Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(=O)NC1C=CC([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33]OC[C@@H]3C)C3C[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=CC=1)C.Cl[C:38]1[N:39]=[C:40]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]2[CH3:58])[C:41]2[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=2[N:43]=1.CC1(C)C(C)(C)OB(C2N=CC(N)=NC=2)[O:61]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:50]([O:49][C:47]([N:45]1[CH2:46][C:41]2[C:40]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]3[CH3:58])=[N:39][C:38]([C:18]3[CH:16]=[N:17][C:12]([NH:13][C:14]([NH:29][CH2:34][CH3:33])=[O:61])=[CH:20][N:19]=3)=[N:43][C:42]=2[CH2:44]1)=[O:48])[CH3:51]
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCNC(=O)Nc1cnc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)cn1
Yield: 58 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine as starting materials, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by flash chromatography using a gradient of 0-40% DCM/MeOH yielding the title compound (69 mg, 0.18 mmol, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH2:21])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:21][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2cccc3c2OC(CN)C3)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c(OC)c1
Yield: 85.4 %

Procedure:
Treatment of (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.42 g, 4.41 mmol) with diisopropylethylamine (0.855 g, 6.62 mmol) followed by benzyl chloroformate (0.828 g, 4.85 mmol) generally according to the procedure described for Intermediate 12 provided 1.58 g (85%) of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C25H25NO5: C, 71.58; H, 6.01; N, 3.34. Found: C, 71.24; H, 5.92; N, 3.09. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (Rt=5.107 min, Chiralcel OD, ethanol); Fraction 2 (Rt=6.134 min, Chiralcel OD, ethanol).
Reaction SMILES: CO[C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C=CCC[C:18](=[O:21])CC.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:22]([NH:29][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[C:12]([O:21][CH3:18])=[CH:13][CH:3]=[CH:4][C:5]=2[CH2:11]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)CCCCC2
Reactant: C=CCCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-hepten-5-one (6.0 g) and benzylamine (3.4 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water at the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (1.2 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (7.27 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH3:37][N:38]1[CH2:44][CH2:43][CH2:42][N:41]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40][CH2:39]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:48]1[CH2:49][CH2:50][CH:45]([N:41]2[CH2:42][CH2:43][CH2:44][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:46][CH2:47]1)=[O:14])[CH3:2]
Reactant: CN1CCCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg (1.01 mmol) 1-methyl-4-piperidin-4-yl-[1,4]diazepan.
Reaction SMILES: C(C1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[CH:8][C:7]=2[CH:21]=1)=O.[C-:22]#N.[Na+].[C:25]([OH:28])(=[O:27])[CH3:26]>CO.[O-2].[Mn+4].[O-2]>[CH3:22][O:27][C:25]([C:26]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[CH:8][C:7]=2[CH:21]=1)=[O:28]
Reactant: O=Cc1ccc2oc(-c3ccc4ccccc4n3)cc2c1
Reactant: CC(=O)O
Reactant: [C-]#N
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CO
Product: COC(=O)c1ccc2oc(-c3ccc4ccccc4n3)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(5-formylbenzofuran-2-yl)quinoline (0.92 g), manganese (IV) oxide (4.6 g), sodium cyanide (2.2 g) and acetic acid (0.6 ml) in methanol (200 ml) was stirred at ambient temperature for 1.5 hours. The resulting mixture was filtered and filtrate was poured into water (400.ml). The appeared precipitates were collected by filtration and washed with water. The precipitates were subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate (50:1). The fractions containing objected compound were combined and concentrated under reduced pressure to give 2-(5-methoxycarbonylbenzofuran-2-yl)-quinoline (0.48 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]2[CH:10]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH:8]2[CH:4]1[CH2:5][NH:6][CH2:7]2.C(=O)([O-])O.[Na+].CS(O[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1)(=O)=O.C(OCC)C>COCCOC.O>[NH3:6].[CH3:2][C:3]1([C:9]2[CH:10]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:36][CH:37]=1)[CH2:7]2
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCc3ccc(NS(C)(=O)=O)cc3)CC21
Product: N
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide hydrochloride salt (Preparation 53, 100 mg, 0.33 mmol) in ethylene glycol dimethyl ether (10 ml) was added sodium hydrogen carbonate (1.5 g, 18 mmol) and 4-[(methylsulfonyl)amino]phenethyl methanesulfonate (P. E. Cross, J. E. Arrowsmith, G. N. Thomas, R. P. Dickinson, DD 281 599 A5, 97 mg, 0.33 mmol) and the reaction mixture was heated at 60° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil. The oil was further purified by preparative HPLC (condition 9) to give the title compound as a colourless glass (11 mg, 7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH2:25][O:26][CH2:27][CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:4]2[N:3]=1.[CH3:29][CH2:30][N:31]([CH:35](C)C)C(C)C.CNC([OH:42])C>C(#N)C>[CH2:27]([O:26][CH2:25][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]2[N:3]=[C:2]([CH2:35][NH:31][CH2:30][CH2:29][OH:42])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]2[N:15]=1)[CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(C)O
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Solvent: CC#N
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(CNCCO)nc2c1-c1ccc(C)cc1

Procedure:
5-Chloro-2-(ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (22 mg), DIPEA (0.1 mL) and N-methylaminoethanol (0.1 mL) are stirred for 12 hours in an acetonitrile (7 mL) solvent at 84° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The collected organic layer is washed with brine and dehydrated with anhydrous MgSO4. The solvent is removed by distillation under reduced pressure and the remainder is purified by column chromatography to yield the target compound (18 mg).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:24]2[CH2:25][CH2:26][CH2:27][C:22]2=[O:9])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: O=C1CCCC1=Cc1ccc(Cl)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 28.1 g (0.20 mol) of p-chlorobenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate, and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in 95% ethanol to yield 32.9 g of light yellow flaky crystal product with a yield of 66.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:34])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(=O)O)s4)c3c2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a mixture of 0.048 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid, 0.046 g (0.12 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.008 g (0.15 mmole) of ammonium chloride and 1 mL of dimethylformamide was added 0.052 mL of diisopropylethylamine. The mixture was stirred at ambient temperature for 1 hour, filtered and then purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.027 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.2) as a white solid. MH+/Z=467
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:10]=[C:9]([CH2:11][C:12]([O:14]C)=[O:13])[CH:8]=[CH:7][C:6]=1[N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:27])=O)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)#[N:4].[C:28]([Cl:33])(=O)[C:29](Cl)=O>C(N(CC)CC)C>[Cl:33][C:28]1[CH:29]=[CH:3][C:5]([CH2:10][O:2][NH:1][C:25]([C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[C:3]#[N:4])[CH:17]=[CH:18]3)=[O:27])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)O)ccc32)c(C#N)c1
Reactant: NO
Solvent: CCN(CC)CC
Product: N#Cc1cc(CC(=O)O)ccc1-n1ccc2cc(C(=O)NOCc3ccc(Cl)cc3)ccc21

Procedure:
O-chlorobenzyl)hydroxylamine was reacted with 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylic acid in the presence of triethylamine and oxalyl chloride according to the method of Example 5, Step E, to provide 2-(4-(5-((4-chlorobenzyloxy)carbamoyl)-1H-indol-1-yl)-3-cyanophenyl)acetic acid. 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.56-7.64 (m, 3H), 7.50 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 6.85 (d, J=4.1 Hz, 1H), 4.98 (s, 2H), 3.81 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:22])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]1O.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:29][C@@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C:19]1[CH:20]=[C:3]([O:2][CH3:1])[C:4]([OH:22])=[CH:5][C:6]=1[CH2:7][CH2:8]3
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: ClCCl
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](F)CC[C@@H]12
Temperature: -35 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
215 mg of 2-methoxy-estra-1,3,5(10)-triene-3,17β-diol was dissolved in 20 ml of absolute dichloromethane and cooled to −35° C. Then, 280 μl of diethylamino sulfur trifluoride was added, and the cold bath was removed. After 1 hour, it was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane (3×). The combined organic phases were dried and concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate=10:1) yielded 49% crude product, which was purified by means of HPLC (Chiracel OD-H 250×4.6 mm; n-heptane/2-propanol=95/5). 46 mg (21%) of 17α-fluoro-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene was obtained as colorless crystals.
Reaction SMILES: CCO.[CH3:4][NH:5][NH2:6].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24](Cl)[C:23]([C:27]([O:29]CC)=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]3[NH:6][N:5]([CH3:4])[C:27](=[O:29])[C:23]3=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNN
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cn1[nH]c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 63 %

Procedure:
Added at room temperature (about 20° C.) to an EtOH solution (20 ml) of 2.0 g of 2-methylhydrazine was a chloroform solution (12 ml) of 5.3 g of the ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-carboxylate synthesized in Referential Example 63. The resultant mixture was stirred for 3 hours. The solvent was distilled off and ethyl acetate was added to the resultant solid. After thoroughly mixing the thus-obtained mixture, 3 g of crystals were collected by filtration (yield: 63%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C@H:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@H:23]1[C@H:30]2[C@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]2)[C@@H:25]([CH2:33][F:34])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C@H:9]([NH:12][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@H:23]1[C@H:30]2[C@H:26]([O:27][C:28]([CH3:31])([CH3:32])[O:29]2)[C@@H:25]([CH2:33][F:34])[CH2:24]1)[CH2:10][CH3:11]
Reactant: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: CC[C@@H](N)Cc1sccc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Cc1sccc1Cl)Nc1ncnc2c1ncn2[C@@H]1C[C@H](CF)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-1-(3-Chloro-thiophen-2-ylmethyl)-propylamine hydrochloride (1.36 g, 6 mmoles) and 6-chloro-9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro -cyclopenta-1,3-dioxol-4-yl)-9H-purine (1.63 g, 5 mmoles) prepared as described above were combined in nBuOH (40 ml), iPr2NEt (3.5 ml, 20 mmoles) was then added and the resulting solution was stirred at reflux under an argon atmosphere. After 5 h, the reaction mixture was cooled down to room temperature, partitioned between water, brine and EtOAc, the aqueous layer was separated and extracted two times with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate is concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel eluting with 2% MeOH in CH2Cl2 to yield [(R)-1-(3-chloro-thiophen-2-ylmethyl)-propyl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl -tetrahydro-cylopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.O>CC(O)(C)C>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nsc2ccccc12
Reactant: C1CNCCN1
Solvent: CC(C)(C)O
Solvent: O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 2.5 °C

Procedure:
A mixture of piperazine (10.2 g, 0.118 mmol) and 3-chloro-1,2-benzisothiazole (4.0 g, 0.024 mmol) in t-BuOH (4 mL) was refluxed overnight. The reaction mixture was poured into water (100 mL) and extracted with toluene (200 mL). The organic phase was dried over MgSO4 and evaporated until about 20 mL remained, under vacuum. The resulting suspension was cooled at 0-5° C. overnight. The precipitate was filtered and dried under vacuum to provide 3-(piperazin-1-yl)benzo[d]isothiazole as an intermediate (3.36 g, 15.4 mmol, 65%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH2:28][CH3:29].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 120 °C

Procedure:
A mixture of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1 g) and butylamine (1.5 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and then heated for 24 hours to a temperature in the region of 120° C. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (10 cc) and ethyl acetate (25 cc). After extraction, the organic phase is separated, washed with distilled water (10 cc) and then with saturated aqueous sodium chloride solution (20 cc), dried over potassium carbonate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.15 g) is thereby obtained in the form of a viscous yellow oil which is subsequently used as it is.
Reaction SMILES: [H-].[Na+].[H][H].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(O)C.C(OCC)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:8]([C:7](=[O:14])[C:6]([F:15])([F:16])[F:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)C(F)(F)F

Procedure:
A 1 L four neck round bottom flask, fitted with reflux condenser, dropping funnel, argon inlet, and magnetic stirrer was charged with 7.17 g (0.149 mol) of a 50% (w/v) oil dispersion of sodium hydride and 300 mL of dry ethyl ether. Absolute ethanol (9.0 mL) was slowly added to the stirred solution. After the evolution of hydrogen stopped, a mixture of 25 g (0.136 mol) of ethyl 4,4,4-trifluoroacetoacetate and 21.3 g (0.136 mol) of 4-methoxybenzyl chloride was added over a 1 hour period. The resulting mixture was refluxed overnight, cooled, extracted with water, 1 N hydrochloric acid, dried over anhydrous magnesium sulfate and rotary-evaporated under reduced pressure. The crude reaction mixture (33.5 g) was chromatographed on a 60 mm xx 300 mm silica gel column with ethyl acetate/hexane (25/75). Similar fractions were combined and gave 9.4 g (23%) of the (spectroscopically complex) product as an oil. NMR(CDC13): 1.26(m,3H), 3.77(s,3H), 4.12(m,2H), 7.08(m,2H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([OH:13])=[O:12].C1C=CC=CC=1>CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1c(N)cccc1Cl
Reaction time: 1 h
Yield: 96 %

Procedure:
To prepare this compound, trimethylsilyldiazomethane (2 M in hexanes, 1.5 equiv) was added to a solution of the 2-amino-6-chlorobenzoic acid (1 equiv) in 2:1 benzene:methanol (0.2-0.3 M) at room temperature. After 1 hour, the solvent was removed under reduced pressure to afford methyl 2-amino-6-chlorobenzoate in 96% yield. That product was used without further purification or was purified by flash chromatography (7:3 hexanes:ethyl acetate) in 91% yield.