Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C:43](O)=[O:44])[CH2:19][C@H:18]([O:20][C@@H:21]2[O:35][C@@H:34]([CH3:36])[C@H:24]3[O:25][C@H:26]4[N:31]([C@H:23]3[CH2:22]2)[CH2:30][CH2:29][O:28][C@@H:27]4[O:32][CH3:33])[C:17]2[C:4](=[C:5]([OH:42])[C:6]3[C:7](=[O:41])[C:8]4[C:13]([C:14](=[O:38])[C:15]=3[C:16]=2[OH:37])=[C:12]([O:39][CH3:40])[CH:11]=[CH:10][CH:9]=4)[CH2:3]1.C(N(CC)CC)C.[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[OH:42][C:5]1[C:4]2[CH2:3][C@@:2]([OH:1])([C:43]([N:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)=[O:44])[CH2:19][C@H:18]([O:20][C@@H:21]3[O:35][C@@H:34]([CH3:36])[C@H:24]4[O:25][C@H:26]5[N:31]([C@H:23]4[CH2:22]3)[CH2:30][CH2:29][O:28][C@@H:27]5[O:32][CH3:33])[C:17]=2[C:16]([OH:37])=[C:15]2[C:6]=1[C:7](=[O:41])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([O:39][CH3:40])[C:13]=1[C:14]2=[O:38]
Reactant: C1CNCCN1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)O)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)N1CCNCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 56 (9 mg) in anhydrous dichloromethane (5 ml) under argon atmosphere, anhydrous triethylamine (1.6 mg, 0.0158 mmol), piperazine (3.6 mg, 0.0424 mmol), HOBt (2.1 mg, 0.0158 mmol) and EDC (3.0 mg, 0.0158 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated under vacuum and the residue was then purified by flash column chromatography (DCM/MeOH/AcOH/H2O 45/4/1/0.5) on silica gel (230-400 mesh). The product obtained was dissolved in DCM and washed with satd. NaHCO3 (x2) and water (x2). The organic solvent was evaporated under vacuum to afford 5.0 mg of 57. MS (ESI): 696 [M+H]+. Retention time=4.01 min (method 1, Example 3b).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=3)[CH2:15]2)[N:4]=1.[H][H]>[Ni]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:26])([F:27])[F:25])[CH:20]=3)[CH2:15]2)[N:4]=1
Reactant: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1N

Procedure:
A suspension of Raney®-Nickel in a methanolic solution of 5b (0.76 g in 50 ml, 1.98 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.69 g, 1.96 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[C:20]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH-].[OH:36][CH2:37][CH2:38][N+:39]([CH3:42])([CH3:41])[CH3:40]>CO>[OH:36][CH2:37][CH2:38][N+:39]([CH3:42])([CH3:41])[CH3:40].[F:1][C:2]1[C:20]([N:21]2[CH2:22][CH2:23][CH:24]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([O-:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCC(Nc5ccc(F)cc5)CC4)cc3nc21
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)[O-])c(=O)c2cc3cc(F)c(N4CCC(Nc5ccc(F)cc5)CC4)cc3nc21

Procedure:
Choline 7-fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 1, but from 1.6 g of 7-fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid in 16 cm3 of methanol and 1.3 cm3 of a 45% solution of choline hydroxide in methanol. After recrystallizing twice from 25 cm3 of 2-propanol on each occasion, 1.1 g of choline 7-fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 200-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:25]([C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NC(=O)Nc3ccccc3)c2)s1
Yield: 35.5 %

Procedure:
N-[5-(5-Amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (20 mg, 0.07 mmol) and phenyl isocyanate (0.023 mL, 0.21 mmol) were stirred in THF (0.6 mL) at 40° C. for 2 hours. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.93 minutes; 10 mg, 36%); 1H NMR Spectrum: (DMSOd6) 12.23 (1H, s); 9.56 (1H, s); 8.69 (1H, d); 8.54 (1H, s); 8.15 (1H, d); 7.48 (2H, d); 7.32 (2H, t); 7.02 (1H, t); 2.40 (3H, s); 2.16 (3H, s); Mass Spectrum: M+H+ 402 and 404.
Reaction SMILES: C1O[C:4]([CH:17](Br)[CH3:18])([CH2:5][N:6]2[C:10](=[O:11])[C:9]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]3[C:7]2=[O:16])[O:3]C1.[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O>[C:10]1(=[O:11])[N:6]([CH2:5][C:4](=[O:3])[CH:17]([N:21]=[N+:22]=[N-:23])[CH3:18])[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: CC(Br)C1(CN2C(=O)c3ccccc3C2=O)OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(N=[N+]=[N-])C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 3, 1-phthalimido-3-bromo-2-butanone ethyleneketal in dimethyl sulfoxide is heated with sodium azide to give 1-phthalimido-3-azido-2-butanone, ethylene ketal.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CN([CH:27]=[O:28])C>C1COCC1>[CH3:16][O:17][C:18]1[C:23]([CH:27]=[O:28])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccccn1
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ncccc1C=O
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirred solution of 1.7M t-butyl lithium in THF (35.0 mL, 59.6 mmol, 2.60 equiv.) with THF (150 mL) at −78 degrees was added dropwise 2-bromomesitylene (4.56 mL, 29.8 mmol, 1.30 equiv.). After stirring for 1 h, 2-methoxy-pyridine (2.5 g, 22.9 mmol) was added dropwise. This solution was warmed to −23 degrees and stirred for 3 h and then cooled to −78 degrees again. DMF (2.66 mL, 34.4 mmol, 1.5 equiv.) was added, the solution was stirred at −78 degrees for 1 h. The reaction was quenched at this temperature with brine (150 mL) and extracted with ether. The combined ether was dried over K2CO3 and evaporated on vacuo. The residue was chromatographed with 50%-80% EtOAc/Hexanes to give 2-methoxy-pyridine-3-carbaldehyde (2.34 g, 17.1 mmol, 74.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([C:14]#[N:15])([CH3:13])[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:4]=4)[CH:49]=[CH:48][CH:47]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ccc(Cl)c(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of 4-chloro-3-(1-cyano-1-methylethyl)benzoic acid (83 mg, 0.370 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (40 μL, 0.462 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.308 mmol) produced in Example 12(ii) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (108 mg, 66%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=[O:9].[Fe+2:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-2:9].[Fe+2:17]
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Nc1ccccc1
Product: [O-2]

Procedure:
In the aniline process (described e.g., in U.S. Pat. No. 4,145,228), however, mononitrobenzene is reacted with cast iron scrap in the presence of iron (II) and/or aluminum chloride solutions to produce both aniline and iron oxide. Separation of the crude aniline from the iron oxide is not as easily achieved as separation of iron oxide from water. In fact, such separation is commonly carried out in two stages. In the initial separation stage, crude aniline and a slurry in which iron oxide, water and by-products are present, are obtained from the reaction mixture. In a second step, the iron oxide is separated from the water and the inorganic by-products via conventional methods. Several methods for separation of the aniline from the slurry are known. Examples of such separation techniques are (1) vacuum distillation, (2) filtration, (3) steam distillation and (4) a combination of decantation and steam distillation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,4-difluorophenyl)-carbamic acid tert-butyl ester (Tetrahedron, (1992), 48(35), 7373) (15.1 g) in tetrahydrofuran (120 ml) at 0° C. was added potassium tert-butoxide (94 ml of a 1.0 M solution in tetrahydrofuran) dropwise. After stirring for 2 hr methyl bromoacetate (9.1 ml) was added dropwise and ice-bath removed and reaction mixture stirred at room temperature overnight. Reaction mixture concentrated under reduced pressure, diluted with ethyl acetate and washed with water and brine, dried (Na2SO4) and concentrated to leave the sub-title compound as a brown oil (18.0 g).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8](=[O:13])[C:7]([C:14]([NH:16][C:17]2[C:22]([CH2:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:25][CH3:26])=[O:15])=[C:6]1[CH3:27])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[Br:34]Br>C(Cl)Cl>[Br:34][C:9]1[C:8](=[O:13])[C:7]([C:14]([NH:16][C:17]2[C:18]([CH2:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:23][CH3:24])=[O:15])=[C:6]([CH3:27])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[CH2:11][CH3:12]
Reactant: CCCCn1c(CC)cc(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1c(C)c(C(=O)Nc2c(CC)cccc2CC)c(=O)c(Br)c1CC
Reaction time: 6 h
Yield: 72.3 %

Procedure:
To a mixture of 700 mg (1.90 mmol) of 1-butyl-6-ethyl-N-(2,6-diethylphenyl)-1,4-dihydro-2-methyl-4-oxo-3-pyridinecarboxamide, 14 ml of methylene chloride and 1.2 g (7.40 mmol) of sodium carbonate was added a solution of 303 mg (1.90 mmol) of bromine in 5 ml of methylene chloride under vigorous stirring. After the completion of addition the mixture was stirred for 6 hours. The insoluble product in methylene chloride was filtered off and the filtrate was concentrated in vacuo to give a crystalline residue. The residue was recrystallized from benzene and cyclohexane to afford 615 mg of the title compound having mp. 132.5°-133.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)([CH3:11])[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][CH:14]2[CH2:15][CH2:16][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)N1CCC(O)C1
Product: CC(C)N1CCC(Oc2ccc(Br)cn2)C1

Procedure:
Prepared from 2,5-dibromopyridine and 1-isopropylpyrrolidin-3-ol by the method of Example 10 (b).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[OH:12]O>C(O)(=O)C>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N+:7]=1[O-:12]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: OO
Solvent: CC(=O)O
Product: Nc1ccc(C(F)(F)F)c[n+]1[O-]

Procedure:
The title compound was prepared by following the procedure described for Intermediate-40 using 5-(trifluoromethyl)pyridin-2-amine (0.500 g, 3.08 mmol), acetic acid (5.0 mL) and 50% hydrogen peroxide (2.0 mL) to afford 0.475 g of the desired product. 1HNMR (DMSO-d6): δ 6.88 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.49 (s, 2H), 8.49 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)CC>N1C=CC=CC=1>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCCO
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Cinnamoyl chloride (7.3 g) is added to a suspension of 2-amino-7-chloro-1,8-naphthyridine (7.2 g) in pyridine (80 cc). After stirred for 2 hours at 20° C., the suspension obtained is poured into distilled water (500 cc). The suspension is filtered, washed with water (3×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). The solid obtained (10.6 g; m.p. 263° C.) is dissolved in boiling 1-propanol (1200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with 1-propanol (3×50 cc), diethyl ether (2×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-phenylpropenamide (11.4 g), m.p. 263° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:20])[CH:10]([OH:19])[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>CN(C)C=O>[CH2:1]([O:8][C@H:9]([CH3:20])[CH:10]([O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](OCc1ccccc1)C(O)C#Cc1cccnc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1ccccc1)C(C#Cc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
(3RS,4R)-4-Benzyloxy-1-pyridin-3-yl-pent-1-yn-3-ol (Example 30b), 1.745 g) was stirred in dimethylformamide (20 ml) with tert-butyldimethylsilyl chloride (1.18 g) and imidazole (0.89 g) at room temperature for 22 hours. Water was added and the reaction was extracted with diethyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 4:1 isohexane/ethyl acetate gave the subtitle compound as an oil (2.014 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:17])([F:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[Br:25][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:16])([F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(F)(F)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1

Procedure:
To tert butyl 2-{4-(methyl)phenyl}-2,2-difluoroacetate(see X. Creary, J. Org. Chem. 1987, 52, 5026) (4.8 g) in CC14 (80 mL) was added NBS (3.8 g), followed by benzoyl peroxide (100 mg). The reaction mixture was heated at reflux and was irradiated with a sun lamp for 1.5 h. The mixture was cooled down and diluted with hexane (50 mL) purified by filtration on a pad of silica gel. The filtrate was concentrated to give the title product for step 2 as a yellow-brown liquid (6.4 g) 1H NMR δ: (CD3COCD3), 1.48 (9H, m), 4.70 (2H, s), 7.62 (4H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[C:38](Cl)(=[O:40])[CH3:39]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:38](=[O:40])[CH3:39])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Acetyl chloride (0.28 mL, 0.42 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)acetamide (0.053 g, 49% yield) as a light tan solid. LCMS retention time=3.789 minutes and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.78-7.82 (m, 1H), 7.59 (t, 1H, J=8 Hz), 7.44-7.48 (m, 1H), 7.38-7.42 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.42 (s, 2H), 3.87 (t, 2H, J=8 Hz), 3.28 (s, 3H), 2.04 (dd, 2H, J=4 Hz and 12 Hz), 1.78 (s, 3H), 1.61-1.70 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[Li+].[CH3:16][CH:17]([N-]C(C)C)C.C(I)C>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([CH2:16][CH3:17])[CH:2]=1
Reactant: COC(=O)CC1=CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1C=C(CC(=O)OC)c2ccccc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl inden-3-ylacetate from Example 13, Step 1 (1 g, 5.32 mmol) in THF (10 mL) at -70° C. was added dropwise a solution of LDA (12.2 mL, 0.87 M, 2 eq.) in THF. The resulting orange solution was stirred for 30 minutes at -70° C. and then ethyl iodide (0.47 mL, 5.85 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was left to warm to room temperature while a precipitate appeared. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 1N HCl, then with brine, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel, eluting with a 1:19 mixture of ethyl acetate-hexane to afford pure title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:13][C:4]1[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=[C:2]([C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[CH:3]=1
Reactant: COc1cc(Br)cn2ncc(C#N)c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#N)c12
Temperature: 100 °C

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50.0 mg, 0.198 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (61.9 mg, 0.298 mmol), tri-t-butylphosphonium tetrafluoroborate (5.8 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (0) (9.1 mg, 9.9 μmol), and potassium fluoride (38.0 mg, 0.655 mmol) were suspended in DMF (2 ml) and sparged with argon for 10 minutes. The mixture was heated to 100° C. for 2 h. The reaction mixture was cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05%. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give an off-white solid. The residue was further purified by column chromatography on silica gel (methanol/dichloromethane gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H); 8.53 (s, 1H); 8.36 (s, 1H); 8.08 (s, 1H); 7.26 (s, 1H); 4.05 (s, 3H); 3.87 (s, 3H). LRMS (ESI) calculated for C13H12N5O [M+H]+, 254.1; found 254.1.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(O)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ccncc2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared as above) (14.4 g, 50 mmol), 4-chloropyridine HCl (1.0 eq., 8.0 g), TEA (2.2 eq.) are mixed in ethanol, and maintained under reflux overnight. The desired compound, N-t-butoxycarbonyloxy 2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine, is isolated by column chromatography, (silica gel) eluted with EtOAc and carried to the next step.