Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 63 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-chlorosalicylaldehyde (4.00 g) in N,N-dimethylformamide (40 mL) under nitrogen was added sodium hydride in portions (0.64 g). To the resulting reddish solution was added a solution of 1-fluoro-2-nitrobenzene (3.50 g) in N,N-dimethylformamide (10 mL) in one lot. The reaction was then stirred at 63° C. under nitrogen for 24 hours. The reaction was evaporated under vacuum, and the residue was partitioned between chloroform and 1 N NaOH. The layers were separated, and the aqueous layer was extracted once more with chloroform. The combined chloroform extracts were washed with 1 N NaOH, water, 1 N HCl, water, and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue was crystallized from cyclohexane to yield the title compound as a light yellow solid. Mp: 103°-105° C.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][NH:22][CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][N:22]([CH:27]2[CH2:28][O:25][CH2:26]2)[CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC1
Reactant: O=C(OCc1ccccc1)N1CCNCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(C2COC2)CC12CC2
Reaction time: 68 h

Procedure:
A mixture of 4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester oxalate (200 mg, 0.59 mmol), oxetan-3-one (50 mg, 0.69 mmol), NEt3 (82 μL, 0.59 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at r.t. for 2 h before the addition of sodium triacetoxyborohydride (164 mg, 0.78 mmol). The resulting mixture was stirred for 68 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound. LCMS (method H): RT 2.01 min, [M+H]+ 303.3
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[N:20]([CH:22]=[CH:23][N:24]=4)[CH:21]=3)=[CH:13][N:14]=2)[N:11]=1.[F-].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[N:24]1[CH:23]=[CH:22][N:20]2[CH:21]=[C:16]([CH2:15][C:12]3[N:10]4[N:11]=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=12
Reactant: NCCO
Reactant: Clc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OCCNc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
Ethanolamine (277 μL, 4.55 mmol) was added to a solution of (6-Chloro-3-imidazo[1,2-a]pyridin-6-ylmethyl-imidazo[1,2-b]pyridazine (Example 74, 65 mg, 0.228 mmol) and KF (67 mg, 1.138 mmol) in NMP (1.5 mL). The RM was stirred at 180° C. for 2 h. The mixture was diluted with EtOAc and washed with 1 M Na2CO3 (1×) and water (3×). The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The aqueous phase was further extracted with DCM (4×). The organic layer was then dried over Na2SO4, filtered and concentrated. The combined residues were purified by preparative LCMS to afford the title compound as a yellow oil (tR 2.62 min (conditions 4), MH+=309.1, 1H-NMR in DMSO-d6: 8.84 (s, 1H); 8.28 (d, 1H); 8.16 (d, 1H); 7.95 (m, 3H); 7.86 (s, 1H); 7.72 (m, 1H); 7.16 (d, 1H); 4.40 (s, 2H); 3.52 (t, 2H); 3.32 (m, 2H)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:41][CH2:42]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:35]=[O:36])[N:7]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1

Procedure:
A solution of 6-bromo-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (15.1 mmol) in 100 mL of dry THF is added dropwise to a solution of n-butyl lithium (15.5 mmol) in 20 mL of tetrahydrofuran (THF) at −78° C. under N2 over 12 minutes. After 10 minutes the reaction mixture is treated with dimethylformamide (7.5 mL) in THF (15 mL), and quenched after 15 minutes with aqueous 10% HCl. The product is extracted into cold chloroform which is washed with saturated sodium chloride solution, filtered, and the solvent is evaporated. The residue is triturated with CH3CN, filtered, and recrystallized from ethyl acetate to provide the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=O)=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=[N:34][OH:35])=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=NO)c1ccccc1C
Yield: 47.3 %

Procedure:
A mixture of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (0.49 g), hydroxylamine hydrochloride (0.1 g) and pyridine (0.1 g) in ethanol (10 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×50 mL) and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and filtered and the solvent is removed in vacuo, to give a yellow oil. Flash chromatography on silica gel, eluting with a mixture of petroleum ether (b.p.40-60° C.) and ethyl acetate (7:1 v/v), gives ethyl (RS)-4-(5-benzyloxy-2-hydroxyiminomethylphenoxy)-4-(2-methylphenyl)butanoate (E:Z ratio 4:1), (0.24 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]([CH3:37])([OH:36])[CH2:32][CH2:33][CH2:34][OH:35]>>[CH3:37][C:31]([OH:36])([CH2:30][NH:29][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH2:32][CH2:33][CH2:34][OH:35]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(O)(CN)CCCO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(O)CCCO)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 5-amino-4-methylpentane-1,4-diol were reacted to give 410. [M+H]+ 495.6
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19].O>CN(C=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2]2[S:19][C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2s1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,5-difluorobenzaldehyde (217.28 μL, 2 mmol) and potassium carbonate (595.53 mg, 2.5 mmol) in DMF (3 mL) was added ethyl thioglycolate (219.30 μL, 2 mmol) dropwise with ice cooling.7 The mixture was stirred at room temperature for 30 min and at 60° C. for 12 h, poured into water, and extracted with EtOAc. The extract was washed with water, dried, and concentrated, and the residue was suspended in EtOH and collected by filtration gave 8 as crystals; (271.34 mg, 60.5%). 1H-NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.83-7.78 (m, 1H), 7.55-7.51 (m, 1H), 7.26-7.19 (m, 1H), 4.46-4.39 (q, 2H), 1.46-1.41 (t, 3H). 13C NMR (300 MHz, CDCl3): δ 162.47, 159.25, 139.63, 137.60, 136.29, 129.75, 124.11, 116.24, 110.65, 61.74, 14.29.
Reaction SMILES: [C:1]([O:8]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].B1C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:28]1[CH:33]=[C:32]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=1>C1COCC1.CN(C=O)C>[NH2:34][C:32]1[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=[C:28]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:33]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C=CCCCC(=O)OC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc(CCCCCC(=O)O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of methyl hex-5-enoate (12 mg, 0.1 mmol) in THF (0.5 ml) under argon at 0° C. was added 9-BBN (0.2 mmol, 0.4 ml of 0.5 M solution in THF). The mixture was warmed to room temperature and stirred for 16 h. Potassium phosphate (3 M in H2O, 0.2 mmol) was added followed by the addition of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmol) in DMF (0.5 ml) and Pd(dppf) Cl2—CH2Cl2 (5 mg, 0.005 mmol). The reaction mixture was heated at 90° C. for 16 h under argon. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 2:1 THF:MeOH (3 mL) and was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 4 hours followed by the addition of 2N hydrochloride solution (1.0 ml). The solution was heated at 65° C. for 2 h, cooled to room temperature, concentrated and purified by prep-LC to afford the title compound (8.2 mg): LC/MS RT=2.74 min. Mass calculated for, M+H 376.17, observed 376.17.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[NH4+].[OH-]>CCCCCC.CCOCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Brc1ccccn1
Reactant: COc1ccc(C=O)cc1OC
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccn2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 187.5 ml of 1.6 M solution of butyllithium in hexane was cooled to -40° under nitrogen and 39.5 g (0.25 M) of 2-bromopyridine in 100 ml of ether added dropwise. The mixture was stirred 15 minutes at -40° and a solution of 41.5 g (0.25 M) of 3,4-dimethoxybenzaldehyde in 200 ml of ether added. After stirring at -15° for 45 minutes, the mixture was poured into 500 g ice/100 ml conc. HCl. The separated aqueous layer was made alkaline with conc. NH4OH, extracted with methylene chloride and the dried extract concentrated. The residual oil crystallized from benzene/hexane to give 3,4-dimethoxyphenyl-2-pyridyl carbinol, mp 92°-94°.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[CH2:36][NH2:37].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[CH:20]=[C:15]4[C:14]([CH2:21][N:37]([CH2:36][C:29]5[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=5[O:27][CH3:26])[C:16]4=[O:17])=[CH:13][C:12]=3[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(C)c(Cc4ccc(-n5cccn5)cc4)cc3C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 460.8 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.30 g), (2,4-dimethoxyphenyl)methanamine (0.02 g) and anhydrous magnesium sulfate (0.21 g) in THF (6.00 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (6.00 mL) and THF (6.00 mL), sodium triacetoxyborohydride (0.38 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.25 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:16][C:17](=[O:18])[C:12]3=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]2)=[C:4]([Cl:31])[CH:3]=1.C([Mg]Cl)(C)C.CN([CH:40]=[O:41])C>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:40]=[O:41])[CH:3]=[C:4]([Cl:31])[C:5]=1[N:9]1[C:13]2=[N:14][C:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]1
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Br)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(C=O)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO4), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469(M−H)−.
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C:17]([O-:19])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[Na+].O>CS(C)=O>[CH3:4][CH2:5][C@H:6]([C:17]([O:19][CH2:1][CH3:2])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1
Reactant: CCBr
Reactant: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H](CC)[C@H](CO)Cc1cncn1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
9.80 mmoles of ethylbromide (1068 mg) were added dropwise within about an hour to a solution containing 9.80 mmoles (2432 mg) of pilocarpic acid sodium salt in 60 ml of dimethyl sulfoxide. The solution was stirred at room temperature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two portions of each 150 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 150 ml of distilled water, with 150 ml of 2% sodium bicarbonate solution and with 150 ml of distilled water. The ethyl acetate extracts were dried on calcium sulfate (30 min) and the ethyl acetate evaporated under reduced pressure, and the pilocarpic acid ethyl ester obtained was crystallized from a chloroform/ petroleum ether-mixture, whereby 448 mg (1.76 mmoles) of the ester were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=O)[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[Cl:31]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:31][C:17]1[C:16](=[O:30])[CH2:15][CH2:14][C:13]2[C:18]=1[CH2:19][CH2:20][C@@H:21]1[C:12]=2[C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:9]=2)[CH2:28][C@@:26]2([CH3:27])[C@H:22]1[CH2:23][CH2:24][CH2:25]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]12C[C@H](c3ccc(CCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC3=C(Cl)C(=O)CCC3=C1[C@@H](c1ccc(CCCO)cc1)C2
Yield: 74.7 %

Procedure:
To a solution of 11.9 g of 11β-[4-(3-hydroxypropyl)phenyl]-estra-4.9-diene -3,17-dione prepared to preparation 1 in 100 ml of DMF, under inert atmosphere and at 60° C., 4.93 g of N-chloro succinimide is added and stirred for 10 mn at this temperature. It is poured into water, drawn off, washed, dried, evaporated under reduced pressure until 16.2 g of raw expected product is obtained that is purified by chromatography by eluting with the compound CH2Cl2/Acetone 85/15. 9.34 g of pure expected product is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[N:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[CH:21]2)=[C:14]=[S:15]>C(O)C>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:14](=[S:15])[NH:13][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[CH:21]2
Reactant: OCCC1Cc2ccccc2N1
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3c4ccccc4CC3CCO)cccc2cn1
Reaction time: 24 h
Yield: 54 %

Procedure:
2-(2-Hydroxyethyl)indoline (43 g) and 5-isothiocyanato-3-methylisoquinoline (52 g) are dissolved in ethanol (800 cc). The solution, which is kept for 24 hours at a temperature of about 20° C., deposits a solid which is isolated by filtration, washed with ethanol (3×50 cc) and dried. (RS)-2-(2-Hydroxyethyl)-N-(3-methylisoquinol-5-yl)indoline-1-carbothioamide (51 g), a white solid, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:38](O)=[O:39])[CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[NH2:41][C@H:42]([CH2:46][OH:47])[CH:43]([CH3:45])[CH3:44]>>[OH:47][CH2:46][C@@H:42]([NH:41][C:38]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:39])[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)c1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)[C@@H](CO)NC(=O)c1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1

Procedure:
By treating 200 mg of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic acid obtained by Example 126 and 94.5 μl L-valinol in accordance with Example 127, 102 mg of the title compound was obtained as white crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCCl)cc[n+]([O-])c1C

Procedure:
1.0 ml of thionyl chloride was gradually added to a solution of 0.92 g (5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 10 ml of chloroform under cooling with ice. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 100 ml of methyl ethyl ketone twice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvnet: chloroform/methanol=19:1) to obtain 0.56 g of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to isopropylamine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-isopropylterephthalamide. MS (Q1) 394 (M)+.