Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]1[C:9](=[O:10])[O:8][CH:7]([CH:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[OH-:34].[Li+]>O1CCCC1>[F:1][C:2]([CH3:32])([CH3:33])[CH2:3][CH2:4][CH:5]([CH2:6][CH:7]([OH:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([OH:8])=[O:10]
Reactant: [OH-]
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (4 g, 8.90 mmol) in tetrahydrofuran was added lithium hydroxide (1 M in water, 28 mL) and stirred for 2 hours. The reaction was then concentrated, and concentrated from benzene (2×) to give the title compound (4.2 g, 100%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=3)[C:14]([O:16]C(C)(C)C)=[O:15])[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.BrC1C=C(C=CC=1)C(OC(C)(C)C)=O.C[Si](C#C)(C)C.C([O-])([O-])=O.[K+].[K+].BrC1C(N)=NC=C(Br)N=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=3)[C:14]([OH:16])=[O:15])[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2cc3nc(Br)cnc3n2COCC[Si](C)(C)C)c1
Agent: C#C[Si](C)(C)C
Agent: CC(C)(C)OC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(-c2cccc(C(=O)O)c2)cc2nc(Br)cnc21
Temperature: 60 °C
Yield: 90 %

Procedure:
tert-Butyl 3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoate (2.5 g, 4.96 mmol, prepared using A from tert-butyl 3-bromobenzoate [Frontier Scientific] with trimethylsilylacetylene, Q with K2CO3, A with 3,5-dibromopyrazin-2-amine, B and C) and K2CO3 (0.685 g, 4.96 mmol) in MeOH (20 mL) were added to a flask. The mixture was heated to about 60° C. for about 17 h. An aqueous 40% NaOH solution (2 mL) was added and the mixture was heated to about 60° C. for about 17 h. The mixture was cooled to rt and acidified with about 3 mL of 5 N aqueous HCl and then extracted with EtOAc (100 mL). The solids were removed by filtration then the filtrate was dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (2.01 g, 90%): LC/MS (Table 2, Method b) Rt=2.80 min; MS m/z 448 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.N.[Na].[CH3:16][Si](C=[N+]=[N-])(C)C.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.C(O)(C)(C)C.O1CCCC1>[CH3:16][O:13][C:11](=[O:12])[CH2:10][CH2:9][C:5]1[CH2:4][CH:3]([OH:2])[CH2:8][CH2:7][CH:6]=1
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CCC1=CCCC(O)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 35.6 %

Procedure:
Under an atmosphere of argon, 2.18 g (12.09 mmol) of 3-(3-methoxyphenyl)propionic acid was put into a three-neck flask, and tetrahydrofuran (20 mL) and tert-butylalcohol (20 mL) were added thereto. After cooling to −78° C., about 150 mL of liquid ammonia was added thereto, and then sodium was added piece by piece. After the reaction was completed, ethanol was added to stop the reaction, and ammonia was removed at room temperature. After sodium dihydrogen phosphate was added thereto to make the reaction mixture acidic, it was extracted with chloroform, dried over magnesium sulfate and filtered, followed by evaporation of the solvent under a reduced pressure. An aqueous solution of acetic acid (acetic acid:distilled water=4:1) was added to the residue and stirred for 45 minutes, and then the solvent was removed under a reduced pressure. To the obtained residue was added 50 mL of ethanol, followed by 8 mL (16 mmol) of 2M trimethylsilyldiazomethane at 0° C. After stirring for 1 hour, the reaction mixture was concentrated under a reduced pressure and then 50 mL of ethanol was added to the obtained residue. Then, 450 mg (11.9 mmol) of sodium borohydride was added thereto at 0° C., and after the reaction was completed, saturated aqueous ammonium chloride solution was added. The resulting mixture was concentrated under a reduced pressure and extracted with ethyl acetate after the saturated aqueous sodium bicarbonate solution was added. The solvent was removed under a reduced pressure, and then the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=7:3 to 1:1) to obtain 793 mg (4.3 mmol) of 3-(5-hydroxycyclohexa-1-enyl)propionic acid methyl ester. Its physical property is shown below.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:19]([NH2:21])=[O:20])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][CH2:16][NH2:17])[C:7]=2[N:18]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:22]([NH:17][CH2:16][CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:5]=[C:4]([C:19]([NH2:21])=[O:20])[C:3]([NH2:2])=[N:18][C:7]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (16, 50.0 mg, 0.186 mmol) in pyridine (2 mL) was added DMAP (23.0 mg, 0.188 mmol) and acetic anhydride (23 μL, 0.243 mmol). The reaction was stirred at RT under an atmosphere of argon. After 1 h, the reaction was concentrated and the crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 9-[2-(acetylamino)ethyl]-2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (22, 11 mg, 19%). NH4OAc standard conditions. DAD Retention time =5.18 min. M+H=312. 1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.01 (t, J=5.7 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.58 (br s, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H), 1.71 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[NH:25][CH3:24])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. Methylamine (2M in THF, 25.0 mL, 50.0 mmol) was added, and the mixture was stirred overnight. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (2.01 g, 45%). LC-MS: tR=0.95 min; ES+: 325.30.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:27])=[CH:4][C:5]2[O:26][CH2:25][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH:18]4[CH2:23][CH2:22]OCC4)[C:9]3=[O:24])[C:6]=2[CH:7]=1.[CH3:28][C:29]1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2O[N:30]=1.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[C:3]([CH3:27])=[CH:4][C:5]2[O:26][CH2:25][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[CH:23]=[CH:22][CH:28]=[CH:29][N:30]=4)[C:9]3=[O:24])[C:6]=2[CH:7]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp 165-168° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.67 (d, J=6.0 Hz, 1H), 8.12-8.06 (m, 1H), 7.59-7.55 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.20 (m, 1H), 7.03-6.98 (m, 2H), 6.76 (s, 1H), 6.55 (s, 1H), 5.18 (s, 2H), 4.74 (ABq, 2H), 2.13 (s, 3H), 2.01 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.5, 159.1, 154.0, 146.7, 142.6, 141.5, 138.3, 132.6, 129.1, 126.7, 124.5, 124.4, 124.1, 123.7, 123.5, 111.3, 109.7, 79.5, 57.8, 43.7, 20.2, 19.2; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1COCCN1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2c3c(cccc3c1N1CCOCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-5-methoxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted with morpholine (3 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.25 g of 2-benzyloxy-5-methoxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione (0.25 g, 0.6 mmol) was performed as described in Example 18, to give 0.17 g of the title compound, mp 329-241° C. (dec.);
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:5]1=[S:18])[CH:2]=[CH2:3].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[C:11]1([C:10]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]2[NH:6][C:5](=[S:18])[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]2=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCN1C(=O)C(C(=O)c2ccccc2)NC1=S
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(=C(OCc2ccccc2)c2ccccc2)NC1=S
Temperature: 25 °C
Yield: 123.7 %

Procedure:
To a solution of 3-allyl-5-benzoyl-2-thiohydantoin (0.098 g, 0.0003 mol) and benzyl chloride (0.042 g, 0.00033 mol) in tetrahydrofuran (2 mL) was added a solution of 1M potassium tert-butoxide in tetrahydrofuran (0.33 mL, 0.00033 mol) under argon. A cherry solid was formed in the reaction mixture. The resulting mixture was heated at reflux for 1 hr and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (40 mL), washed with 3M HCl (2×20 mL) and brine (1×20 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give 0.13 g of a brown oil which solidified on standing. This solid was triturated with hexane (5 mL) once and then was dried under high vacuum. NMR (CDCl3) δ (10.9 s br, 1H), 8.6-8.9 (m, 2H), 7.3-7.9 (m, 8H), 4.7 (S, 2H), 4.4 (d, 2H).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH:16]=1)[CH3:14])[CH3:9].IC>CC(O)(C)C.C1COCC1>[CH3:9][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C:24](=[O:34])[CH2:25][CH2:26]2)=[CH:21][CH2:20]3)[CH2:17][CH:16]=1)[CH3:14])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
To a stirred suspension of KOtBu (900 mg, 8.2 mmol) in tBuOH (25 mL) at 45° C. was added cholesta-4,16-dien-3-one (620 mg, 1.6 mmol) in THF (5 mL) and the whole stirred for 20 minutes. Iodomethane (1 ml) was added and the reaction stirred a further 12 hours., concentrated to one half the original volume and poured into 20 mL ice water. Extraction with ethyl acetate, drying over magnesium sulphate and concentration gave a residue which was purified by flash chromatography to give the title compound (220 mg).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3I)[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3[C:37]3[CH:38]=[C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]1C)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 25; 30 mg; 0.052 mmol) was treated with 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (Intermediate 26; 20 mg; 0.067 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (3.4 mg; 0.0052 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-({6-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]-2,3-dihydro-1H-inden-5-yl}methyl)-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=636.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.84-7.79 (m, 2H), 7.75 (s, 1H), 7.33 (dd, J=8.7, 2.5 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J=2.3 Hz, 1H), 7.13 (s, 1H), 6.95-6.92 (m, 1H), 5.41 (d, J=15.3 Hz, 1H), 4.93 (d, J=10.5 Hz, 1H), 3.93 (d, J=15.4 Hz, 1H), 3.81 (s, 3H), 3.65-3.61 (m, 1H), 3.57-3.54 (m, 1H), 3.44-3.36 (m, 1H), 2.99-2.94 (m, 4H), 2.20-2.10 (m, 3H), 1.76-1.64 (m, 1H), 1.33-1.25 (m, 6H), 1.05-1.02 (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:27])=[C:16]([O:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=3)[C:11]=2[N:10]=[N:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:27][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:28])=[O:5])[N:9]=[N:10][C:11]=2[C:16]=1[O:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Cn1nnc2c(Oc3cc(Cl)cc(C#N)c3)c(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Reaction time: 1 h

Procedure:
tert-Butyl[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetate (50 mg, 0.12 mmol) was dissolved in TFA (3 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure to yield the title compound. 1H NMR (DMSO-d6) δ 7.90 (d, J=8.9 Hz, 1H), 7.84 (m, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.52 (m, 1H), 7.58 (m, 1H), 5.70 (s, 1H).
Reaction SMILES: COC1CCCC=1.CON=O.[CH3:12][O:13][C:14]1([O:21][CH3:22])[CH2:18][CH2:17][CH2:16][C:15]1=[N:19][OH:20]>OS(O)(=O)=O.O=S(=O)=O>[CH3:22][O:21][C:14]1([O:13][CH3:12])[CH2:18][CH2:17][CH2:16][CH:15]1[N:19]=[O:20]
Reactant: COC1(OC)CCCC1=NO
Agent: COC1=CCCC1
Agent: CON=O
Agent: O=S(=O)(O)O
Product: COC1(OC)CCCC1N=O

Procedure:
1,1-Dimethoxy-2-nitrosocyclopentane dimer was prepared as in Example 1 by reacting 1-methoxycyclopentene (15.9 g., 0.162 mole) with an excess of methylnitrite (29.7 g., 0.48 mole) using 0.5 mole percent of 20% oleum as catalyst. The product (20.5 g.) was mostly the desired dimer with a small amount of 1,1-dimethoxy-2-oximinocyclopentane. An additional 5 grams of product were recovered by flash evaporation of the wash liquors. The structure was confirmed by IR and nmr.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(NC(C)C)(C)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: Ic1cccs1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(C#Cc1cccs1)OCC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of propargylaldehyde diethyl acetal (405 mg) in diisopropylamine (8 ml) were added 2-iodothiophene (1.2 g) and copper(II) acetate monohydrate (66.4 mg). The suspension was flushed with a stream of N2. Pd(PPh3)4 (75 mg) was added, the reaction mixture was flushed with nitrogen again. The suspension was stirred for 1 h at 55° C. A precipitate was formed and it was necessary to dilute the reaction mixture with diisopropylamine (6 ml) to keep it stirring. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→17/3 (v/v)] as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: COc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (41 mg, 31%), MS (ISP) m/z=401.6 [(M+H)+], mp 142° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine (intermediate L) (0.1 g, 0.33 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.39 mmol).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)=[CH:21][CH:20]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 2-(4-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (151 mg, yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[C:37]1([CH2:43][CH2:44][CH:45]=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:46][CH:45]([CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:15][CH2:14][CH2:13][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: O=CCCc1ccccc1
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(CCNC(=O)C(O)CCc2ccccc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (8.0 g, 34 mmol) and triethylamine (8.3 g, 82 mmol) are dissolved in dichloromethane (80 ml). Bis(trichloromethyl) carbonate (triphosgene, 4.0 g, 14 mmol) in dichloromethane (40 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (7.0 g, 38 mmol) in dichloromethane (70 ml) is added and the mixture is stirred for 2 hours at −40° C. 3-Phenylpropionaldehyde (4.8 g, 36 mmol) in dichloromethane (50 ml) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture is hydrolysed with 5N HCl (25 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane 6:3) to give 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-4-phenyl-butyramide (Compound E1.01).
Reaction SMILES: C(O)(=O)C.[BH3-]C#N.[Na+].[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=1.[CH3:26][C:27]1([CH3:34])[O:31][CH:30]([CH2:32][NH2:33])[CH2:29][O:28]1>CO>[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH2:16][NH:33][CH2:32][CH:30]2[CH2:29][O:28][C:27]([CH3:34])([CH3:26])[O:31]2)[CH:13]=[N:14][CH:15]=1
Reactant: O=Cc1cncc(Cl)c1COC1CCCCO1
Reactant: CC1(C)OCC(CN)O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)OCC(CNCc2cncc(Cl)c2COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid (133 μL) and NaBH3CN (14.8 mg, 0.235 mmol) were added to a stirred solution of 5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine-3-carbaldehyde (40 mg, 0.157 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (203 μL, 1.57 mmol) in MeOH (1 mL). After stirring for 2 h at room temperature the solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 370.9 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.C(=O)C1C=CC=CC=1>>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Solvent: O=Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCl

Procedure:
Analogously to the building block synthesis of 4-chloromethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and benzaldehyde gave 4-chloromethyl-5-methyl-2-phenyloxazole.