Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)CC(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CC(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Yield: 41 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-Amino-5-methyl-hexanoic acid (175 mg, 1.2 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 2.4 mL, 1.2 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 4.5 hours. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The crude product was purified by MPLC (methylene chloride-methanol) to provide the title compound as an off-white solid in 41% yield. MS ESI(−) m/e: 432.1062 (M−1).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:45])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (360 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 80% ethyl acetate in isohexane, to afford the product (395 mg, 57.5%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 2.54 (3H, s), 3.09-3.13 (2H, m), 3.16-3.21 (1H, m), 3.29-3.34 (1H, m), 3.87-3.92 (2H, m), 4.51 (1H, qn), 5.92-5.95 (1H, m), 7.43-7.47 (1H, m), 7.52-7.55 (2H, m), 8.14 (1H, d), 8.41 (1H, s), 8.59 (1H, s), 9.42 (1H, d), 9.96 (1H, s); m/z (ES+) (M+H)+=631; HPLC tR=2.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 146°-149° C.,
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(B(O)[OH:31])=CC=1>>[F:10][C:8]([F:9])([F:11])[C:7]1[CH:2]=[CH:3][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([OH:31])[C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCc2cncc(-c3ccc(C(F)(F)F)c(F)c3)c21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: OC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 97 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-4 [C2]) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 97% yield. MS: 280.1 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH3:17])[C:4]=1[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].C(S)C.Cl>CN(C)C=O.O>[OH:2][C:3]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[C:7]([CH3:17])[C:4]=1[C:5]#[N:6]
Reactant: COc1cc(N2CCOCC2)cc(C)c1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(O)c1C#N
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a solution of 2-methoxy-6-methyl-4-morpholin-4-yl-benzonitrile (0.9 g, 3.88 mmol) in dimethylformamide (15 ml) are added potassium carbonate (2.1 g, 15.5 mmol) and ethanethiol (2.3 ml, 31.0 mmol) and the resulting mixture is heated at 90° C. for 16 h. The reaction mixture is poured onto cold water (50 ml), acidified with 2M hydrochloric acid to pH 3 and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by flash column chromatography (silica gel, 30% ethyl acetate/hexane) affording 2-hydroxy-6-methyl-4-morpholin-4-yl-benzonitrile (0.41 g, 1.88 mmol, 48%).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>CO>[F:51][C:48]([F:49])([F:50])[O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][CH:43]=1
Reactant: FC(F)(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCc2ccc(OC(F)(F)F)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 37) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from MTBE and heptane.
Reaction SMILES: [Cl-].[CH3:2][NH+:3]1[CH2:7][CH2:6][N:5]([CH3:8])[CH:4]1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11].[F:14][C:15]([F:21])([F:20])[S:16]([OH:19])(=[O:18])=[O:17]>O>[O-:19][S:16]([C:15]([F:21])([F:20])[F:14])(=[O:18])=[O:17].[CH3:8][NH+:5]1[CH2:6][CH2:7][N:3]([CH3:2])[CH:4]1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CCN(CC)C1N(C)CC[NH+]1C
Agent: [Cl-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
10.98 g (53.4 mmol) of 1,3-dimethyl-2-diethylaminoimidazolidinium chloride are dissolved in 70 cm3 of water, and 8.24 g (54.9 mmol) of trifluoromethanesulfonic acid are added at room temperature over the course of 5 min while the reaction mixture is stirred vigorously using a magnetic stirrer. The reaction mixture is stirred at room temperature for a further 5 min. All volatile components of the mixture are removed under reduced pressure. The residue is washed twice with 50 cm3 of diethyl ether and dried at 60° C. in an oil bath for three hours under a vacuum of 7.0 Pa, giving 16.7 g of a crystalline material (m.p. 67-68° C.). The yield of 1,3-dimethyl-2-diethyl-aminoimidazolidinium triflate is 97.9%, based on 1,3-dimethyl-2-diethyl-aminoimidazolidinium chloride.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=CC(=O)N2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].C(OC1C=CC([C@@H](O)CBr)=CC=1[CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])C1C=CC=CC=1>>[N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH:15]=1)[OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 5 in place of (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsilyl)oxy]ethyl]quinolin-2(1H)-one. ES/MS calcd. for C22H31N3NaO3Si+ 436.2. found m/z=436.2 (M+Na)+.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:10][CH2:11][CH:12]=C)[CH2:8][OH:9])[CH3:6].C(=O)=[O:16].O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CC(C)=O>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:8][OH:9])[CH2:10][CH2:11][CH:12]=[O:16])[CH3:6]
Reactant: O=C=O
Reactant: C=CCCC(O)(CC)CO
Agent: O=[O+][O-]
Agent: [CH2-]C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC(O)(CO)CCC=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 2S 2-ethyl-2-hydroxyhex-5-enol acetonide (1.2 g, 6.52 mmol) in dichloromethane (25 mL) was brought to -78° C. (dry ice, acetone) and ozone was bubbled through until the reaction mixture turned a pale blue (approx 15 min.) The reaction mixture was then flushed with nitrogen for 1 h, triphenylphophine (850 mg, 3.26 mmole) was added and the mixture was allowed to slowly warm to room temperature. The solvent was removed under reduced pressure and the residue was taken up in hexane, filtered and again concentrated. Flash chromatography on 50 g of silica gel, eluting with 3:2 hexane/ether, gave 0.92 g (76%) of the title aldehyde. TLC Rf 0.39 (silica gel, 3:2 hexane-ether).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH+:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](=O)[CH3:29])=[CH:22][CH:21]=1>CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:29][C:28]1[N+:8]2[C:9]3[C:14]([C:15]([CH3:17])([CH3:16])[C:7]=2[CH:6]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[CH:27]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COc1ccc(C=CC(C)=O)cc1
Reactant: CC1=[NH+]c2ccccc2C1(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: COc1ccc(-c2cc(C)[n+]3c(c2)C(C)(C)c2ccccc2-3)cc1

Procedure:
2,3,3-Trimethyl-3H-indolium perchlorate (5 g.) and 4-p-methoxyphenylbut-3-ene-2-one (10 g.) were heated together on the steam bath for three hours. The cooled mixture was diluted with methanol and filtered. The product was purified by recrystallization from acetonitrile. Yield 4.1 g.; m.p. 298°-300° .
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:24](=[O:25])[C:23]3[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCCC1(c2cccc(C(F)(F)F)c2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1>>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:5]3[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]4[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)(C)C4)CC2)cc1
Yield: 21.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol) synthesized in Reference example 96 and 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 123 mg (yield 22%). That is, sodium t-butoxide (398 mg, 4.14 mmol) was added to a mixture of toluene (30 mL) containing 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol), 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), palladium acetate (15 mg, 0.069 mmol) and BINAP (129 mg, 0.207 mmol), and the mixture was stirred under argon atmosphere and under heated reflux for 12 hours. After cooled to room temperature, saturated saline was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-80:20). Crystallization was performed using ethyl acetate-hexane to give 123 mg of the title compound as a colorless crystal (yield: 22%). Melting point was 152 to 154° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH:20]([CH3:22])[CH3:21].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reactant: CC(C)CN1CCCC1CN
Solvent: O
Solvent: OCCOCCO
Product: CC(C)CN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A suspension of 5.2 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 4.5 g of 1-isobutyl-2-aminomethylpyrrolidine in 20 ml of diethylene glycol is heated at 130°-140° C. and stirred for 18-19 hours. The reaction solution is cooled to room temperature and poured into 150-200 ml of water while stirring. Under ice-cooling crystals are deposited thoroughly and collected by suction filtration. The crude crystals are washed with cold water, dissolved in chloroform and separated on a column of silica gel (developing solvent: methanol/chloroform=1/9). Crystals obtained are recrystallized from about 35 ml of methanol to give crystals of N-(1-isobutyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 182°-184° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([C:10]1[C:11]([Cl:26])=[N:12][C:13]([CH3:25])=[N:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH:8]=C.CC(C)=O.O>C(O)(C)(C)C.O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[Cl:26][C:11]1[N:12]=[C:13]([CH3:25])[N:14]=[C:15]2[C:10]=1[CH:7]=[CH:8][N:16]2[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]
Reactant: C=CCc1c(Cl)nc(C)nc1Nc1ccc(Cl)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: Cc1nc(Cl)c2ccn(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 20 h
Yield: 50.4 %

Procedure:
Sodium periodate (3.83 g, 17.9 mmol) was added to a stirred solution of (19) (1.94 g, 5.90 mmol) in 3:1 acetone-water (55 mL). The mixture was heated briefly to obtain homogeneity, and a 2.5% solution of osmium tetroxide in t-butanol (0.4 mL) was added. After 20 h, the mixture was diluted with water (50 mL) and saturated sodium thiosulfate (50 mL), and extracted with ethyl acetate. The combined extracts were concentrated under vacuum, and the residue was stirred in dichloromethane (40 mL) and 4 N HCl (5 mL) for 4 h. The mixture was poured into saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed (elution with dichloromethane) to afford 0.929 g (50%) of diazaindole (20) as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:21][CH2:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([CH2:7][CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.96 g of crude (trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl ]methanol in 20 ml of dry pyridine is treated at 0° C. with 2.1 g of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 15 hours, then diluted with 200 ml of methylene chloride and washed several times with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 1:9) gives [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl ]cyclohexyl]cyclohexyl]methyl p-toluenesulfonate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:34])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 9.1 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2H-chromene (prepared as described in Preparation 21), 2g of 10% w/w palladium-on-carbon and 150 ml of methanol was stirred for 10 hours under 3-5 atmospheres (about 3-5-bars) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:10]S(C)=O.C1(=O)C=CC(=O)C=C1>C(Cl)Cl>[O:1]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[CH:2][CH2:10]1
Reactant: c1ccc2occc2c1
Reactant: CS(C)=O
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCl
Product: C1=Cc2ccccc2OC1
Reaction time: 36 h
Yield: 12 %

Procedure:
(±) 1,5-Dimethoxy-2′-isopropenyl dihydrofuroanoxanthone (107). DMSO (118 mL) was added to a mixture of (106) (1.21 g, 3.56 mmol), Pd[(CH3CN)4BF)2] (0.79 g, 1.78 mmol) and benzoquinone (recrystallized from EtOH, 3.84 g, 35.6 mmol). The solution was stirred 36 h, then poured into a separatory funnel containing CH2Cl2 (400 mL), and washed with H2O (2×300 mL). The layers were separated and the H2O layer was washed with CH2Cl2 (200 mL). The organic layers were combined and washed with sat. NaCl (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (50% EtOAc/hex), loading the product on the column in a minimum amount of CH2Cl2 to afford 0.15 g chromene (12%) and then 0.97 g (81%) of benzofuran (107) as a white solid. (LH-64-50).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].N1CCCC1C(O)=O.[CH2:21]1[O:31][C:24]2([CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[O:23][CH2:22]1>C1(C)C=CC=CC=1>[O:23]1[C:24]2([CH2:29][CH2:28][CH:27]([CH:8]([S:5]([CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])(=[O:6])=[O:7])[C:9]#[N:10])[CH2:26][CH2:25]2)[O:31][CH2:21][CH2:22]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: O=C(O)C1CCCN1
Solvent: Cc1ccccc1
Product: N#CC(C1CCC2(CC1)OCCO2)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 4.02 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile, 100 ml of toluene, 0.23 g of DL-proline and 3.32 g of 1,4-cyclohexanedione monoethylene ketal was heated and stirred for 3 hours under the reflux condition. After 20 ml of toluene was distilled off, the reaction mixture was cooled to room temperature. To the reaction mixture was added 100 ml of tetrahydrofuran. The mixture was cooled to 0° C. and then 1.01 g of sodium borohydride was added thereto. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. Thereto 100 ml of water and 100 ml of ethyl acetate were added. While the reaction mixture was stirred, 100 ml of an aqueous 1N hydrochloric acid solution was added dropwise, followed by extraction with 100 ml of ethyl acetate twice. An organic layer was washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution, 100 ml of an aqueous saturated sodium chloride solution and 100 ml of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.45 g of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(3,3,3-trifluoropropylsulfonyl)acetonitrile (hereinafter referred to as the present compound (27)) represented by the following formula (27).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1B(O)O>>[CH:33]1[C:34]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:32]=1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc5ccccc5c4)nc23)CC1
Yield: 91.8 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (164 mg, 0.450 mmol) and 2-naphthylboronic acid (124 mg, 0.720 mmol) were converted to 141 mg of the title compound by the procedure of Example 3. (91%). MS(FD) m/e 341.8 (M+). EA calculated for C23H23N3: C, 80.94; H, 6.74; N, 12.32. Found: C, 88.11; H, 6.87; N, 12.27.