Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2].[Tb+3:2].[O-2].[O-2].[Tb+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Tb+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [O-2]
Agent: [Tb+3]
Product: O=[N+]([O-])[O-]

Procedure:
The lanthanum and terbium raw materials may be lanthanum oxide and terbium oxide. Lanthanum oxide is added to concentrated nitric acid to form lanthanum nitrate, which is then preferably diluted. Terbium oxide is added to concentrated nitric acid to form terbium nitrate solution, which is then preferably diluted. The diluted lanthanum nitrate solution and the diluted terbium nitrate solution are then combined to form a single rare earth solution. Hydrated cerium nitrate is then added to the rare earth solution. The molar ratio of the rare earth elements in the rare earth solution is thus about x mole La:y mole Ce:z mole Tb where x=0.39 to 0.73, y=0.17 to 0.45 and z=0.10 to 0.17. The molar ratio of the rare earth elements is preferably about 0.6 mole La:0.225 mole Ce:0.165 mole Tb.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18]>C1COCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:16][CH2:17][CH3:18])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: CCCN
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: CCCNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added propan-1-amine (5.6 mL, 67.7 mmol) and the reaction mixture was stirred for 1.5 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 6-methoxy-2-(propylamino)quinoline-3-carbaldehyde SLA 28172 as an orange solid (1.68 g, 99% yield).
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22][OH:23]>>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([O:23][CH3:22])=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(OC)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in methanol (2 ml) was added NaH (60% dispersion in mineral oil, 0.085 g, 2.14 mmol) under nitrogen atmosphere and the reaction mixture was refluxed for 3 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. Water (10 ml) was added to the residue and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 2% methanol in dichloromethane as solvent system to give the product (0.013 g, 22%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[C:28](Cl)=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:28]3[C:27](=[CH:32][CH:31]=[CH:30][N:29]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2cccnc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1ncccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Dissolve (3-{[3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester (0.74 g, 0.0015 mol) in N,N-dimethylformamide (10 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.38 mL, 0.0017 mol) and stir for 15 min. at ambient temperature. Quench the dark mixture with water and follow by the addition of solid sodium chloride. Extract with ethyl acetate and wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane to give the isolation of 0.61 g (89%) of the desired product as a white fluffy solid. MS(ES): (M+1)+ 447.1, 448.1 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(S(O)(=O)=O)(F)(F)F.C1C(=O)N([I:25])C(=O)C1>CC#N>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:25])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccccc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81626.9 %

Procedure:
To a solution of 2-hydroxy-benzonitrile (47.6 g, 0.400 mmol) in CH3CN (500 mL) was added CF3SO3H (40 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 20 min, and then NIS (108 g, 0.48 mmol) was added. The mixture was stirred at room temperature overnight, then concentrated, diluted with H2O (300 mL) and extracted with EA (300 mL×3). Combined organic portions were dried over sodium sulfate, filtered and reconcentrated. Purification via column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) afforded the title product (80 g) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: CNCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)CCO
Yield: 73.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with 2-(methylamino)ethanol (0.35 ml, 4.3 mmol) to give the title compound as a solid (160 mg, 73%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum (2 rotamers) 1.60 (m, 3H), 3.18 and 2.93 (s, 3H), 3.65-3.40 (m, 4H), 5.00 and 4.73 (t, 1H), 5.79 (s, 2H), 5.90 and 5.81 (q, 1H), 7.35-7.30 (m, 2H), 7.51 (s, 1H), 7.85-7.70 (m, 3H), 8.11 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 11.09 (br s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[OH:12][CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[CH:14]=[CH:15]/[C@H:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[N:17]1[CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].IC(C)C>CC(C)=O.CCOC(C)=O>[CH:3]([O:30][C:29](=[O:31])[CH2:28][CH2:27][CH2:26][C:25]#[C:24][CH2:23][N:17]1[C:18](=[O:22])[CH2:19][CH2:20][CH2:21][C@@H:16]1/[CH:15]=[CH:14]/[CH:13]([OH:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([CH3:4])[CH3:2]
Reactant: O=C(O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 0.08 h
Yield: 46.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (15 μL, 0.10 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-ynoic acid (25 mg, 0.068 mmol) in acetone (0.68 mL) at rt. After 5 min, 2-iodopropane (34 μL, 0.34 mmol) was added. After 18 h at rt, the reaction mixture was diluted with EtOAc (25 mL) and washed with aqueous HCl (0.5 M, 10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→5% MeOH/CH2Cl2, gradient) afforded 13 mg (47%) of the title compound.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[CH3:27])(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:28])=[O:9])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:37]1(B(O)O)[CH2:39][CH2:38]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:37]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=4[CH3:27])(=[O:18])=[O:17])[CH2:12][C@@H:11]3[CH3:28])=[O:9])=[CH:4][CH:3]=2)[CH2:39][CH2:38]1
Reactant: OB(O)C1CC1
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(I)nc2)[C@@H](C)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(C3CC3)nc2)[C@@H](C)C1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 2.4 %

Procedure:
Argon was bubbled through a solution of 4-({(3S)-4-[(6-iodo-3-pyridinyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl)-3-methylbenzonitrile (50.0 mg, 0.098 mmol) (may be prepared as described in Example 50), potassium phosphate (72.8 mg, 0.343 mmol) and cyclopropylboronic acid (25.2 mg, 0.294 mmol) in toluene (3 mL) and water (200 μl) for 30 min. Tricyclohexylphosphine (2.75 mg, 9.80 μmol) and palladium(II) acetate (1.100 mg, 4.90 μmol) were added and the resulting pale yellow solution heated at 100° C. for 2 h. LCMS had not changed from 1 min, at 45° C. The solution was cooled and concentrated under vacuum to leave a pale yellow solid. Purification by MDAP and concentration of the desired fractions gave the title compound (1.0 mg) as a clear film, and a batch of recovered 4-({(3S)-4-[(6-iodo-3-pyridinyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl)-3-methylbenzonitrile (28.2 mg) starting material.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)[CH:15]=1.[C:28](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH3:28])[CH2:25][CH2:26]3)[CH:20]=2)[CH:15]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Reaction time: 0.25 h

Procedure:
3-(1,3-Benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (1.8 g) was added to a mixture of acetic acid (2.86 μL) and 37% aqueous formaldehyde (0.583 ml) dissolved in methanol (40 ml) and the resulting solution was stirred for 15 minutes. Sodium cyanoborohydride (0.377 g) was then added and the mixture was stirred for a further 3 hours. The reaction mixture was concentrated to dryness and diluted with DCM and purified by flash chromatography on silica gel (eluting with a gradient of 5 to 10% 7N methanolic ammonia in dichloromethane). The solvent was evaporated to dryness and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (1.180 g); Mass Spectrum: M+H+ 375.1; RT 1.73 min; NMR Spectrum: (DMSOd6) 8.53 (d, 1H), 8.44 (d, 1H), 8.32 (d, 1H), 7.92 (d, 1H), 7.85 (m, 1H), 7.80 (m, 1H), 7.64 (br s, 2H), 7.46 (m, 2H), 4.13 (m, 1H), 2.88 (br m, 2H), 2.23 (s, 3H), 2.04 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][C:6]2([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1>CN1CCCC1=O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH2:31][NH:32][C:33]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:12]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:36][CH:35]=2)=[O:41])=[CH:42][CH:43]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: COC(=O)C1(C)CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1(C)CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
Methyl 6-cyano-7-fluoro-4-methylchroman-4-carboxylate (10 mg, 0.040 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (28 mg, 0.20 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (11 mg, 0.040 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. and stirred for 5 hours. The reaction was allowed to cool, loaded directly onto a 25 samplet and eluted on the horizon with 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes to yield the title compound (12 mg, 59% yield). MS (ESI)=504.9 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[Cl:18])(=[O:9])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([F:17])=[CH:13][C:12]=1[Cl:18])(=[O:8])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Oc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 95.9 %

Procedure:
A 95% sulfuric acid (35 ml) was added to 2-chloro-4-fluorophenyl methanesulfonate (22.5 g), to which was then added dropwise a mixture of 95% sulfuric acid (7.5 ml) and 61% nitric acid (10.3 g) under ice-water cooling and stirring to effect nitration reaction. After the completion of the addition, the reaction mixture was stirred for further 30 minutes at room temperature and then poured onto ice pieces and extracted with toluene. The toluene extract as separated was washed with 1N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. The toluene was distilled off to afford the titled compound (25.9 g) as pale yellow crystals with melting point 64°-65.5° C.
Reaction SMILES: [Xe][F:2].[Cl:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[CH:9]=[C:8]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([F:2])=[C:8]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:21]1
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: F[Xe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cn1c(=O)c2c(c(F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
Xenon fluoride (56 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in acetonitrile (10 ml), and the resulting mixture was stirred overnight at room temperature. After a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, the acetonitrile was distilled off under reduced pressure, and the residue was extracted twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (8 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OC2C3C(=CC=CC=3)N(C3C=CC(Cl)=CC=3)N=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34]([OH:48])=[N:35][N:36]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47].CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C(OC(N1CCC(OS(C)(=O)=O)CC1)=O)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:48][C:34]2[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[F:31])[N:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1nn(-c2ccccc2F)c2cccc(F)c12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccc(Cl)cc3)c3ccccc23)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3cccc(F)c23)CC1
Yield: 51 %

Procedure:
4-[4-Fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 46) was prepared as described above for Intermediate 42 using Intermediate 45 (300 mg, 1.218 mmol), PS-BEMP resin (1.108 g) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 2) (374 mg, 1.34 mmol) in DMF (10 ml) to afford 265 mg (51%) of Intermediate 46 as a yellow oil. MS (M+1)=430.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH3:13][Mg]Br.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:12])[CH3:13]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of quinoline-2-carboxaldehyde (7.85 g) in THF (100 mL) was added dropwise 1.4M methyl magnesium bromide in toluene and THF (46 mL). After total addition, the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into aqueous satured NH4Cl (500 mL), extracted with ethyl acetate (2×200 mL), washed with brine (100 mL), and dried (MgSO4). The solution was evaporated to dryness and chromatographed on flash silica gel using ethyl acetate:hexane (3:7) as eluant to yield the title product as a light orange solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH2:14]1.S(=O)(=O)(O)O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]1
Reactant: c1ccc2oc(CCCN3CCC4(CC3)OCCO4)cc2c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CCN(CCCc2cc3ccccc3o2)CC1

Procedure:
A solution of 6 g of the product of Step A, 60 ml of 10% sulphuric acid and 30 ml of tetrahydrofuran is heated at 50° C. for 12 hours, and then evaporated. The residue is taken up in ether, rendered basic with 20% sodium hydroxide solution, extracted with ethyl acetate, dried and evaporated, enabling the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][Si](C(C)(C)C)(C)C)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: Cl
Solvent: CO
Product: COC(=O)c1coc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.6 %

Procedure:
To 6-(tert-butyl-dimethyl-silanyloxy)-benzofuran-3-carboxylic acid methyl ester (2.4 g, 7.7 mmol) was added 1% HCl in MeOH (70 mL) and the resulting solution was stirred (rt, 14 h). The reaction mixture was concentrated in vacuo. The resulting solid was dissolved in DCM (100 mL) and sat. NaHCO3 (50 mL) was added. A solid formed and was filtered to afford the title compound as a white solid (1.4 g, 94%). MS (ESI): mass calcd. for C10H8O4, 192.04; m/z found, 193.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.24 (s, 1H), 7.77 (d, J=8.5, 1H), 6.94 (d, J=1.4, 1H), 6.86 (dd, J=8.5, 1.7, 1H), 3.90 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[CH3:26][S:27][CH2:28]Br>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:13]4[N:12]([CH2:26][S:27][CH3:28])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CSCBr
Reactant: CCn1ncc2c3[nH]c4cc(-c5ccccc5)nn4c(=O)c3cnc21
Product: CCn1ncc2c1ncc1c(=O)n3nc(-c4ccccc4)cc3n(CSC)c12

Procedure:
By treating the product of Example 29 with methylthiomethyl bromide according to the procedure of Example 2, 3-ethyl-3,11-dihydro-9-phenyl-11-methylthiomethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](Cl)=[N:9][C:8]([Cl:13])=[N:7][C:6]=2[N:5]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]2[O:16]C(=O)C)[CH:4]=1)#[N:2].[NH3:32]>>[CH:4]1[N:5]([CH:14]2[O:26][CH:25]([CH2:27][OH:28])[CH:20]([OH:21])[CH:15]2[OH:16])[C:6]2[N:7]=[C:8]([Cl:13])[N:9]=[C:10]([NH2:32])[C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#N)c3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Reaction time: 12 h
Yield: 51 %

Procedure:
5-Cyano-2,4-dichloro-7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (5, 2.85 g) was covered with 50 ml of liquid ammonia and the solution was allowed to stand at room temperature for 12 hr while sealed in a steel vessel. The excess ammonia was allowed to evaporate and the residue was triturated with 50 ml of cold water. The water insoluble solid was collected by filtration, washed with 10 ml of water and dissolved in a minimum amount of boiling methanol. The methanol solution was then concentrated to ~100 ml or until the product began to crystallize. The solution was then allowed to stand at -5° for 12 hr. The white to light tan crystalline solid was collected by filtration, washed with 15 ml of methanol and dried in a vacuum oven for 2 hr at 100° over drierite to yield 1.00 g (51%) of 6, mp 258-260° dec.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Br:12])/Br.[CH3:17][S:18][C:19](=[NH:21])[NH2:20].Cl>O>[Br:12][C:11]1[C:9]([C:8]([OH:16])=[O:15])=[N:20][C:19]([S:18][CH3:17])=[N:21][CH:13]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CSC(=N)N
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(C(=O)O)n1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
At 5° C. triethylamine (16.9 ml) was added dropwise to a solution of mucobromic acid (10.31 g) and 2-methyl-isothiourea (11.13 g) in water (200 ml). After stirring at 5° C. for 3 h, the reaction mixture was allowed to warm up (room temperature) and stirring was continued for another 54 h. The reaction mixture was acidified with conc. HCl (33%). The title product was obtained by filtration. Yield: 4.1 g. MS-ESI: [M+H]+=249/251