Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20])=[O:37]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)ccc4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (90 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 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 purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (186 mg, 74%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1>N1C=CC=CC=1.CCOCC>[C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (0.02 mol) of isovaleric acid chloride were added to 2.02 g (0.01 mol) of 9-amino-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 30 ml of absolute pyridine, and the mixture was stirred for 8 hours at room temperature. The mixture was then diluted with ether, and the precipitated crystals were separated off. The crystals were dissolved in water, the aqueous solution was purified with active charcoal and the free base was then precipitated by the addition of ammonia. It was filtered off under suction and dried.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1ccccc1CN)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.74 g, 3.2 mmol) and N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamide (0.76 g, 3.5 mmol) in a manner analogous to Example 2d. Product isolated as a white foam (0.847 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.87 (d, J=6.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.40-7.28 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.38 (t, J=5.4 Hz, 1H), 4.73 (d, J=6.1 Hz, 2H), 3.30 (s, 3H), 3.00 (s, 3H). MS=366 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1nc(C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) in DMF (10 mL) was added K2CO3 (479.7 mg, 3.471 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water, brine and concentrated under reduced pressure to give the product (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO>[NH2:27][S:24]([NH:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:25])=[O:26]
Reactant: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A solution of N-[2-({4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (3.7 g, 8.8 mmol) in methanol (70 mL) was treated with 2 M NaOH (18 mL, 35 mmol) and stirred at 25° C. for 2 h. The reaction mixture was quenched with 6 N HCl to pH˜7 and the methanol was removed under reduced pressure. The solid that precipitated was filtered and washed with water to give the desired product (3.2 g, 92%) as a white solid. LCMS for C11H14ClFN7O4S (M+H)+: m/z=394.0. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (dd, J=6.8, 2.1 Hz, 0.05H), 7.32-7.29 (m, 0.1H), 7.18 (dd, J=9.1, 9.1 Hz, 0.95H), 6.93 (dd, J=6.4, 2.7 Hz, 0.95H), 6.71-6.66 (m, 0.95H), 6.33 (br s, 1H), 3.35-3.27 (m, 2H), 3.10-3.06 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13]C)=[CH:12][C:7]=2[O:6][CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1
Reactant: COc1ccc2c(CC(C)(C)C)coc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)Cc1coc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −10° C. solution of the product of Step D (2.379 grams) in dry methylene chloride (35 mL) was added 1M boron tribromide solution (CH2Cl2; 3.70 mL). Warming to ambient temperature was followed by stirring for 1 hour. The reaction was partitioned between isopropyl acetate and aqueous sodium bicarbonate. The organic was washed twice with water and dried over magnesium sulfate. Filtration and removal of volatiles provided a residue which was chromatographed over silica gel (5:1 hex/ethyl acetate), giving the title compound.
Reaction SMILES: C[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)S([O-])(=O)=O.[NH3:18].CS([O-])(=O)=O>CO>[CH3:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([CH3:16])[CH:13]=1)[O:9][CH2:8][CH:7]([NH2:18])[CH3:2]
Reactant: Cc1cc(C)cc(OCCC(C)S(=O)(=O)[O-])c1
Reactant: N
Agent: CS(=O)(=O)[O-]
Solvent: CO
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A 20 cc autoclave was charged with 5.42 g (21 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethyl-methanesulfonate and 6 ml of methanol, and ammonia was added in an amount of 7.67 g which was 20 times, by mole, as much as the above methanesulfonate. The mixture was continuously stirred at 100° C. for 8 hours to finish the reaction. After the reaction mixture was allowed to cool, remaining ammonia was removed, and the reaction mixture was transferred into a 500 ml beaker with 50 ml of water and 20 ml of ethyl ether. A 20% hydrochloric acid aqueous solution was added until the reaction liquid was made acidic, and the reaction liquid was washed with 50 ml of diethyl ether three times. Then, while the water layer was cooled, a 20% sodium hydroxide aqueous solution was added to make it alkaline, and the reaction liquid was subjected to extraction with 50 ml of diethyl ether three times. The extract was dried over 10 g of anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 3.25 g of 1-(3,5-dimethylphenoxy)-2-aminopropane (boiling point 113° C./3 mmHg). This amount of 3.25 g corresponded to a yield of 86.6%, or was very high. The results of NMR and IR analyses were as follows.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:29][NH2:30]>CCO>[N:15]1([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17][C:12]2([C:3]3[CH:2]=[N:30][NH:29][C:4]=3[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11]2)[CH2:13][CH2:14]1
Reactant: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Reactant: NN
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.95 g, 5.10 mmol) and hydrazine (161 μL, 5.10 mmol) in EtOH (39 mL) was stirred at room temperature for 1 hour and then at 50° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (10-100% ethyl acetate in hexane) to afford benzyl 1H-spiro[chromeno-[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11 g, 58%). ESI-MS m/z calc. 375.2, found 376.3 (M+1)+; Retention time: 1.71 minutes (3 min run).
Reaction SMILES: CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3].C1(O)CCCCC1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:29]=[C:30]3[C:43]([C:44](=O)[C:45]=2[CH:46]=1)=[CH:42][C:41]1[C:32]([C:33](=O)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([CH3:48])[CH:35]=2)=[CH:31]3.Cl>C1COCC1.CC(C)=O>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]2[C:45](=[CH:44][C:43]3[C:30]([CH:29]=2)=[CH:31][C:32]2[C:41](=[CH:40][C:39]4[C:34]([CH:33]=2)=[CH:35][C:36]([CH3:48])=[CH:37][CH:38]=4)[CH:42]=3)[CH:46]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1=C2)C(=O)c1cc(C)ccc1C=3
Agent: CCC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: OC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc2cc3cc4cc5cc(C)ccc5cc4cc3cc2c1
Temperature: 145 °C

Procedure:
To a 500 mL three necked round bottom flask with a thermometer, and a distillation head was added 32.76 grams of aluminum tri(sec-butoxide) and 200 mLs of cyclohexanol. To this was added 9 grams 3,10-Dimethylpentacene-5,12-dione. The reaction mixture was heated to 145° C. At 140° C., 8.7 grams of a distillate was collected. The reaction mixture was heated at 140° C. for 43 hours and cooled to room temperature. A solid was isolated by centrifugation. The supernate liquid was poured off and the solid was slurried with 140 mLs of 1N HCl and isolated on a Buchner funnel. The solid was slurried three times with 100 mLs each 1N HCl and the solvent was poured off each time. The solid was slurried three times with 100 mLs of acetone and isolated by filtration. The solid was slurried three times with 100 mLs of THF and isolated by filtration. The residue was air dried to give 2,9-dimethylpentacene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:13]2[CH:14]=[C:15]([NH2:16])[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
2-methoxypyridine-5-boronic acid (0.133 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.091 g in 76% yield.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)(=[O:6])=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Sodium perborate tetrahydrate (105 mg, 0.68 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (10 mL) at 50° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a white solid (138 mg, 87%): Rf 0.5 (20% methanol in dichloromethane). 1H NMR (MeOH-d4, 300 MHz): δ 7.90 (4H, m, Ar—H), 7.70 (4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.29-7.49 (5H, m, Ar—H), 4.62 (1H, m, CHN) 4.41 (2H, s, PhCH2S), 3.42 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C33H31NO7S 585.674, found 586 (M+H)+, 608 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18](=O)[C:19]#[CH:20])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(O)(O)(=O)=O.[CH:27]1([NH:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28]1.[O-]CC.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][N:33]=[C:31]([NH:30][CH:27]4[CH2:29][CH2:28]4)[N:32]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)c1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CC1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1cccc2c(-c3ccnc(NC4CC4)n3)c(-c3cccc(Br)c3)nn12
Yield: 39 %

Procedure:
In a similar manner as described in Example 46 from 1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.45 g, 1.25 mmol), N-cyclopropylguanidine sulfate and sodium ethoxide (0.61 mL, 21 wt % in ethanol, 1.6 mmol) at room temperature was obtained 4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (0.21 g, 39%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.57 (d, 1 H), 8.12 (d, 1 H), 7.86 (t, 1 H), 7.57 (m, 2 H), 7.28 (m, 2 H), 7.06 (d, 1 H), 6.37 (d, 1 H), 5.38 (bs, 1 H), 2.84 (m, 1 H), 0.88 (m, 2 H), 0.63 (m, 2 H); MS m/z 440 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[N:38][CH:39]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:36]3[CH:37]=[N:38][CH:39]=[C:34]([CH2:33][O:32][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH:35]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cncc(CO[Si](C)(C)C(C)(C)C)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.5 g, 3.80 mmol), 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid (1.22 g, 4.57 mmol), potassium carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.027 g, 0.038 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at 110° C. in a pressure vessel for 6 hours and allowed to cool to room temperature. An analysis by LC/MS indicated the reaction was incomplete, and additional dichlorobis(triphenylphosphine)palladium(II)(0.035 g) was added. The reaction was heated at 110 C for 16 hours and allowed to cool to room temperature. The DME was removed under reduced pressure, and the resulting mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was dissolved in dichloromethane (15 mL) purified by chromatography according to the method described in Example 62 to provide 1.37 g of 1-{4-amino-7-[5-(tert-butyldimethylsilanyloxymethyl)pyridin-3-yl]-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[CH:13]([CH2:19][NH:20]C(OC(C)(C)C)=O)[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([CH2:19][NH2:20])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:29])=[O:5])=[O:28])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[3-(acetylthio)-2-tert-butyloxycarbonylaminomethylpropanoyl]-L-proline-tert-butyl ester (1.5 g) is dissolved in a mixture of anisole (6 ml) and trifluoroacetic acid (12 ml) and the solution is stored at room temperature for 1 hour. The solvent is removed in vacuo, the residue is distributed between water and ether. The aqueous phase is washed twice with ether and freeze-dried to yield 1-(3-acetylthio-2-aminomethylpropanoyl)-L-proline.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[C@@H:9]1[CH3:25])=[O:7])(C)(C)C.CC1C=C(C)N=C(N[C@@H]2CCCN(C([C:43]3[CH:48]=[CH:47][C:46](F)=[CH:45][C:44]=3[N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=O)[C@H]2C)N=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:51]1[N:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][N:16]=3)[C@@H:9]2[CH3:25])=[O:7])[N:54]=[CH:53][CH:52]=1
Reactant: Cc1cc(C)nc(N[C@@H]2CCCN(C(=O)c3ccc(F)cc3-n3nccn3)[C@H]2C)n1
Reactant: C[C@H]1[C@H](Nc2ccc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@H]1[C@H](Nc2ccc(C(F)(F)F)cn2)CCCN1C(=O)c1ccccc1-n1nccn1

Procedure:
(±)-trans-tert-butyl-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylate. Prepared analogous to Example 1 substituting (±)-trans-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone with the title compound from Step B, intermediate A-1 with intermediate A-4 and HATU with HBTU. MS (ESI) mass calcd. for C21H21F3N6O, 430.2; m/z found 431.2 [M+H]+. MP=154.7° C. (Mixture of 4 isomers, undefined ratio). 1H NMR (300 MHz, DMSO) δ 8.36 (d, J=21.8 Hz, 0.44H), 8.24 (d, J=12.9 Hz, 0.36H), 8.08 (d, J=1.3 Hz, 1.62H), 7.97 (s, 0.47H), 7.91 (d, J=8.2 Hz, 0.41H), 7.83-7.32 (m, 4.20H), 7.32-7.21 (m, 0.48H), 7.06-6.96 (m, 0.47H), 6.82 (d, J=8.9 Hz, 0.76H), 6.71 (dd, J=13.9, 7.0 Hz, 0.59H), 6.60 (s, 0.10H), 6.15 (d, J=8.8 Hz, 0.10H), 4.93 (d, J=6.0 Hz, 0.12H), 4.68 (q, J=6.8 Hz, 0.39H), 4.41 (t, J=13.4 Hz, 0.65H), 4.17-3.83 (m, 0.78H), 3.81-3.61 (m, 0.73H), 3.20 (d, J=14.4 Hz, 0.35H), 2.94 (t, J=11.7 Hz, 0.52H), 2.85-2.66 (m, 0.46H), 2.19-1.49 (m, 3.53H), 1.49-1.22 (m, 2.07H), 0.74 (d, J=6.9 Hz, 1.40H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:19](OCC)(OCC)OCC>>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]3[CH:19]=[N:2][N:1]=[C:3]3[N:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1
Product: FC(F)(F)c1cccc(-c2ccn3cnnc3n2)c1

Procedure:
A mixture of 2.0 g. of 2-hydrazino-4-(m-trifluoromethylphenyl)pyrimidine and 25 ml. of triethyl orthoformate is refluxed for 8 hours. Cooling gives the desired compound, m.p. 202°-203° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[C:7]([O:14][CH3:15])[CH:6]=1)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[CH:27]([NH2:29])=[O:28]>>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([C:3]2[N:29]=[CH:27][O:28][CH:2]=2)=[CH:6][C:7]=1[O:14][CH3:15]
Reactant: NC=O
Reactant: COc1cc(C(=O)CBr)cc(OC)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(-c2cocn2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.8 g, 0.96 mmol) in formamide (7 mL) in an oven-dried flask under argon was heated at 100° C. for 10 hours then 110° C. for 5 hours. After cooling to room temp, EtOAc and saturated aqueous NaHCO3 were carefully added and the mixture was stirred for 15 minutes. It was then extracted with EtOAc twice and the combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. Purification by chromatography (20-40% EtOAc-hexanes) provided 4-(4-bromo-3,5-dimethoxyphenyl)oxazole as a yellow solid (0.387 g, 58% yield).