Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH3:20]/[C:21](/[CH2:28][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(/C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-(1-methylpropoxy)phenol (0.84 g, 5.06 mmol) and potassium carbonate (0.66 g, 0.48 mmol) in 10 ml of dimethylformamide (DMF) at 5° is added ethyl 4-bromo-3-methyl-2-butenoate (1.0 g, 0.48 mmol). The mixture is allowed to warm to RT and is stirred at RT for 20 hours. The reaction mixture is poured into water and extracted with ether. The organic layer is washed with 10% sodium hydroxide to remove any starting phenol, dried and the solvent removed. The product is purified by preparative thin layer chromatography (prep. TLC). The second main band is collected to give ethyl (Z)-3-methyl-4-[4-(1-methylpropoxy)phenoxyl]-2-butenoate, MS m/e 292 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])C.C([CH2:33][C:34](=[NH:36])[S-])C1C=CC=CC=1.Br>N1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:5])=[N:36][C:34]([CH3:33])=[N:11][C:10]=23)=[CH:13][CH:14]=1
Reactant: N=C([S-])CCc1ccccc1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Agent: Br
Solvent: c1ccncc1
Product: Cc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (21.4 g, 57 mmol) and benzylthioacetimidate.HBr (12.6 g, 51 mmol) in pyridine was heated at 115° C. (see Yuan et al., Bioorg. & Med. Chem. Lett., 12, 2133–2136 (2002)). Additional benzylthioacetimidate.HBr (12.6 g) was added after 0.5 h and 1.5 h. The reaction mixture was stirred for an additional 1 h at 115° C. After cooling to room temperature, a yellow solid precipitated out of solution. The reaction mixture was poured over ice water and acidified with conc. HCl (210 ml). Additional ice was added to keep the reaction mixture cool. The yellow solid was collected by filtration and washed with H2O to give the desired product, I-4A-1a (24 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.[CH3:21][N:22]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([Sn](C)(C)C)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3S(C2C=CC=CC=2)(=O)=O)=[O:29])=[N:23]1.C1(S)C=CC=CC=1>CN(C=O)C>[CH3:21][N:22]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][C:9]([CH3:11])=[CH:10][C:3]=34)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)=[O:29])=[N:23]1
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Reactant: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3cc(NC(=O)c4nn(C)cc4C)c4cn[nH]c4c3)ccnc2[nH]1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (63 mg) in DMF (0.4 ml) was added to 1,4-dimethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-3-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18 SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 2 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 8 mg.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]1([CH3:22])[CH3:21]>>[CH3:21][C:16]1([CH3:22])[C:17](=[O:20])[CH2:18][CH2:19][CH:15]1[NH:14][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: CC1(C)C(=O)CCC1N
Reactant: NC(=O)c1cnn2cccc2c1Cl
Product: CC1(C)C(=O)CCC1Nc1c(C(N)=O)cnn2cccc12
Yield: 18.5 %

Procedure:
According to the procedure described in Example 1, 4-chloropyrrolo[1,2-b]-pyridazine-3-carboxamide (100 mg, 0.511 mmol, from Preparation 3) was reacted crude 3-amino-2,2-dimethylcyclopentanone (195 mg, from Step 2). Purification with reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 30 to 100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave the title compound (27 mg, 18% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (1 H, s), 7.50-7.70 (1 H, m), 6.86-7.37 (1 H, m), 6.47-6.90 (1 H, m), 4.49-4.78 (1 H, m), 2.18-2.70 (3 H, m), 1.75-2.26 (1 H, m), 1.03-1.17 (6 H, m); MS (ES+) m/z: 287.2 (M+H); HPLC retention time: 2.487 min (analytical HPLC Method A).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([OH:13])=[O:12])[NH:6][C:5]1=[O:14])=[N+:2]=[N-:3].[C:15]1([C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[C:15]1([CH:21]([O:12][C:11](=[O:13])[CH2:10][O:9][CH2:8][C@H:7]2[NH:6][C:5](=[O:14])[C@H:4]2[N:1]=[N+:2]=[N-:3])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)O
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of (±)-(cis)-[(3-azido-2-oxo-4-azetidinyl)methoxy]acetic acid (0.880 g, 4.42 mmole) was treated with a solution of diphenyl diazomethane (858 mg, 4.42 mmole) in acetone (12 ml). The reaction was stirred at room temperature for nineteen hours and then combined with another run (621 mg acid, 3.12 mmole). The solvent was removed in vacuo and ethyl acetate was added and evaporated. The residue was dissolved in ethyl acetate (70 ml), dried (sodium sulfate), filtered, and concentrated to 2.6 g of a heavy yellow-red oil. The crude product was chromatographed on silica gel (230-400 mesh, 100 g) with 50% hexane-ethyl acetate. Concentration of the appropriate fractions and removal of solvents produced a heavy oil which was triturated with ether to produce a white solid which was filtered and dried to yield 1.34 g of the title compound. An additional 463 mg was obtained from the mother liquor. The total yield was 1.804 g.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].CCOC(C)=O.[ClH:25]>C(O)(=O)C.Cl[Cu]>[Cl:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a mixture of 3-amino-4-(methoxycarbonyl)benzoic acid (781 mg, 4.0 mmol) suspended in acetic acid (10 mL) and conc. HCl (10 mL) was added aq. NaNO2 (276 mg, 4.0 mmol, 5 mL) at 0° C. The resulting mixture was stirred for 30 minutes. CuCl (400 mg, 8.0 mmol) in 10 mL of conc. HCl. was added to the mixture at 0° C. The resulting mixture was stirred at 30° C. for 6 hours. Followed a standard aqueous/EtOAc workup procedure (800 mg, yield 93%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([N:39]1[CH2:44][C@H:43]([CH3:45])[NH:42][C@H:41]([CH3:46])[CH2:40]1)=[N:34]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[C@H:43]([CH3:45])[CH2:44][N:39]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[CH:38][C:29]=4[Cl:28])[N:34]=3)[CH2:40][C@@H:41]2[CH3:46])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([NH2:18])[N:15]=[CH:14][N:13]3[CH:19]=2)[CH:7]=[CH:8][CH:9]=1.[N:20]1([C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:34])[C:30]=2[C:31](O)=[O:32])=[O:25])[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:20]1([C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:34])[C:30]=2[C:31]([NH:18][C:16]2[CH:17]=[CH:12][N:13]3[CH:19]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:2][F:1])[CH:5]=4)[N:11]=[C:14]3[N:15]=2)=[O:32])=[O:25])[CH2:21][CH2:22][CH2:23]1
Reactant: Nc1cc2nc(-c3cccc(OCF)c3)cn2cn1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(OCF)c3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-Fluoromethoxy-phenyl)-imidazo[1,2-c]pyrimidin-7-ylamine (100 mg, 0.387 μmol) was combined with EtOAc (2.0 ml) to give a light yellow suspension. 4-(Azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (97 mg, 465 μmol) and DIPEA (300 mg, 406 μl, 2.32 mmol) were added. The reaction mixture was cooled down to 0° C. and n-propylphosphonic acid anhydride, cyclic trimer (616 mg, 582 μl, 968 μmol) was added drop by drop. After stirring at 0° C. for 30 min the reaction mixture was allowed to warm-up and stirred at RT overnight. The reaction mixture was then diluted with and 10% NaHCO3 aq. solution and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated under vacuum. The crude product was purified by flash chromatography (10 g SiO2; eluent: CH2Cl2 to CH2Cl2/MeOH/NH3 140:10:1). The obtain material was dissolved in CH2Cl2 and the product was precipitated with Et2O, filtered off, washed with Et2O, and dried overnight at HV. Yellow solid (89 mg, 47%). MS (m/z)=450.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:20][CH2:21][CH2:22]Cl)[CH2:18][CH3:19].O>CN(C)C=O>[CH2:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: CCCOCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (3.04 g) and anhydrous potassium carbonate (5.52 g) in N,N-dimethylformamide (20 ml) was added 2-propyloxyethyl chloride (2.94 g), and the mixture was stirred at room temperature overnight, and then stirred at 80° C. for 8 hours. To a reaction solution was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (5.21 g; crude).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH:33]4[CH2:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NC1Cc2ccccc2C1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.96 (M+H+); retention time=0.98 minutes.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1>>[F:25][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][C:15]([OH:26])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCSc1ncccc1CCl
Reactant: COC(=O)CCc1ccc(O)c(F)c1
Product: CCCSc1ncccc1COc1ccc(CCC(=O)O)cc1F
Yield: 72.5 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.030 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.038 g, 73%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ncc(C(F)(F)F)cc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To butyl lithium (7.2 ml, 1.6M in hexanes, 11.5 mmol) in tetrahydrofuran (12.0 ml) at −78° C. was slowly added diisopropylamine (1.14 g, 11.3 mmol) in tetrahydrofuran (4.0 ml), and the resulting solution allowed to warm to 0° C. over 45 mins. A mixture of 2-methoxy-5-trifluoromethylpyridine (2.00 g, 11.3 mmol) and trimethylsilyl chloride (3.2 ml, 25.2 mmol) in tetrahydrofuran (8.0 ml) was then slowly added and the mixture stirred for 30 mins. at 0° C., before being quenched with water (50 ml). The mixture formed was extracted with ethyl acetate (2×70 ml), and the extracts washed with brine (50 ml), dried (Na2SO4) and concentrated to give the product as an orange oil (1.36 g, 48% yield).
Reaction SMILES: C(O)CC.Cl[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>O>[N:18]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: N#Cc1ccc(OCCCCl)cc1
Reactant: c1c[nH]cn1
Solvent: CCCO
Solvent: O
Product: N#Cc1ccc(OCCCn2ccnc2)cc1
Yield: 82.3 %

Procedure:
To 30 ml of n-propanol, there were added 2.695 g of 4-(3-chloropropoxy)benzonitrile and 10.21 g of imidazole and the resulting mixture was heated under reflux for 24 hours. After concentration of the reaction mixture, water was added to the residue obtained, followed by extraction with chloroform, washing of the resulting extract with water and then drying the same. After concentration of the extract, the residue obtained was recrystallized from a mixture of ether and n-hexane, followed by addition of n-hexane, filtration and drying to give 2.575 g (yield 75.3%) of 4-[3-(1H-imidazolyl)propoxy]benzonitrile having a melting point of 60.0°-61.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[NH2:38]>>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47]
Reactant: CN(C)CCOc1ccc(N)cc1Cl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CN(C)CCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-chloro-4-{[2-(dimethylamino)ethyl]oxy}aniline in a manner analogous to Example 125. 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.53 (s, 1H), 8.84 (d, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.58 (m, 1H), 7.53-7.44 (m, 3H), 7.34 (d, 1H), 7.24 (m, 2H), 7.12 (m, 1H), 7.05 (d, 1H), 4.08 (m, 2H), 2.66 (m, 2H), 2.25 (s, 6H); HRMS: calc. C34H29N7O2F2Cl (M+H)+ 640.2039 found 640.2047.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO>[NH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: NN
Solvent: CO
Product: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To a suspension of 2-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]-1H-isoindole-1,3(2H)-dione (20.0 g, 44.0 mmol) in methanol (400 mL) was added hydrazine (8.00 mL). The mixture was stirred at ambient temperature for 48 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with ethyl acetate/methanol/ammonia (10/1/0.2) to afford the crude product which was recrystallized from ethyl acetate to yield the title compound (8.0 g) in 56% yield as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 1H), 7.17 (dd, 1H), 7.06 (dd, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 5.89-5.82- (ABq, 2H), 4.93 (d, 1H), 4.66 (d, 1H), 3.95-3.74- (m, 2H), 3.06 (t, 2H), 1.59-1.35- (br, 2H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.9, 148.8, 142.3, 132.4, 128.9, 124.0, 123.4, 119.5, 108.6, 103.1, 101.5, 93.6, 80.5, 58.2, 43.4, 39.8; MS (ES+) m/z 325 (M+1), 308 (M−16).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]/[CH2:43][C:44]([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])([CH3:46])[CH3:45].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]/[CH2:43][C:44]([O:47][Si:48]([CH2:49][CH3:50])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:45])[CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 99 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (211 mg, 0.719 mmol), sodium hydride (60% in oil, 43 mg, 1.08 mmol), 15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 6 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (140 mg, 99%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:44])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[C:39][Si](C)(C)C)[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.Cl.[OH:46]C1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[C:38]([C:34]1[CH:33]=[C:32]([N:5]2[C:4](=[O:44])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=[C:6]2[CH:12]([NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][NH:19]3)[CH3:13])[CH:37]=[CH:36][CH:35]=1)(=[O:46])[CH3:39]
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 139 was treated with 4N HCl in MeOH at 70° C. for 16 hours in accordance with the procedure described for compound 121 (step D). This reaction afforded compound 144, the structure of which is shown below. m/z=440 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: COCCc1ccc(Cl)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-chloro-5-(2-methoxyethyl)phenyl]methanol from the previous step (I eq.) in CH2Cl2 (0.4 M) was added Dess-Martin periodinane (1.2 eq.) portionwise. The resulting suspension was stirred at RT for 2 h. The reaction was quenched with sat. aq. NaHCO3 and sat. aq. NaHSO3. The biphasic mixture was allowed to stir at RT for 20 min before it was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a colorless oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→9:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.