Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC(C)=C(CO)N=1)C1C=CC=CC=1.[CH2:16]([C:23]1[NH:24][C:25]([CH2:30][CH2:31][CH3:32])=[C:26]([CH2:28][OH:29])[N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[NH:24][C:25]([CH2:30][CH2:31][CH3:32])=[C:26]([CH:28]=[O:29])[N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCc1[nH]c(Cc2ccccc2)nc1CO
Agent: Cc1[nH]c(Cc2ccccc2)nc1CO
Product: CCCc1[nH]c(Cc2ccccc2)nc1C=O

Procedure:
The general procedure of Example 26 is repeated but replacing the 2-benzyl-5-methyl-4-imidazolemethanol employed in that example with 2-benzyl-5-n-propyl-4-imidazolemethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].C[Si](C)(C)[O:33][CH:34]=[C:35]([CH3:37])[CH3:36].[BH4-].[Na+]>CN(C=O)C.F[Zn]F>[OH:33][CH2:34][C:35]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30])([CH3:37])[CH3:36]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Reactant: CC(C)=CO[Si](C)(C)C
Agent: F[Zn]F
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1C(C)(C)CO
Reaction time: 0.17 h

Procedure:
To a microwave vial was added difluorozinc (16 mg, 0.15 mmol) and Pd(tBu3P)2 (7.6 mg, 0.015 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 mL) was added and the reaction mixture was allowed to stir for 10 minutes. (4-Bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (140 mg, 0.30 mmol) dissolved in DMF (0.5 mL) was added followed by trimethyl(2-methylprop-1-enoxy)silane (83 μL, 0.45 mmol). The reaction vessel was placed in an oil bath held at 80° C. for 16 hours. The reaction mixture was filtered, quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in MeOH (2 mL). NaBH4 (34 mg, 0.90 mmol) was added and the reaction mixture immediately turned from yellow to brown. The mixture was filtered and purified by HPLC (1-99%) MeOH:H2O to provide [4-(2-hydroxy-1,1-dimethyl-ethyl)-3-methoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 461.5. found 462.2 (M+1)+. Retention time: 2.73 minutes (4 min run).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 21.3 %

Procedure:
The title compound (68 mg, 21.5%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (267 mg, 0.794 mmol, prepared in example 1), 4-trifluoromethylbenzeneboronic acid (180 mg, 0.948 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 190 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: O.[C:2]1(C)[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.O.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.CC(C)=O>C1C=CC=CC=1>[CH3:3][C:2]1([CH3:7])[C:22]2=[CH:23][CH:24]=[CH:25][N:21]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccccc1-n1cccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccccc2-n2cccc21

Procedure:
p-Toluenesulfonic acid monohydrate (110 mg) is dissolved in 70 ml of dry benzene and the solution heated at reflux with a water-separator for about 10 minutes. A solution of 1-(o-hydroxyphenyl)-pyrrole (1.1 g) in dry benzene (80 ml) is added, followed by 10 ml of acetone. The reaction mixture is heated at reflux with the water-separator for 15 hr, cooled, and washed with a solution of NaHCO3. The benzene solution is evaporated to dryness. The residue is subjected to chromatography on silica gel, using chloroform as eluent. Evaporation of the first portion of the eluate gives the title compound, m.p. 38° - '° C, νmaxCHCl3 1600, 1510, 1345 cm-1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCN3CCCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from 2-piperidin-1-yl-ethylamine (5.2 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 6.6 mg of 8-indan-5-yl-5-oxo-2-(2-piperidin-1-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.22 (s, 1H), 8.45 (s, 1H), 7.32 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 6.22 (br, 1H), 4.36 (q, 2H), 3.22 (m, 2H), 3.00 (m, 4H), 2.10-2.60 (m, 8H), 1.60 (m, 6H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H31N5O3: 462.24 (M+H). Found: 462.4.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](Br)=[O:6].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>CCCCCCC>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:6]
Reactant: CC(C)(C)O
Reactant: Cc1cccc(CBr)c1C(=O)Br
Solvent: CCCCCCC
Product: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
20 g (24 mmol) of 2-bromomethyl-6-methylbenzoyl bromide solution (35% solution in heptane) are added to a mixture of 15 ml of n-heptane and 25 ml of tert-butanol. After stirring at 40° C. for one hour, 400 ml of n-heptane are added. The solution is washed successively with 60 ml of sat. sodium hydrogencarbonate solution and washed four times with 20 ml each time of water. Subsequently, the solvent is removed fully under reduced pressure. When the conversion is quantitative, tert-butyl 2-bromomethyl-6-methylbenzoate is obtained as a virtually colorless oil having 93% purity and having a molecular weight of 284.04 (C13H17BrO2); MS (ESI): 302.1 [M+NH4]+.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8](=NO)[CH3:9])[CH2:4][CH2:3]1.C(Cl)(=[O:14])C>C(N(CC)CC)C>[NH:2]1[CH2:7][CH:6]=[C:5]([C:8](=[O:14])[CH3:9])[CH2:4][CH2:3]1
Reactant: CC(=NO)C1=CCN(C)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.66 g of 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone oxime, 6.8 ml of triethylamine, and 3.8 ml of acetyl chloride were stirred at room temperature overnight under a nitrogen atmosphere. Isolation of the product in the conventional manner produced 8.07 g of 1-(1,2,3,6-tetrahydro-4-pyridinyl)ethanone, O-acetyloxime which was converted to the hydrochloride salt, mp 104.5°-105.5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1>O>[CH:14]1([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCC2)C1

Procedure:
tert-butyl (3S)-3-(cyclobutylamino)pyrrolidine-1-carboxylate was prepared by a method similar to that described in preparation 1 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and cyclobutanone (15 equivalents: 10 eq. added first, 5 eq. added before the second azeotropic removal of water) except that the crude product was purified by column chromatography on silica gel to yield the title compound, 542 mg (28%).
Reaction SMILES: [Ca].Cl[C:3]([N:5]([C@@H:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[C:30]([OH:34])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:3]([N:5]([C@@H:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7]1)=[O:4])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)O
Agent: [Ca]
Product: C[C@H](c1cccc2ccccc12)N(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 14.9 g of triphosgene dissolved in 400 ml of methylene chloride was added dropwise a solution containing 25.68 g of tert-butyl(R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylate (the compound obtained in the above-mentioned Reference example 1.005 (1)) and 31.5 ml of triethylamine in 100 ml of methylene chloride at −20° C. Further, 7.5 g of triphosgene was added to the same, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→2:1) to obtain 10.63 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate and 9.22 g of tert-butyl(R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate shown in the following Reference example Table, respectively. (2) To 18.52 g of tert-butyl(S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate was added 1.0 liter of tert-butanol, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated, and then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.24 g of tert-butyl(S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate (the following Reference example 1.006(a)).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: CCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
120 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 120 mg of potassium carbonate were dissolved in 1.5 ml of water and 7.5 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.034 ml of propyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>O.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: COc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 150 °C
Yield: 46.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[3-(methyloxy)phenyl]-3-piperidinecarboxamide (190 mg, 0.426 mmol), 3 mL of EtOH, Hunig's base (0.223 l, 1.277 mmol), and hydrazine anhydrous (0.053 ml, 1.702 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered off and the yellow filtrate was evaporated. To the resulting brown liquid was added EtOAc (1 mL), and the mixture was warmed to 50° C. Two layers formed. The top layer is EtOAc solution, and it was pipeted to a different vial. The bottom layer is the comparatively pure product. This compound was treated with water at 50° C., and a solid was formed. This material was filtered and dried to give the title compound (90 mg) as a light yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (m, 1H), 1.61-1.85 (m, 2H), 2.01 (m, 1H), 2.79-3.06 (m, 2H), 3.74 (s, 3H), 4.36-4.79 (m, 2H), 5.37 (s, 2H), 6.02-6.15 (s, 2H), 6.55-6.74 (m, 2H), 7.09-7.26 (m, 2H), 7.32-7.41 (m, 1H), 7.51-7.78 (m, 2H), 7.91-8.00 (m, 1H), 10.01 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=[CH:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C(/OC)c1ccccc1C=Cc1csc(-c2ccc(F)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)/C=C(/OC)c1ccccc1/C=C\c1csc(-c2ccc(F)cc2)n1
Solvent: CO
Product: COC(=O)/C=C(/OC)c1ccccc1CCc1csc(-c2ccc(F)cc2)n1

Procedure:
3 g (7.6 mmol) of methyl 2-{2-[2-(4-fluorophenyl)-4thiazolyl]-(Z)-ethenyl}-(E)-β-methoxycinnamate in 100 ml of methanol are hydrogenated in the presence of 0.2 g of Pd/C (10%) under a gage pressure of 0.05 bar of hydrogen and at 20°-25° C. until hydrogen uptake ceases (1 h). The mixture is then filtered and concentrated.
Reaction SMILES: [C:1]([N:5]([C:29](=[O:38])[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)[NH:6][C:7]([C:9]1[CH:27]=[CH:26][C:12]2[O:13][CH2:14][CH:15]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[O:16][C:11]=2[C:10]=1[CH3:28])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:5]([C:29](=[O:38])[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)[NH:6][C:7]([C:9]1[CH:27]=[CH:26][C:12]2[O:13][CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:11]=2[C:10]=1[CH3:28])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(CO[Si](C)(C)C(C)(C)C)CO3)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(CO)CO3)C(C)(C)C)c1
Yield: 100 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added 3,5-dimethylbenzoic acid N-tert-butyl-N′-[3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carbonyl]-hydrazide (0.26 g, 0.48 mmol), THF (5.0 mL), and 1 M solution of tetrabutylammonium fluoride (TBAF) in THF (1.39 mL, 1.39 mmol). The mixture was stirred at room temperature for three hours. The THF was evaporated and the residue was taken up in ethyl acetate. This solution was washed once with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated with hexane to give a white solid, 3,5-dimethylbenzoic acid N-tert-butyl-N′-(3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carbonyl)-hydrazide, (0.205 g, 0.48 mmol) in 100% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 1.59 (s, 9H), 1.89 (d, 3H), 2.25 (s, 6H), 3.79 (m, 2H), 4.04 (m, 1H), 4.18 (m, 1H), 4.33 (m, 1H), 6.33 (dd, 1H), 6.56 (dd, 1H), 7.03 (s, 1H), 7.12 (s, 2H), 9.51 (s, 1H); TLC Rf=0.03 (ether/hexane).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=2[N:7]=1.[CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>>[CH:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=3[N:7]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: O=CN1CCNCC1
Reactant: Sc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: O=CN1CCN(c2nc(N3CCOCC3)c3ncnc(S)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-mercapto-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: >300° C., decomp.) and N-formyl-piperazine.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.CCN(C(C)C)C(C)C>C1COCC1>[N:40]1([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:32]=3[N:31]=[CH:30][N:29]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.1 %

Procedure:
In a 50 mL round-bottomed flask equipped with a stirring bar were placed 3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (22) (1.005 g, 2.090 mmol) and BOP (1.850 g, 4.181 mmol). THF (20 mL) and DIPEA (0.55 mL, 3.135 mmol) were added and the mixture was allowed stir at room temperature for 23 h. The mixture was evaporated and CH2Cl2 (50 mL) added. The mixture was washed with water, dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 1.038 g (83% yield) of compound 26 as a white foam. Rf (20% EtOAc in hexanes)=0.14. 1H NMR (500 MHz, CDCl3): δ 8.54 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 8.14 (d, 1H, Ar—H, J=8.3), 7.55-7.41 (m, 3H, Ar—H), 6.55 (t, 1H, H-1′, J=6.1), 4.65 (m, 1H, H-3′), 4.06 (q, 1H, H-4′, J=3.1), 3.92 (dd, 1H, H-5′, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 2.7), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.52 (m, 1H, H-2′), 0.93, 0.92 (2 s, 18H, tert-Bu), 0.11 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 159.0, 153.6, 151.3, 143.5, 128.9, 128.7, 124.8, 120.6, 120.0, 108.6, 88.2, 85.0, 71.6, 62.6, 41.7, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C28H44N7O4Si2 (M++H) 598.2993. found 598.2986.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CN
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Product: CNc1c(C(N)=O)cnn2cc(Br)cc12
Yield: 98 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 200 mg, 0.733 mmol), and methylamine (0.5 mL, 8M solution in EtOH) was heated to 80° C. for 1 hr in the CEM microwave. The reaction mixture was evaporated in vacuo to give the title compound (192 mg, 98%). HPLC (condition G): retention time=0.77 min. LCMS (condition B): m/z 269.0, 271.0.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>O1CCCC1>[CH:1]1([NH:4][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of cyclopropylamine (1.0 g, 18 mmol) and triethylamine (3.7 mL, 27 mmol) in tetrahydrofuran (20 mL) was added 2-nitrobenzenesulfonyl chloride (3.9 g, 18 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The reaction solution was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and concentrated. The residue was washed with hexane and collected by filtration to obtain the title compound (3.7 g, 87%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH2:5][N:4]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:30])[C:17]([C:25]([O:27]CC)=[O:26])=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:31])[CH2:3]1.[ClH:32]>>[ClH:32].[NH2:1][C@H:2]1[C@@H:6]([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH2:5][N:4]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:30])[C:17]([C:25]([OH:27])=[O:26])=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:31])[CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3C[C@@H](N)[C@@H](n4ccnn4)C3)c(F)cc2c1=O
Agent: Cl
Product: N[C@@H]1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@@H]1n1ccnn1
Yield: 85 %

Procedure:
Ethyl 7-[cis-3-amino-4-(1,2,3-triazol-1-yl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (200 mg, 0.47 mmol) was heated with 8 ml of 6N hydrochloric acid at 110° C. for 18 hr. The solution was then evaporated to dryness and the residue was crystallized from methanol-ether to yield 160 mg (85%) of the desired hydrochloride, m.p. 240° C. (dec). 1H NMR (TFA) δ: 9.27 (s, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 8.3 (d, 11.6Hz, 1H), 6.64-6.45 (m, 1H), 5.35-4.66 (m, 5H), 4.20-4.02 (m, 1H), 1.7-1.2 (m, 4H). Anal. calcd. for C18H19ClFN7O3. 1.5 H2O: C, 46.76; H, 4.80; N, 21.2; Cl, 7.67. Found: C, 46.85; H, 4.31; N, 20.62; C1, 8.36.