Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: Cc1nc(NC(=O)c2cc(F)ccc2F)sc1C(=O)NCc1ccccc1
Yield: 86 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,5-difluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 86% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.63 (t, J=5.8 Hz, 1H), 7.60-7.17 (m, 8H), 4.36 (d, J=5.8 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 388.2 (M+1).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.[N:41]1([S:46](Cl)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:46]([N:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)(=[O:48])=[O:47])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)N6CCCC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.12 g, 0.28 mmol), DIEA (0.48 mL, 2.8 mmol) in DMA (2.75 mL). Pyrrolidine-1-sulfonyl chloride (0.07 g, 0.41 mmol, Matrix) was added dropwise and reaction mixture was stirred at ambient temperature for about 1 h. K2CO3 (0.190 g, 1.37 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide, which was dissolved in NaOH (1 N aqueous, 1.10 mL, 1.10 mmol) and 1,4-dioxane (1 mL) and heated at about 50° C. for about 1 h. The crude material was purified by preparative reverse phase HPLC (Table 2, Method 1) to give N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide (0.042 g, 37%) as a white solid: LC/MS (Table 1, Method a) Rt=1.81 min; MS m/z 416 (M+H)+.
Reaction SMILES: [Na].[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH4:21]>CO>[CH2:15]([O:13][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH2:21][CH2:4][CH2:3][CH2:2][CH2:11][CH3:10])[CH:7]=2)[CH:2]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CCCCCCBr
Agent: [Na]
Solvent: CO
Product: CCCCCCOc1ccc2cc(OCCCCCC)ccc2c1

Procedure:
A solution of sodium (3.04 g, 132 mmol) in dry methanol (60 ml) was refluxed for 30 minutes and cooled. A solution of 2,6-naphthalenediol (9.0 g, 56.2 mmol) in dry methanol (40 ml) was added and the mixture refluxed for 30 minutes and cooled. 1-Bromohexane (17.5 ml, 125 mmol) was added and the reaction mixture was refluxed under an argon atmosphere for 19 h. The solvent was evaporated and ether (250 ml) was added. It was washed with aqueous sodium hydroxide solution (10%, 100 ml) and water (2×100 ml) to yield a dark brown solution. After refluxing with activated charcoal for 30 min and filtration, the solution was evaporated to yield an oil which was recrystallised from methanol (250 ml). The fine white platelets were collected at the pump and washed with a little cold methanol to give (12) (8.33 g). A recrystallisation gave more product (0.67 g, 49% total yield), m.p. 78.0°-79.0° C., Rf 0.83 (dichloromethane), (Found: C, 80.7; H, 10.0; M+, 328.2404) C22H32O2 requires C, 80.4; H, 9.8; M, 328.2404); vmax (KBr)/cm-1 3050 w, 2900 s, 2840 s, 1590 s, 1495 m, 1455 m, 1385 s, 1375 (s), 1225 s, 1165 s, 1110 s, 1070 s, 1045 s, 995 s, 965 s, 850 s; 1HNMR (400 MHz; CDCl3) δ0.93 (6H, t, J=6.8 Hz, --CH3), 1.42-1.32 (8H, m, alkyl), 1.50 (4H, qn, J=7.3 Hz, OC2H4 --CH2), 1.84 (4H, qn, J=7.1 Hz, ArOCH2 --CH2), 4.04 (4H, t, J=6.6 Hz, O--CH2), 7.09 (2H, d, J=2.1 Hz Ar1,5 --H), 7.13 (2H, dd, J=8.8 Hz, 2.2, Ar3,7 --H), 7.62 (2H, d, J=8.9 Hz, Ar4,8 --H); δC (100 MHz; CDCl3) 14.1, 22.6, 25.8, 29.3, 31.6, 68.0, 106.9, 119.2, 128.0, 129.7, 155.5; m/z (EI) : 328 (M, 16%), 244 (13,M--C6H12), 160 (100,M-2C6H12), 131 (21), 55 (21).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12]#[N:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=[O:22])[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[O:1][C:20]=1[C:19]([C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=1)=[O:22])[O:9][CH2:8][CH2:7][CH2:6]3
Reactant: N#Cc1cc2c(cc1O)OCCC2
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)c2oc3cc4c(cc3c2N)CCCO4)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a stirred solution of 7-Hydroxy-chroman-6-carbonitrile from method II-3 (30 mg, 0.17 mmol) and 3-methoxyphenacyl bromide (78.5 mg, 0.34 mmol, 2.0 eq) in anhydrous N,N-dimethylformamide (1.0 mL) was added potassium carbonate (47.3 mg, 0.34 mmol, 2.0 eq), and the orange reaction mixture was stirred at 100° C. for 17 h. The resulting dark wine colored reaction was poured into ethyl acetate (10 mL) and water (10 mL). This mixture was then extracted with EtOAc (2×10 mL). The combined organic layers were then dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by pre-HPLC to afford the desired product as a yellow solid (30.7 mg, 54.9%). 1H-NMR (CD3CN) δ 7.73 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.44 (t, 1H), 7.34 (dd, J=2.8, 8.5 Hz, 1H), 6.80 (s, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 2.93 (t, 2H), 2.03 (m, 2H); MS LC-MS (MH+=324).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Li+].[CH3:19]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][S:9]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[CH2:34][C:25]4([CH2:33][C:27]5([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH2:26]4)[O:24][C:21]3=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH:5]([O:4][C:2]([N:30]1[CH2:31][CH2:32][C:27]2([CH2:26][C:25]3([O:24][C:21]4=[CH:22][N:23]=[C:18]([C:15]5[CH2:16][CH2:17][N:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:13][CH:14]=5)[CH:19]=[C:20]4[CH2:34]3)[CH2:33]2)[CH2:28][CH2:29]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.15 mL) is added to a mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), triethylamine (40 μL), and dichloromethane (5 mL) at room temperature. The solution is stirred for 3 h and then concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:4) to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34].[CH3:35][N:36]1CCNC[CH2:37]1.ON1C2C=CC=CC=2N=N1.Cl.[CH2:53]([N:55]=[C:56]=N)[CH3:54].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[C:25]([C:28]([N:55]5[CH2:53][CH2:54][N:36]([CH3:37])[CH2:35][CH2:56]5)=[O:29])=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH3:33])=[C:3]1[CH3:34]
Reactant: CCN=C=N
Reactant: CN1CCNCC1
Reactant: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)O)n4Cc4ccccc43)cc2C)CCCC1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)N5CCN(C)CC5)n4Cc4ccccc43)cc2C)CCCC1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
10-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-benzoyl]-10,11-dihydro-5H pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (0.200 g, 0.438 mmol) of Step A, N-methylpiperazine (0.058 mL, 0.526 mmol), 1-hydroxy benzotriazole (0.065 g, 0.482 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.482 mmol) were combined in amine-free N,N-dimethylformamide (1.8 mL), followed by addition of N,N-diisopropylethyl amine (0.114 mL, 0.657 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel using a solvent gradient from 0 to 8% of methanol in chloroform to afford 0.180 g of the title compound as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH2:3]1.Cl[C:21]([O:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>C1COCC1.C(Cl)Cl>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:21]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: O=C(Cl)OC1CCCC1
Reactant: c1cc2c(ncc3cnc([C@@H]4CCCNC4)n32)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC1CCCC1)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
To a solution of (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.06 g, 0.19 mmol) in THF (1 mL) was added TEA (0.08 mL, 0.57 mmol) and the reaction was stirred at ambient temperature for about 10 min. To the reaction mixture was added cyclopentyl chloroformate (0.02 mL, 0.15 mmol, Waterstone) and the mixture was stirred at about 45° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude material was dissolved in DCM (5 mL) and washed with water (5 mL). The organic layer was separated and the aqueous layer was back extracted with DCM (2 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-cyclopentyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (0.015 g, 21%): LC/MS (Table 1, Method b) Rt=1.87 min; MS m/z: 354 (M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:19][C:11](=[O:18])[C:12]([CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:21]
Reactant: ICCSc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)OCC
Temperature: 52 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A mixture of 2-iodoethylphenyl sulfide (19.81 g, 75 mmol), diethyl malonate (4.80 g, 30 mmol), potassium carbonate (10.35 g, 75 mmol) and DMF (40 mL) was heated at 52° C. for 18 hours. More potassium carbonate (10 g) was added and the reaction was continued at 52° C. for another 8 hours. The reaction mixture was cooled, diluted with ice water and the product extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid diethyl ester (5.648 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[C:17]([CH3:30])[CH:16]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:4]3[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[C:17]([CH3:30])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 11A and 706 mg (2.56 mmol) of the compound from Example 83A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 616 mg (56% of theory) of the target compound were obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CNCCC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoro-quinoline, prepared as described in Application Example 1, and 3 g of N-methyl-N-(b-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)[C:4]=2[CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:12]=[C:13]([N:28]4[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]4)[CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Yield: 66.3 %

Procedure:
A solution of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (100 mg, 0.40 mmol) and 1-N-Boc-piperazine (380 mg, 2.0 mmol) in dimethyl sulfoxide (3.0 mL) was heated at 95° C. 4 h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane 25% EtOAc) to give the desired product 110 mg 66% yield. MS (ESI) m/z: 415.1 [M+H]+
Reaction SMILES: [C:1]([O:9][C:10]1[CH:20]=[CH:19][C:13]([CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([NH2:39])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]([OH:18])[C:15](=[O:17])[NH:39][CH:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)CCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Oc1ccc(C(O)C(=O)O)cc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(CCc1ccc(OCc2ccccc2)cc1)NC(=O)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
As pointed out above, a preferred embodiment of this invention employs a mixture of all four optical isomers of the compound of Example 7. This racemic mixture can be prepared by the method described above by reaction of dl-4-(benzoyloxy)mandelic acid with dl-1-methyl-3-(4-benzyloxyphenyl)propylamine in the presence of DCC to give racemic 1-(4-benzyloxyphenyl)-2-oxo-2-[1-methyl-3-(4-benzyloxyphenyl)propylamino]ethanol. Reduction of the latter compound and subsequent removal of the benzyl groups provides racemic 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]-ethanol. This compound is more preferably prepared by the following procedure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[C:9](=O)(ON1C(=O)CCC1=O)[O:10]N1C(=O)CCC1=O.C(N(CC)CC)C.[CH:34]1([NH:37][C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C@@H:54]4[CH2:58][CH2:57][CH2:56][NH:55]4)=[O:53])[S:49][CH:50]=3)=[CH:42][CH:41]=2)=[O:39])[CH2:36][CH2:35]1>CC#N.C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([N:55]2[CH2:56][CH2:57][CH2:58][CH:54]2[C:52](=[O:53])[NH:51][C:48]2[S:49][CH:50]=[C:46]([C:43]3[CH:44]=[CH:45][C:40]([C:38](=[O:39])[NH:37][CH:34]4[CH2:35][CH2:36]4)=[CH:41][CH:42]=3)[N:47]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OCc1ccncc1
Reactant: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccncc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine-4-yl-methanol (400 mg, 3.66 mmol) was dissolved in 12 mL of dry CH3CN. To this solution was added disuccinimidyl carbonate (3.66 mmol, 940 mg) followed by triethylamine (11 mmol, 1.5 mL). This solution was stirred at room temperature for 2 hours and the evaporated. The residue was redissloved in 10 mL of CH2Cl2. To this solution was added 150 mg (0.42 mmol) of pyrrolidine-2-carboxylic acid [4-(4-cyclopropyl carbamoyl-phenyl)-thiazol-2-yl]-amide (General Procedure 3I), followed by triethylamine (5.5 mmol, 0.75 mL), and DMAP (30 mg). Reaction mixture was stirred at room temperature overnight. It was evaporated to dryness, redissolved in 10 mL of DMF and purified using reverse phase HPLC. MS: 492.1(M+H+); H1 NMR (DMSO-d6): δ(ppm) 12.6 (d, 1H), 8.84 (d, 2H), 8.51 (s, 1H), 7.91 (m, 6H), 5.42 (m, 2H), 4.60 (m, 1H), 3.58 (m, 1H), 2.83 (m, 2H), 2.33 (m, 1H), 1.99 (m, 4H), 0.60 (dd, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)cnn1C
Yield: 30 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chlorophenyl isocyanate in a similar manner as described in Example 1.53, providing 12 mg (30%) of Compound 26: LCMS m/z (%)=393 (M+H37Cl, 60), 391 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.80 (s, 1H), 8.71 (s, 1H), 7.62 (s, 1H), 7.57 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.49 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.39 (d, J=4 Hz, 1H), 7.33 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.17 (d, J=8 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6]([CH3:8])C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:34]1[C@@H:36]2[CH2:37][C@H:38]([C:55]3[CH:59]=[CH:58][O:57][CH:56]=3)[C@:39]3([CH2:41][CH2:42][C@H:43]4[C@H:52]([C@@:35]123)[CH2:51][CH2:50][C@H:49]1[C@:44]4([CH3:54])[CH2:45][CH2:46][C@@H:47](O)[CH2:48]1)[CH3:40].[S:60]1C=CC=C1CC(O)=O>O1CCCC1>[C:6]([S:60][C@H:47]1[CH2:46][CH2:45][C@@:44]2([CH3:54])[C@H:49]([CH2:50][CH2:51][C@@H:52]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@:35]43[O:34][C@@H:36]4[CH2:37][C@@H:38]2[C:55]2[CH:59]=[CH:58][O:57][CH:56]=2)[CH2:48]1)(=[O:5])[CH3:8]
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)C[C@H]4O[C@]342)C1

Procedure:
Diisopropyl azodicarboxylate (3.5 ml) was added to a solution of 4.5 g of triphenylphosphine in 85 ml of tetrahydrofuran at 0° C. and the mixture was stirred for 30'. To this mixture a solution of 2.0 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3α-ol and 2.05 ml of thiolacetic acid in 90 ml of tetrahydrofuran was added dropwise and the resulting mixture was stirred for an hr at room temperature. The solvent was evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 95/5 as eluant to give 1.7 g of the title compound (VI-b) as a white solid.