Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C([O-])(O)=O.[Na+].Cl>C1COCC1>[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:36](=[O:38])[CH3:37])[CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
A 20 mL vial was charged with 5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine dihydrochloride (80 mg, 0.159 mmol), triethylamine (0.088 mL, 0.64 mmol) and THF (2 mL). Acetic anhydride (0.015 mL, 0.16 mmol) was added and stirred at ambient temperature for 30 minutes. The reaction was poured into saturated aqueous NaHCO3 and extract with EtOAc (2×20 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (5% methanol in EtOAc) to afford the title compound (47.6 mg, 58.8% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.00 (bs, 1H), 8.23 (d, 1H), 7.44 (m, 2H), 7.40 (d, 1H), 7.21 (t, 1H), 7.11 (d, 2H), 6.70 (s, 1H), 4.41 (d, 1H), 3.12 (m, 1H), 2.83 (tt, 1H), 2.62 (td, 1H), 2.50 (m, 1H), 2.00 (s, 3H), 1.93 (m, 2H), 1.55 (qd, 1H), 1.42 (qd, 1H). Mass spectrum (apci) m/z=475.2 (M+H—HCl).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3ccccn3)ccc2n1
Reaction time: 0.08 h
Yield: 28.1 %

Procedure:
230 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 690 mg of 2-tributylstannylpyridine, 120 mg of tetrakis(triphenylphosphine)palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 5 minutes in a microwave machine set at 100° C., and then for 5 minutes at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 56 mg of N-phenyl-6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate (36C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1 L) at such a rate to maintain a gentle reflux. After the addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)[CH3:2].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[C:28](Cl)[N:27]=1>>[CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:28]3[C:29]([Cl:33])=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[N:27]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:13][CH:12]=1)[CH3:2]
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)cc1
Yield: 84.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (500 mg) described in Preparation Example 167 and 2,3,5,6-tetrachloropyridine (488 mg), the title compound (651 mg) was obtained.
Reaction SMILES: [CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[N:9]=2)([CH2:3][CH3:4])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([N+:35]#[C-:36])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([C:15]1[O:16][CH:36]=[N:35][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])[N:9]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc2ccc(C=O)nc2s1
Reactant: [C-]#[N+]C(c1ccccc1F)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)Nc1nc2ccc(-c3ocnc3-c3ccccc3F)nc2s1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 2-(sec-butylamino)thiazolo[5,4-b]pyridine-5-carbaldehyde (presumed 0.24 mmol, 1.0 eq.), 1-fluoro-2-(isocyano(tosyl)methyl)benzene (0.0874 g, 0.302 mmol, 1.3 eq.), and K2CO3 (0.0654 g, 0.473 mmol, 2.0 eq.) in EtOH (2.4 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was taken up in EtOAc and water. After separation of the layers, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give N-sec-butyl-5-(4-(2-fluorophenyl)oxazol-5-yl)thiazolo[5,4-b]pyridin-2-amine as a yellow solid (0.0264 g, 30% yield). LC/MS (MH)=369.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12][OH:13])[CH2:7][CH2:6][CH2:5]2.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[S:20]([O:13][N:12]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCc2cc(Br)ccc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
To 6-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (2.5 g, 10.41 mmol) in pyridine (5 mL) was added p-toluenesulfonyl chloride (2.184 g, 11.45 mmol) in one lot at room temperature. The reaction mixture was stirred at room temperature for 20 h. Ice cubes (˜10 g) were added to the flask and the contents stirred at room temperature for 30 min. The solid that separated out was filtered and washed with water (3×20 mL), dried over sodium sulfate and concentrated to yield 6-bromo-3,4-dihydronaphthalen-1(2H)-one O-tosyl oxime (3.92 g, 9.94 mmol, 95% yield) as light pink solid. The solid was azeotroped once with toluene (10 mL) and used for the subsequent reaction. MS M+1=395.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH2:23][NH2:24]>C(#N)C>[NH2:11][C:10]1[NH:24][N:23]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: N#CC(C(=O)c1ccc(Cl)cc1)c1ccncc1
Solvent: CC#N
Solvent: ClP(Cl)Cl
Product: Nc1[nH]nc(-c2ccc(Cl)cc2)c1-c1ccncc1
Yield: 54.3 %

Procedure:
A solution of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (3.50 g, 13.6 mmol) in 40 mL acetonitrile and phosphorous trichloride (14.2 ml, 163 mmol) was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in toluene and concentrated again. The residue was then taken up in ethanol (150 mL) and treated with anhydrous hydrazine (1.71 mL, 54.4 mmol). The reaction mixture was heated to reflux for 3 hours, cooled, and concentrated in vacuo. The residue was triturated with a mixture of ethanol and dichloromethane (1:4), and filtered. The solid was washed with the ethanol/dichloromethane mixture, and dried to give 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (2.0 g, 54%): m.p. >300° C. 1H NMR (DMSO/300 MHz) δ 8.40 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.11 (d, 2H), 5.05 (s, 2H). ESLRMS m/z 271 (M+H). ESHRMS m/z 271.0752 (M+H, C14H11N4Cl requires 271.0750).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][OH:21])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][O:21][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
Combine 1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.15 g, 0.3 mmol) and dichloromethane (5 mL). Cool in an ice bath. Add N,N,-diisopropylethylamine (0.12 mL, 86.5 mg, 0.67 mmol), and methanesulfonyl chloride (0.035 mL, 52 mg, 0.46 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with aqueous 1 M hydrochloric acid solution, water, and then a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.23 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:17]=2)=[CH:5][CH:4]=1.N>CO.C(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:20]=3)[C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Yield: 77 %

Procedure:
1-(4-Dimethylamino-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 0.93 g (77%) of the desired product as a viscous oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H39F3N3O2, 449.3; m/z found, 450.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[NH:17]1[CH2:22][CH2:21][N:20]([C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCC(=O)N1CCNCC1)OCc1ccccc1
Yield: 86.2 %

Procedure:
2.23 g of N-benzyloxycarbonyl-β-alanine was coupled with 2.58 g of piperazine. The evaporation residue was suspended in THF, the undissolved material was filtered off and the filtrate was evaporated. Chromatography of the residue on silica gel RP 18 using water/methanol (2-5%) gave 2.51 g of benzyl [2-(4-piperazinylcarbonyl)ethyl]carbamate, MS: 291 (M+).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)cc1
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
(trans)-N,N-Dibenzyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16a (1.41 g, 3.38 mmol) was dissolved in 15 mL of methanol followed by the addition of palladium/carbon (706 mg, 10%) and 0.1 mL of acetic acid, filled with hydrogen three times. The reaction mixture was reacted for 12 hours at 3 atmosphere of hydrogen, added with 3 g alkaline aluminum oxide (200-300 mesh) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (900 mg, yield: 100%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:23]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[NH:16][C:15]1=[O:24]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:21][CH2:22][C:23]4[S:14][C:15](=[O:24])[NH:16][C:17]=4[CH2:18][CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: O=c1[nH]c2c(s1)CCNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]c(=O)sc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-Bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 40 mg (49% of theory). ESI-MS: m/z=394 (M+H)+; Rt(HPLC): 1.11 min. (Method J).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[O:7][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: C1=COCCC1
Reactant: OCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a mixture of pentane-1,5-diol(5.2 g, 0.05 mol) and p-toluenesulfonic acid (0.1 g, 0.53 mmol) in CH2Cl2 (120 mL) was added slowly dihydro-2H-pyran (4.6 g, 0.055 mol) in CH2Cl2 (30 mL) at 0° C. After stirring for 2 h at 0° C. and for another 1 h at room temperature, saturated NaHCO3 (50 mL) was added to the reaction mixture. The CH2Cl2 layer was washed with saturated NaHCO3 (50 mL), water (50 mL), and dried (MgSO4). The residue was purified by column chromatography on silica gel with EtOAc:hexane (1:1, v/v) and subsequent Kugelrohr distillation to give the title product (4, 5.1 g, 54%); bp 80° C.-85° C./0.1 torr; IR(neat): 3450 (broad) and 1135 cm-1 :1H NMR: 1.3-1.9 (m, 12H), 2.4 (b s, lH), 3.3-3.9 (m, 6H), and 4.58 ppm (m, IH).
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH2:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C@H:7]1[C:6]2[C@:19]([CH3:24])([CH:20]=[CH:21][C:22](=[O:23])[C:5]=2[NH:1][C:2]([CH3:4])=[O:3])[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[O:25])[CH2:12][CH2:11]3)[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NC1=C2[C@H](Br)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Yield: 90 %

Procedure:
To a solution of 4-acetamino-androsta-1,4-diene-3,17-dione (3.404 g, 10 mmol) in CCl4 (250 ml) were added N-bromosuccinimide (2.850 g, 16 mmol) and benzoyl peroxide (0.121 g, 0.5 mmol). The solution was heated under reflux for 1 h and then filtered to remove any insoluble material. The filtrate was washed with 5% NaHCO3 solution and with water and the organic phase evaporated to dryness under reduced pressure. The residue was triturated with a small amount of 95% EtOH to give mixture of crude 6α- and 6α-bromoacetamino-androsta-1,4-diene-3,17-dione in 90% yield (3.780 g), which was used in the following fluorination reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[CH3:21][N:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2)nc1CCN1CCCC1

Procedure:
Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) and 4-(N,N-dimethylcarbamoyl)phenylboronic acid, follow a procedure significantly analogous to that found in Example 22 to give the titled compound. MS (m/e): 404.3 (M+1)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=O)[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:33]([NH2:39])[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[CH2:29]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[CH2:26][NH:39][CH2:33][C:34]1[O:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: NCc1ccco1
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)n1c(CNCc2ccco2)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (30 mg, 0.07 mmol) in THF (1 mL) is added furfurylamine (0.03 mL, 0.35 mmol), NaBH(OAc)3 (45 mg, 0.21 mmol), and acetic acid (1 mL). The reaction mixture is stirred for 16 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 20 mg of 1-{4-[4-(7-(1-ethyl-propyl)-6-{[(furan-2-ylmethyl)-amino]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-1-yl}-ethanone as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C1(C)C=CC=CC=1.ClS([N:25]=[C:26]=[O:27])(=O)=O>O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:26]([NH2:25])=[O:27])([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
311 Parts of 2,4-dinitroaniline are stirred in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate for 4hours at 80° C. At 25° C., 360 parts of water are added to the resulting suspension of N-2,4-dinitrophenyl- N'-chlorosulfonyl urea without intermediate isolation of the latter, and the mixture obtained is saponified at 60° C. within 4 hours to yield 2,4-dinitrophenyl urea. After diluting it with water, the mixture is filtered, while hot, and the product is washed with hot toluene and water. After drying in vacuo, there are obtained 347 parts of 2,4-dinitrophenyl urea having a melting point of from 195° to 197° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=[N:3]1.[CH3:10][C:11](C)([O-])C.[K+].BrCCBr.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2([C:8]#[N:9])[CH2:11][CH2:10]2)=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)(C)[O-]
Reactant: Cn1nccc1CC#N
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: Cn1nccc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.3 %

Procedure:
To a solution of 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (65 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) were added potassium t-butoxide (1M in tetrahydrofuran, 1.2 mL, 1.2 mmol) and 1,2-dibromoethane (130 μL, 1.5 mmol). The reaction mixture was stirred for 16 h at room temperature then at 70° C. for 7 h. The mixture was cooled to room temperature, quenched with water (2 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dried under high vacuum. A solution of the residue and 1,2-dibromoethane (65 μL, 0.75 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to a suspension of sodium hydride (washed, 23 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After 16 h, additional portions of 1,2-dibromoethane (25 μL, 0.29 mmol) and sodium hydride (8 mg, 0.35 mmol) were added to the reaction mixture at room temperature. After 2 h, the mixture was quenched with water (3 mL) and extracted with diethyl ether (2×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to yield the volatile 1-(1-methyl-1H-pyrazol-5-yl)cyclopropanecarbonitrile (20.1 mg, 25%) as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.34-1.41 (m, 2H), 1.70-1.76 (m, 2H), 4.03 (s, 3H), 6.10 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([O-:12])[CH3:11].[Na+]>CC(O)C>[CH:10]([O:12][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1)([CH3:11])[CH3:9]
Reactant: CC(C)[O-]
Reactant: Cc1cnc(Br)cn1
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cnc(OC(C)C)cn1
Temperature: 115 °C
Yield: 37.9 %

Procedure:
To a solution of 2-bromo-5-methylpyrazine (3 g, 17.34 mmol) in 2-propanol (14 mL) was added sodium propan-2-olate (3.56 g, 43.3 mmol) and heated under microwave irradiation at 115° C. for 1.1 h. The organic solvent was evaporated before water was added to the residue. The mixture was extracted with dichloromethane (2×75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.0 g). LCMS m/z=153.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.19 Hz, 6H), 2.39 (s, 3H), 5.10-5.20 (m, 1H), 7.84 (s, 1H), 7.99 (s, 1H).