamide (15 mL) was added N-chlorosuccinimide (0.70 g, 5.24 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water. The aqueous layer was extracted with ether washed with water, then brine, and dried over MgSO4 and concentrated to give the title compound as an oil (1.67 g, 100%),
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C([N:13](CC)CC)C.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[NH:13][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1NC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
L-Proline methyl ester hydrochloride (7.2 g, 43.8 mmol) was dissolved in 100 mL of anhydrous DHF at 0° C. To this solution was added triethylamine (4.2 g, 43.8 mmol). After vigorous stirring for 1 hour, the solid triethylamine hydrochloride was removed by filtration. To the filtrate was added 4-benzyloxybenzoic acid (10.0 g, 43.8 mmol) followed by DCC (9.9 g, 48.2 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solid DCU was then removed by filtration, and the filtrate distributed between H2O/ethyl acetate (300 mL ea.). The organic was washed several times with 200 mL portions of H2O to remove DMF. The organic was dried (Na2SO4), and concentrated in vacuo to a solid residue that was chromatographed (SiO2, 15-100% ethyl acetate/hexanes). Isolation provided 5.3 g (35%) of N-(4-benzyloxybenzamido)-L-proline methyl ester as a white solid. MS.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:9]([O:11]N1C(=O)CCC1=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:9]([NH:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(N[C@H](C(=O)ON1C(=O)CCC1=O)c1ccccc1)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Z-Phg-OSu (640 mg) in DMF (10 ml), 463 mg (1.84 mmol) of Tyr(3-tBu)-OMe and 408 mg (3.34 mmol) of DMAP were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give Z-Phg-Tyr(3-tBu)-OMe in the amount of 905 mg (quantitative).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-])=O)=[C:11](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)=O.CC(=O)OCC.O>[Cl:26][C:22]1[CH:21]=[C:20]([C:19]2[NH:15][C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:9](=[O:28])[N:10]([CH3:27])[C:11]=3[CH:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(Cl)c2)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(Cl)c3)cc2n(C)c1=O
Temperature: 110 °C
Yield: 92.8 %

Procedure:
To a solution of (E)-3-(4-(3-chlorostyryl)-3-methyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (70 mg, 0.172 mmol) in HCOOH (3 mL) was added Na2S2O4 (180.0 mg, 1.032 mmol). The reaction was heated at 110° C. for 5 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propylacetate (60 mg, 93.0% yield) as an oil. LCMS: MH+ 375 and TR=1.467 min. Used without further purification.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CC(C)=O>>[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(=O)CCl
Reactant: CC(C)=CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C

Procedure:
Chloroacetone (0.89 ml, 1.04 g, 11.2 mmol) is added to a mixture of 4-(3-methyl-2-butenoxy)phenol (2.0 g, 11.2 mmol), potassium carbonate (25 g) and potassium iodide (2.6 g) in 125 mol of anhydrous acetone. The mixture is heated under reflux for 4.5 hours and then is allowed to cool to RT to give 4-(3-methyl-2-butenoxy)phenoxyacetone.
Reaction SMILES: [SH:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:3]=1[C:4](=O)[CH:5]=[CH:6][CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1.C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>ClCCl>[CH3:19][O:18][C:14]1[C:3]2[C:4]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[S:1][C:2]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(S)c1C(=O)C=CC1C=CC=CC1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sc2cccc(OC)c2c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-mercapto-6′-methoxydihydrochalcone (1.2 g) and triethylamine (0.92 mL) in dichloromethane (10 mL) was added methyl bromoacetate (0.46 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (15 mL). To the solution was added sodium methoxide (28% methanol solution, 1.7 mL), and the mixture was stirred at room temperature overnight. The crystals precipitated from the reaction mixture were collected by filtration and dried under reduced pressure to give the title compound (1.09 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1(/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:23]1([CH:28]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)/C=C/C1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 96 h
Yield: 63.2 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in hexanes) afforded the product (2.73 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][O:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and N,N-dimethyl-1,3-propanediamine.