Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]3([CH2:21][CH2:20][CH2:19]3)[CH2:5][C:4]=2[N:3]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[O:25]1[CH2:22][CH:5]=[C:4]([C:2]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]3[C:8](=[O:18])[CH2:7][C:6]4([CH2:21][CH2:20][CH2:19]4)[CH2:5][C:4]=3[N:3]=2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1c(Cl)nc2c(c1O)C(=O)CC1(CCC1)C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C2=CCOCC2)nc2c(c1O)C(=O)CC1(CCC1)C2

Procedure:
Obtained by starting from ethyl 2′-chloro-4′-hydroxy-5′-oxo-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate. 1,4-Dioxane is used instead of tetrahydrofurane and caesium carbonate instead of sodium carbonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Br)ccc1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.4 g, 0.0071 mol), 3-fluorobenzeneboronic acid (500 mg, 0.004 mol), TEA (3.0 mL, 0.021 mol), cupric acetate (1.0 g, 0.0057 mol) and DCM (40 mL, 0.6 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.71 (s, 3H), 6.52 (dt, J=10.36, 2.40 Hz, 1H), 6.57-6.69 (m, 2H), 6.81 (d, J=8.34 Hz, 1H), 6.99 (dd, J=8.34, 2.27 Hz, 1H), 7.04 (d, J=2.27 Hz, 1H), 7.13 (td, J=8.34, 6.82 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Solvent: C1CCOC1
Product: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 5 h

Procedure:
To a solution of the 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxylic acid (120 mg, 0.33 mmol, 1.0 eq) in 5 mL of THF was added borane-tetrahydrofuran complex (1M, 1 mL, 1 mmol) at 0° C. The reaction mixture was stirred at that temperature for 5 hours. The reaction was quenched with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=354.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[N:11]1([CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1ccc(C(CCn2ccnc2)Oc2ccccc2)cc1
Product: c1ccc(OC(CCn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.05 [M+H]+345.30. 1H NMR (Me-d3-OD) δ 2.30-2.55 (2H, m), 4.25-4.45 (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s), 7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d), 7.85 (1H, s), 7.95 (2H, s).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25](=O)[O:26]C4C=CC([N+]([O-])=O)=CC=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:26])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: Cc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a solution of 4-nitrophenyl 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamate (55.5 mg, 0.115 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added morpholine (0.0500 mL, 0.573 mmol) and triethylamine (0.0500 mL, 0.359 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 33.4 mg (67%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)morpholine-4-carboxamide. LCMS (ESI): RT (Min)=4.234, M+H=431.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.66-3.53 (m, 4H), 3.47-3.37 (m, 4H), 2.21 (s, 3H), 2.15-2.00 (m, 1H), 0.98-0.67 (m, 4H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: CN(C)CC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and N,N-dimethylglycine hydrochloride (16.7 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:37]([CH3:38])=[N:36][N:35](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C4CCCCO4)=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[C:10]([CH3:51])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:9]1)=O)(C)(C)C.Cl>ClCCl>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[C:18]3[NH:35][N:36]=[C:37]([CH3:38])[C:17]3=[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3([CH3:51])[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:15])[CH:21]=2)=[CH:23][CH:24]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Agent: Cl
Solvent: ClCCl
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCNCC3(C)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 3-methyl-4-{3-methyl-1-(tetrahydropyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carbonyl}-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (300 mg) and HCl (4M in 1,4-dioxane, 104 μL) in dichloromethane (2 mL) was stirred at r.t. overnight. A solid precipitated during the reaction, which was filtered off and dried in air. The sticky solid was triturated with acetonitrile and filtered again, washed with acetonitrile and dried in air. 137 mg (64%) of the title compound were obtained as hydrochloride salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[C:39]4[CH:46]=[C:45]([CH:47]=O)[NH:44][C:40]=4[N:41]=[CH:42][N:43]=3)=[CH:33][CH:32]=2)=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[C:39]4[CH:46]=[C:45]([CH2:47][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[NH:44][C:40]=4[N:41]=[CH:42][N:43]=3)=[CH:35][CH:36]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CN4CCOCC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 0.5 ml of tetrahydrofuran, 10 μl of morpholine and 26 mg of triacetoxyborohydride to the 1-(4-fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea synthesized in Example 168, the mixture was stirred overnight at room temperature. The reaction system was subjected to liquid separation and extraction with a tetrahydrofuran-ethyl acetate mixed solvent, and then dried over anhydrous sodium sulfate and concentrated to dryness to obtain 5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 67.3 %

Procedure:
Following General Procedure B, the title compound (150 mg, 68%) was prepared from 5-Chloro-2-methylsulfanyl-phenylamine (110 mg, 0.64 mmol) and 4-Chloro-benzenesulfonyl chloride (134 mg, 0.64 mmol).
Reaction SMILES: [F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCC(CF)(CCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(CF)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 6.36 g. of 4-fluoromethyl-4-trimethylsilyloxy-1-octyne, 11.64 g. (10.6 ml.) of tributylstannane and 40 mg. of azobisisobutyronitrile is heated and stirred at 120° C. under nitrogen for 3 hours. The mixture is cooled, filtered through Celite and washed with hexanes. The hexanes are removed in vacuo and the residual liquid in vacuum distilled through a short path. The product is obtained at b.p. 110°-135° C./0.2-0.25 mm. (The product contains a minor amount of cis isomer.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:18])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:25]3[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][N:24]=3)[C@H:14]([CH3:18])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(c3cc(Cl)ncn3)[C@H](C)C2)c(Cl)c1

Procedure:
Heat a solution of 5-chloro-6-(3-(R)-methyl-piperazin-1-yl)-nicotinic acid ethyl ester (338 mg, 1.2 mmol), 4,6-dichloropyrimidine (179 mg, 1.2 mmol) and potassium carbonate (328 mg, 2.4 mmol) in DMA at 80° C. for 16 h. Partition between EtOAc and brine then separate layers and wash the organic layer with 10% NaOH (3×) followed by brine. Dry (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1ccncc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccncc1)c1cc(F)ccc1F
Yield: 31.4 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660 mmol) obtained in Example 5 and 4-pyridylmethanol (144 mg, 1.32 mmol) were dissolved in toluene (6 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol). The resulting mixture was heated under reflux for 15 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:2 elulate was concentrated. The solid thus obtained was recrystallized from ethyl acetate, whereby the title compound (81.4 mg, 0.207 mmol, 31%) was obtained as colorless needle crystals.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[CH:35]=O.O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43]
Reactant: COCOc1ccc(C=O)cc1OC
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(/C=C/CCO)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
n-Butyllithium (1.6M in hexane, 25 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.03 g) in dry THF (50 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 10 min and then 3-methoxy-4-(methoxymethoxy)-benzaldehyde (3.60 g) in dry THF (10 ml) was added dropwise over 5 min. The mixture was allowed to warm to room temperature, stirred for 4 h, water (10 ml) was added and the majority of the solvent was removed in vacuo at 40°. A solution of the residual oil in ER (200 ml) was washed with water (150 ml), dried, treated with charcoal, concentrated and purified by FCC eluting with EA-H (1:1) to give the title compound (1.55 g). T.l.c. (EA-H 1:1) Rf 0.30.
Reaction SMILES: N1CC[C@H]1C(O)=O.[C:8]([C@H:11]([C@@H:13]([C:15]([O-:17])=[O:16])[OH:14])[OH:12])([O-:10])=[O:9].[OH-].[K+:19]>O>[C:8]([CH:11]([CH:13]([C:15]([O-:17])=[O:16])[OH:14])[OH:12])([OH:10])=[O:9].[K+:19]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: O=C(O)[C@@H]1CCN1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
L-AzeOH-D-tartrate (14.0 g; 56 mmol; prepared analogously to the methods described in international patent application WO 97/02441) was added to water (17 mL) at room temperature. The mixture was heated to 60° C. and an additional amount of water (9 mL) was added to completely dissolve the L-AzeOH-D-tartrate. KOH (10.8 mL; 5.7 M) was added over 7 minutes to resultant the yellowish solution. The reaction mixture was then left to cool at room temperature. It was left at this temperature overnight. The reaction mixture was then cooled on ice for 7 h. Potassium hydrogen tartrate crystallised and was filtered off. The filtration gave potassium hydrogen tartrate as white solid (9.5 g; 91%) and a slightly yellowish aqueous solution containing liberated L-AzeOH. The latter was used in the next step without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:6]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][I:33])[C:6]=2[CH:13]=1
Reactant: II
Reactant: OCCc1csc2ccc(Cl)cc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2scc(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-chloro-1-benzothiophene-3-yl)ethanol (1060 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.1 g (69%); 319 (M+H).
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].CCOCC.[OH:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>C(O)C.C(O)(=O)C>[OH:17][CH:14]1[CH2:13][CH2:12][C:11](=[O:10])[CH:3]([CH3:4])[CH2:16][CH2:15]1
Reactant: CC=[N+]=[N-]
Reactant: O=C1CCC(O)CC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1CCC(O)CCC1=O

Procedure:
To a freshly prepared solution of diazoethane in ether (~550 ml of 0.297 M =163 mmol) cooled to -10° C. and well stirred with a magnetic stirrer in an open 1 liter Erlenmeyer flask is added slowly a solution of 4-hydroxycyclohexanone (14.8 g, 13 mmol) in ethanol (150 ml) over a period of 15 minutes. The cooling bath is removed and the stirred reaction mixture is allowed to come to room temperature and stirred overnight. The excess diazoethane is discharged by adding a few drops of 10% aq. acetic acid and then the solvent is removed in vacuo. The residue is dissolved in ether, washed with a satd. aq. NaHCO3 solution, dried (Na2SO4) and the ether is removed in vacuo. Distillation of the residue in vacuo affords (±) 5-hydroxy-2-methylcycloheptanone which exists as an equilibrium mixture with its tautomeric bicyclic hemiacetal form (bp, 1.4 mm, 97°-99°, 17.51 g, 95%). IR (neat)μ: 2.93 (OH), 5.90 (C=O), NMR (CDCl3)δ: 0.91 (d, J=7 Hz, 2-CH of 2-y), 0.8 (d, J=7 Hz, 2-CH3), 3.4-4.5 (m, ##STR3## and ##STR4## GC-MS: RGC shows two components (~60:40) both of which show M+ 142 and identical fragmentations. MOX derivatization gave a single peak in RGC with M+ 171.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38](C4C(C#N)=CSC=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].OC1C=CC([N:55]2[CH2:60][CH2:59][N:58]([C:61](=[O:63])[CH3:62])[CH2:57][CH2:56]2)=CC=1>>[C:61]([N:58]1[CH2:59][CH2:60][N:55]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][C:25]3[S:24][C:23]([N:20]4[CH2:19][CH2:18][C:17]5[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]6[S:1][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=7[N:3]=6)[CH:14]=[CH:15][CH:16]=5)[CH2:21]4)=[N:27][C:26]=3[C:28]([OH:30])=[O:29])=[CH:40][CH:39]=2)[CH2:56][CH2:57]1)(=[O:63])[CH3:62]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 61 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.36 Hz, 1H), 7.78 (d, J=8.29 Hz, 1H), 7.66 (d, J=7.06 Hz, 1H), 7.33-7.49 (m, 4H), 6.90-6.92 (m, 2H), 6.80-6.82 (m, 2H), 4.82 (s, 2H), 3.90 (t, J=6.29 Hz, 2H), 3.71 (t, J=6.29 Hz, 2H), 3.53-3.56 (m, 2H), 3.13-3.17 (m, 2H), 3.02 (t, J=5.37 Hz, 4H), 2.94-2.96 (m, 2H), 2.02 (s, 3H), 1.92-1.99 (m, 2H). ESI (+)/MS: 697 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6](C2C=CC([C@H]3CC[C@H](OCCC#N)CC3)=CC=2)[CH2:5]1>CO.N.[Ni]>[CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1
Reactant: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OCCC#N)CC3)cc2)C(=O)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COCC1CNC(=O)O1

Procedure:
932 mg (2.6 mmol) of (R)-3-[trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyloxy]-propionitrile were dissolved in 60 ml of methanol saturated with dry ammonia gas and hydrogenated in the presence of 0.9 g of Raney-nickel (Type B 113W Degussa). After 3 hours the catalyst was filtered off under suction and the filtrate was evaporated. The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in alcohol and made acid with ethereal hydrochloric acid. After recrystallization from alcohol-ether there were obtained 825.2 mg of (R)-3-[trans-4-(3-amino-propoxy)-cyclohexyl]-phenyl]-5-methoxymethyl-oxazolidin-2-one.HCl. M.p.: 178°-180°. [α]D =-29.78° (c=1% in CHCl3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.CN1CCOCC1>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([S:29]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:8]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[C:11]4[S:12][CH2:13][CH2:14][N:10]4[N:9]=3)[CH:16]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=S(=O)(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1)c1cccc(F)c1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (prepared as described in Example 1) (30 mg, 0.102 mmol) was dissolved in dry DCM (1 mL). At room temperature 3-fluorobenzensulfonylchloride (0.014 mL, 0.107 mmol, 1.05 eq) was added followed by NMM (0.012 mL, 0.107 mmol, 1.05 eq) and the mixture was stirred for 1 hour. It was then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/MeOH 96:4) to give 27 mg of 3-fluoro-N-[3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-benzenesulfonamide.