Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H:2]([C@@H:9]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4[C@@H](O)C[C@H]3[C@@H]2CC1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[O:30]1C=[CH:34][CH2:33][CH2:32][CH2:31]1.CO>O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:8]1[O:7][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:9][O:6]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1COCCO1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 245.3 %

Procedure:
To a solution of 100.0 g (0.2557 mole) of methyl hyodeoxycholate and 5.68 g of p-toluenesulfonic acid in 2000 ml of p-dioxane was added 153.7 g (1.62 mole, 148.6 ml) of dihydropyran over a period of 30 min under argon atmosphere. After stirring overnight at room temperature, the pH of the solution was adjusted to approximately pH 8 by the addition of 55 ml of 50/50 methanol/29% ammonium hydroxide. The solution was concentrated to a yellow oil under reduced pressure and the residue stirred in heptane 4 hr, then filtered to remove the precipitated p-toluenesulfonic acid. The filtrate was heated with charcoal, filtered, and evaporated to yield 116.8 g (80%) of the di-tetrahydropyranyl ether as a colorless viscous oil.
Reaction SMILES: Br.C([O:5][C:6]1[CH:7]=[C:8]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([O:12]C(=O)C)[CH:11]=1)(=O)C.O.CCOCC>C(O)C.[Pd]>[OH:5][C:6]1[CH:7]=[C:8]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:9]=[C:10]([OH:12])[CH:11]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(O)CNC(C)(C)C)c1
Agent: [Pd]
Agent: Br
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)NCC(O)c1cc(O)cc(O)c1

Procedure:
1.1 g of this salt were dissolved in warm absolute ethanol and 0.1 g 10% palladium charcoal were added. The solution was then hydrogenated at 50°C. and 5 atmospheres pressure overnight. The catalyst was filtered off and the volume of the solution reduced by evaporation. The hydrobromide of 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol with 1 mole of water was precipitated by the addition of ether. M.p. 108°-111°C. The protective acetyl groups may be removed by boiling the 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol hydrobromide with 1% hydrobromic acid for three hours. After evaporation and drying the product was recrystallized as described in Example 2c.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
To a solution of 4-chlorobenzoic acid (15.77 g, 100.7 mmol) in tetrahydrofuran (100 ml) was added 1,1′-carbonyldiimidazole (18.0 g, 111 mmol) at room temperature and the mixture was stirred as it was for 6 hrs. To the mixture was added monoethyl malonate monomagnesium salt (15.9 g, 55.4 mmol) at room temperature and the mixture was stirred at 60° C. for 3 hrs. The reaction solution was diluted with ethyl acetate and water and acidified with conc. hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].SC1C=CC=CN=1.ClC1C([O:24][C:25](=O)[C@H:26]([CH:38]([CH3:40])[CH3:39])[NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=C(Cl)C(Cl)=C(Cl)C=1Cl>ClCCl>[CH2:1]([NH:8][C:25](=[O:24])[C@H:26]([CH:38]([CH3:39])[CH3:40])[NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Sc1ccccn1
Agent: [Na]
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
1.1 ml. of benzylamine is dissolved in 200 ml. of dichloromethane, and 0.13 g. of the sodium salt of 2-mercaptopyridine is suspended therein. Then, 5.0 g. of benzyloxy carbonyl-L-valine pentachlorophenyl ester is added thereto. As determined by thin layer chromatography, the period required to consume one-half of the reactants is about 10 minutes. After three hours, treatment is effected in the same manner as in the previous example, and the dichloromethane layer is concentrated, whereby 3.1 g. of crude crystals are obtained (yield: 91 percent). By recrystallization from ethyl acetate, 2.7 g. of needle-like crystals are obtained. m.p. 174.5° C.
Reaction SMILES: N[C:2]1[C:3](=[O:21])[N:4](CC(OC)=O)[C:5](=[O:15])[N:6](CC2C=CC=CC=2)[CH:7]=1.C[N:23]1CCOCC1.[CH2:29]([S:36](Cl)(=[O:38])=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:30]1([CH2:29][S:36]([NH:23][N:6]2[CH:7]=[CH:2][C:3](=[O:21])[NH:4][C:5]2=[O:15])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)Cn1c(=O)c(N)cn(Cc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccn(NS(=O)(=O)Cc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
EX-1C) A solution of 5-amino-1-Benzyl-3-methoxycarbonylmethyl-2,4(1H,3H) pyrimidinedione (EX-1B; 3.12 g, 10.77 mmol) in 18.0 mL of tetrahydrofuran and dimethylformamide (1:1, 0.62M) was added N-methyl morpholine (3.60 mL, 32.74 mmol) in one portion at room temperature. The resulting mixture was cooled to 0° C. in an ice bath and was allowed to stir for 15 minutes. A solution of benzylsulfonyl chloride (2.26 g, 11.86 mmol) in 18.0 mL tetrahydrofuran was added drop wise over a 30 minute period. After the addition was complete the reaction was stirred for 3 hours at 0° C. The reaction mixture was diluted with ethyl acetate (250.0 mL) and washed with 1N HCl ((2×50 mL), saturated NaHCO3 (2×50 mL), and brine (2×50 mL). The organic solution was dried (MgSO4), filtered and concentrated. Trituration with ethyl acetate and hexanes gave pure 1-Benzyl-3-methoxycarbonylmethyl-%[[(phenylmethyl)sulfonyl]amino]2,4(1H,3H)pyrimidinedione (EX-1C) in 74% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 9.16 (s, 1H), 8.02 (s, 1H), 7.43–7.37 (m, 10H), 5.01 (s, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for C21H22N3O6S 444.1229, found 444.1242.
Reaction SMILES: COC1C(OC)=NS(=O)N=1.[CH3:11][N:12](CC1SC=C(CSCCN)N=1)[CH3:13].[CH3:25][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:39]2[C:43](OC)=[N:42][S:41](=[O:46])[N:40]=2)[N:33]=1)[CH3:27].CNC>>[CH3:25][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:39]2[C:43]([N:12]([CH3:13])[CH3:11])=[N:42][S:41](=[O:46])[N:40]=2)[N:33]=1)[CH3:27]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Agent: CNC
Agent: COC1=NS(=O)N=C1OC
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N(C)C)cs1

Procedure:
When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with one equivalent of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resultant 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of dimethylamine according to the procedure described in Example 28, the title compound is thereby produced.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C@@H:19]12[O:28][C@@H:23]([O:24][C@H:25]1[CH2:26][OH:27])[CH2:22][NH:21][CH2:20]2.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][C@H:25]1[C@H:19]2[O:28][C@H:23]([CH2:22][N:21]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:20]2)[O:24]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC[C@@H]1O[C@H]2CNC[C@@H]1O2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3C[C@@H]4O[C@@H](CO)[C@H](C3)O4)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). (1S,5S,7S)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-ylmethanol, synthesized according the literature (Guarna et al J. Org. Chem. 1999, 64, 7347) (96.2 mg; 0.66 mmol; 1 eq.), and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred 1 hour at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (49) as a white-off powder (73 mg; 26%). M− (ESI): 409.16; M+ (ESI): 411.07. HPLC (method A), Rt: 2.16 min (purity: 95.46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14].FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NCc1cc(Cl)cc(Cl)c1
Product: Cl
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of tert-butyl 4-(3-(3,5-dichlorobenzylamino)-4-(methylsulfonyl)phenyl)-piperazine-1-carboxylate (0.5 mmol), trifluoroacetic acid (5 mL) and dichloromethane (10 mL) was stirred for 3 h and concentrated in vacuo. The residue was dissolved in dichloromethane; this solution was washed with aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The yellow solid residue was dissolved in dichloromethane (1 mL), reacted with 1 N HCl in ether (1 mL) and concentrated in vacuo to yield the title compound as a yellow solid (59%). 1H NMR (400 MHz, CDCl3): δ 9.37 (br, 1 H), 7.62 (d, 1 H), 7.28 (s, 1 H), 7.22 (s, 2 H), 6.24 (dd, 1 H), 5.71 (d, 1 H), 4.43 (d, 2 H), 3.30 (m, 4 H), 2.93 (m, 4 H). MS (ESI) m/z: Calculated: 450.81; Observed: 415.4 (M+H+ corresponding to its free base).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(-c2nccnc2Cl)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-c2nccnc2Cl)cc1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of 0.40 g (1.6 mmol) of [4-(3-chloropyrazin-2-yl)phenyl]acetic acid in 3.0 mL of DMF was added 0.67 g (4.8 mmol) of potassium carbonate and 0.14 mL (2.3 mmol) iodomethane. After 1 h at 40° C., the reaction mixture was cooled, diluted with CH2Cl2, washed three times with water followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-75% EtOAc in hexanes) afforded 0.15 g (36%) methyl [4-(3-chloropyrazin-2-yl)phenyl]acetate. ES-MS M+1=263.0.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]=C.ClCCl.[BH4-].[Na+].C[OH:28]>>[C:16]1([C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:7][NH:8][C:4]=2[CH2:1][CH2:2][OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCO)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-4-phenyl-3-p-tolyl-1H-pyrazole (1.0 g, 3.64 mmol) was dissolved in methanol (40 mL) and dichloromethane (10 mL) and cooled to −78° C. on a dry-ice/acetone bath. Ozone was bubbled through the solution for h, until the solution appeared light blue. To the reaction was added sodium borohydride (0.138 g, 3.64 mmol) and the reaction was removed from the dry-ice bath and stirred at room temperature for 1 h. Excess solvent was removed under reduced pressure and the reaction was extracted with EtOAc/H2O, dried over MgSO4, and purified by column chromatography to give the title compound as white solid (0.54 g). LCMS m/z=279.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 2.71 (t, J=7.33 Hz, 2H), 3.57 (t, J=7.33 Hz, 2H), 4.65 (bs, 1H), 7.03-7.09 (m, 2H), 7.16-7.23 (m, 3H), 7.24-7.31 (m, 2H), 7.32-7.40 (m, 2H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[NH:6]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:3][C:1](=[O:4])[CH2:2][N:6]1[CH2:17][CH2:16][N:15]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:14][CH2:13][N:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CNCCNCCNCCN1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
Sodium acetate (25.298 g: 0.3084 mol) was added to a stirred suspension of 1,4,7,10-tetraazacyclododecane (17.71 g; 0.1028 mol) in N,N'-dimethylacetamide (DMA) (312 mL) at ambient temperature. A solution of bromoacetic acid t-butyl ester (49.8 mL; 0.3084 mol) in DMA (160 mL) was added dropwise to the stirred mixture, and the mixture stirred at ambient temperature for 11 days. A solid precipitate was isolated by suction filtration and washed once with cold DMA (20 mL). Residual DMA was removed by heating the solid at 45° C. under reduced pressure for 20 hrs. The white solid (40.18 g) was dissolved in chloroform (200 mL) and washed with deionized water (3×300 mL). The organic layer was dried over MgSO4 and subsequently concentrated to a solid which was further dried under reduced pressure to yield the title compound as a white powder, 36.3 g (69%).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:9]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:11][CH2:12][CH:13]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=[CH:2]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cn(Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (191 mg, 0.53 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 8 mg, 0.20 mmol). After stirring at 0° C. for 30 min, benzyl bromide (21 μL, 0.18 mmol) was added and the resulting mixture was stirred overnight at room temperature. The next morning the mixture was concentrated under reduced pressure to afford a brown residue. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1→10:1:1) afforded the product as a yellow oil (39 mg, 48%). 1H NMR (CDCl3) δ 1.57-1.70 (m, 3H), 1.93-2.16 (m, 5H), 2.46 (br s, 8H), 4.12 (d, 2H, J=9.0 Hz), 4.36 (s, 2H, 4.83 (s, 2H), 5.94(s, 1H), 6.99 (br s, 4H), 7.17 (s, 1H), 7.28 (s, 3H), 7.36 (d, 2H, J=9.0 Hz), 8.42 (s, 2H). 13C NMR (CDCl3) δ 19.23, 23.41, 25.39, 32.47, 50.23, 50.97, 62.04, 115.12, 122.07, 127.64, 128.49, 129.23, 136.52, 138.84, 147.33, 160.82. ES-MS m/z 452 [M+H]+. Anal. Calcd. for C29H33N5.0.5CH2Cl2: C, 71.71; H, 6.94; N, 14,17. Found: C, 71.78; H, 7.23; N, 14.10.
Reaction SMILES: O[C:2]1[CH:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:7])[O:5][CH:6]=1.O.[NH2:15][NH2:16]>C(O)C>[OH:5][CH2:6][C:2]1[N:16]=[N:15][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1OC=C(O)C1c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(CO)=C1c1ccccc1

Procedure:
4-Hydroxy-3-phenyl-2-furanone (3 g, 0.017 mol) was dissolved in ethanol (17 ml) with hydrazine hydrate (0.83 ml, 0.017 mol) and heated at reflux for 10 days (over this time the solvent evaporated). The residue was redissolved in ethanol (17 ml) and heated at reflux then allowed to cool and the solid that crystallised out was collected by filtration (2.2 g, mp=173° C.). Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ 4.45 (1H, s), 5.31 (1H, s), 7.14 (1H, t, J=7.3 Hz), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.3 Hz); MS (ES+) m/e 191 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=2)[C:9]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:8]1[CH3:28])=[O:4].C([O-])=O.[NH4+]>[Pd].CO.O1CCCC1>[C:18]([CH2:17][CH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:8]([CH3:28])=[C:9]2[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: COC(=O)CCn1c(C)c(Cc2cccnc2)c2cc(/C=C/C(=O)O)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCn1c(C)c(Cc2cccnc2)c2cc(CCC(=O)O)ccc21
Temperature: 60 °C
Yield: 88.1 %

Procedure:
A mixture of (E)-3-[1-(2-methoxycarbonylethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indol-5-yl]-2-propenoic acid (2.02 g), 10% palladium on carbon (0.20 g) and ammonium formate (1.68 g) in methanol (20 ml) and tetrahydrofuran (20 ml) was heated at 60° C. for 4 hours and then cooled and filtered. The residue was washed with methanol, and the filtrate and washings were combined and evaporated. The residue was triturated with dilute acetic acid to give a gummy solid. The solid was filtered off and boiled with ether to give the title compound as a crystalline solid (1.79 g), m.p. 144°-146° C. Found: C,69.60; H,6.20; N,7.16. C22 H24N2O4 requires: C,69.45; H,6.36; N,7.37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:40][CH2:41][CH:36]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:37][CH2:38]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 316 mg (2.05 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 mL of 1-methyl-2-pyrrolidinone is heated at 105° C. for 16 hours. The solvents are removed in vacuo. A 10 mL portion of water is added to the residue, from which a tan solid is precipitated out. The solid is filtered off and washed with water. After drying in vacuo, the solid is suspended in ethyl acetate and stirred for 1 hour. The solid is filtered off, washed with ethyl acetate and dried in vacuo to provide 140 mg of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-pyrrolidin-1-yl-piperidin-1-yl)-quinoline-3-carbonitrile as a yellow solid, mp 225-229° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]#[N:13])[CH:3]=1.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>C(O)(C)(C)C.O>[CH2:27]([O:26][C:23]([C:24]1[O:16][N:15]=[C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)[N:13]=1)=[O:25])[CH3:28]
Reactant: NO
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(O)c2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1nc(-c2cc(O)c3ccccc3c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixed solution of 4-hydroxynaphthalene-2-carbonitrile (0.34 g), hydroxylamine hydrochloride (0.14 g) and potassium carbonate (0.30 g) in tert-butylalcohol (4.5 mL) and water (0.5 mL) was stirred at 80° C. for 6 hours. To the reaction mixture was added hydroxylamine hydrochloride (0.14 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol). This compound (0.22 g) was dissolved in dichloromethane (5.3 mL). To the mixture were added ethyl oxalyl chloride (0.35 mL) and pyridine (0.52 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added water, and the organic layer was washed with water and a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (0.15 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH2:33]([S:40][C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: SCc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(c1cc(SCc2ccccc2)nc2c(C=O)cnn12)C1CC1
Reaction time: 0.03 h
Yield: 47.1 %

Procedure:
Diisopropylethylamine (256 μL, 1.48 mmol) was added to tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (250 mg, 0.74 mmol) suspended in ethanol (2.5 mL). Benzyl mercaptan (191 μL, 1.48 mmol) was added and the reaction was homogeneous after ˜2 min. After 10 min, the reaction was diluted with ethanol (3 mL) and the precipitate was filtered and washed with ethanol (10 mL) to yield tert-butyl 5-(benzylthio)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (148 mg, 47%). LCMS (ES): >95% pure, m/z 425 [M+1]+.