Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]([NH:19]C(=O)OC(C)(C)C)([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CCO>[NH2:19][C:16]([CH3:17])([CH3:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Yield: 84.5 %

Procedure:
Tert-butyl 2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate (1.26 g, 3.05 mmol) was dissolved in 10 mL of EtOH and treated with 10 mL of 2 M HCl in EtOH. After heating at reflux for 2 h, the reaction mixture was cooled and concentrated under reduced pressure. The resulting yellow solid was dissolved in 50 mL of H2O and extracted with CHCl3 (20 mL). The organic layer was discarded and the aqueous portion was made basic (pH˜12) by addition of concentrated NH4OH solution. This was then extracted with CHCl3 (4×20 mL) and the combined organic portions were dried with Na2SO4 and concentrated to give 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine (808 mg) as a light brown powder.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29](C(OCC=C)=O)[N:28]=1.Cl.C1C[O:45][CH2:44]C1>C1CCCCC1.CO>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]2[C:16]=1[C:17]([C:29]1[N:28]=[C:27]([O:26][CH3:25])[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1)([OH:19])[O:18][C:44]2=[O:45]
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: C=CCOC(=O)c1nc(OC)cc(OC)n1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CO
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)ccc(Cl)c32)n1

Procedure:
A mixture of 1.22 g of TMEDA and 60 ml of THF is prepared under anhydrous condition and cooled to -10° with stirring. 36.03 g of a 20.5% solution of n-BuLi in cyclohexane is added and after 30 mins stirring the solution is cooled to -60°. A solution of 10.0 g of 2,5-dichlorobenzoic acid in 40 ml of THF is added over 10 min. at -60°. After a further 30 mins of stirring this solution is added over 15 min under argon pressure to a solution of 8.97 g of allyl 4,6-dimethoxypyrimidine-2-carboxylate in 60 ml of THF at -25° and the clear yellow solution cooled to -25°. After stirring at -20° for 60 mins, 60 ml of 10% HCl are added and the temperature allowed to rise to 13° with stirring over a 15 min period. The organic phase is separated and evaporated to yield a viscous residue to which is added 17 ml of methanol. The resulting suspension is cooled in an ice/water bath, filtered and the crystals washed with 2×10 ml methanol and dried under vacuum at 70° C. to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>C1COCC1>[C:19]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
Compound 2f (500 mg, 1.6 mmol) in 10 mL of THF was treated with acetyl chloride (0.15 mL, 2.08 mmol) and triethylamine (0.22 mL, 2.08 mmol). After stirring for 2.5 h the solid was collected. The filtrate was evaporated in vacuo to give 0.48 g of Compound 3f. MS m/z=331 (M+1).
Reaction SMILES: [Mg].[CH3:2]I.[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl>CCOCC.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]([F:14])([F:15])[F:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Magnesium (3.71 g/0.153 mol) was placed into a flask of the egg-plant type, followed by the replacement of air by nitrogen and addition of 30 ml of ether. While gently stirring the mixture, a solution of methyl iodide (24.4 g/0.172 mol) in ether (20 ml) was slowly added dropwise to the mixture, and the resulting mixture was refluxed with heating for 30 minutes. The mixture was cooled to room temperature, and a solution of 4-trifluoromethylbenzaldehyde (25.1 g/0.144 mole) in ether (20 ml) was slowly added dropwise to the mixture. The mixture was refluxed with heating for 2 hours, 30 ml of water was added dropwise to the mixture with ice cooling, and hydrochloric acid (2N) was further added until the aqueous layer became transparent. The aqueous layer was separated from an ethereal layer, the aqueous layer was subjected to extraction with ether, and the ethereal layers were combined, and the combined layer was washed with an aqueous solution of common salt three times. After removal of ether, the layer was distilled at a reduced pressure, giving 1-(1-hydroxylethyl)-4-trifluoromethylbenzene [compound (I)] represented by the formula CF3C6H4CH(OH) CH3, b.p. 53°~55° C. (50.5 Pa), colorless transparent liquid, yield 98.3%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-:21].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][C:11]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:21])=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:19]
Reactant: [Cl-]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccc2oc3ccc(C(=O)CCCCl)cc3c2c1

Procedure:
To a solution of 30 g (0.18 mole) of dibenzofuran and 62.7 g (0.44 mole) of 4-chlorobutyryl chloride in 1.0 l. of dry methylene chloride previously cooled to -10° C. was added portionwise 49.9 g (0.37 mole) of aluminum chloride with stirring. When the addition was complete the reaction mixture was heated at reflux for 2 hours then stirred at room temperature for an additional 12 hours. The reaction mixture was decomposed with ice water/HCl to give the desired product which was recrystallized from isopropyl alcohol. M.P. 102°-104° C., λmaxCHCl3 252, Elcm1% 1790.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[N:4]=1.N1(C2C=C[C:25]([CH:26]=[O:27])=CC=2)C=CC=N1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:25][CH:26]=[O:27])=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COc1ccnc(-c2ccc(C=O)cc2)n1
Product: COc1ccnc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methoxy-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 13) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 241 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:14][C:4]1[CH:5]=[C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(C)(C)C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)(C)C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g, 0.10 mol) in TFA (80 mL) was cooled to 0° C. N-bromosuccinimide (17.8 g, 0.10 mol) was added in small portions keeping the temperature below 5° C. The orange solution was stirred for 2 h/25° C. and evaporated to dryness. Water (200 mL) was added and the mixture was stirred vigorously for 1 h. The crude product was filtered off and recrystallized from boiling MeOH. The pure product was isolated as white needles. Yield: 19.3 g (76%). GCMS: >99%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:52][CH2:53]5)=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 42.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-9) (200 mg, 0.53 mmol) was coupled with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 40) (251 mg, 0.64 mmol) in sodium carbonate (168 mg, 1.59 mmol) PdCl2 (dppf) (19 mg, 0.0265 mmol), 1,2-Dimethoxyethane/water (25/3 ml) to afford 160 mg (59.47% yield) of the titled compound. MS: m/z=707.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].[C:17]1([S:23]([O-:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].C(O)=O>O.CO>[C:17]1([S:23]([CH:7]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(N)=O
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(c1cccnc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine-3-carbaldehyde (5.36 g, 50 mmol), tert-butyl carbamate (11.7 g, 100 mmol, 2 equivalents), sodiumphenylsulfinate (20.36 g, 124 mmol, 2.48 equivalents), formic acid (1.89 ml, 2.30 g, 1 equivalent), methanol (55 ml) and water (111 ml) are mixed and vigorously stirred at room temperature for 3 d. The product precipitates in the form of colorless crystals which are collected by filtration, washed with water and a little MTBE and dried in vacuo. Yield: 4.10 g (24% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13]>C(#N)C.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: C=C(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 0.5 h

Procedure:
After 26.8 g of 5-aminobenzotriazole was dissolved in a mixture of acetonitrile (300 ml) and pyridine (40 ml), 46.5 g of methacrylic acid chloride was added dropwise. The resulting solution was concentrated and 200 ml of a 10% aqueous solution of sodium hydroxide was added. After the mixture was agitated for 30 minutes, it was neutralized with dilute hydrochloric acid and the end compound was obtained as a solid precipitate in an amount of 27.3 g (yield, 6.7%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:29])[CH3:28]>>[CH2:27]([O:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:28]
Reactant: CCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of ethanol was stirred while heating at 60° C. for two hours and then at 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3-ethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 69”).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[Br-].[CH:15]1([Zn+])[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: [Zn+]C1CCCC1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)nc(C2CCCC2)c1
Temperature: 85 °C

Procedure:
Under argon, Pd(dppf) (2.00 g, 2.4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (32.0 g, 0.159 mol) in THF (100 mL). A 0.5 M solution of cyclopentylzincbromide in THF (330 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 3 h before it is cooled to rt. The reaction mixture is concentrated, diluted with 1 N aq. HCl (275 mL) and extracted with TBME (275 mL). The org. extract is washed with 1 N aq. HCl (275 mL), filtered over Celite and washed with water (275 mL). The org. extract is concentrated and dried to give crude 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (34.8 g) as a brown oil. This material is dissolved in ethanol (180 mL), water (45 mL) and 32% aq. NaOH solution (45 mL). The mixture is stirred at 90° C. for 30 min before it is cooled to rt. The ethanol is evaporated and the remaining solution is diluted with water (150 mL) and extracted with DCM (200 mL). The aq. phase is acidified by adding 32% aq. HCl (45 mL) and then extracted twice with DCM (2×100 mL). The org. extracts are combined and concentrated. The crude product is purified by crystallisation from hot acetonitrile (174 mL). The crystalline material is collected and dried at 50° C. under HV. From the mother liquor a second crop of crystalline material can be obtained. The two crops are combined to give 2-cyclopentyl-6-methoxy-isonicotinic acid (24.1 g) as a pale grey crystalline powder; LC-MS: tR=0.93 min, [M+1]+=222.02; 1H NMR (CDCl3): δ1.68-1.77 (m, 2H), 1.81-1.90 (m, 4H), 2.03-2.12 (m, 2H), 3.15-3.25 (m, 1H), 3.99 (s, 3H), 7.18 (d, J=1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])([CH3:11])[CH2:10]1)[CH:7](O)[CH2:6][CH2:5]2)([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+].[C:21]1(C)C=CC=CC=1>>[CH:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])([CH3:11])[CH2:10]1)[C:7]([CH3:21])=[CH:6][CH2:5]2)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(C)C12CCC(O)C(C1)C(C)(C)C2
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CC1=CCC2(C(C)C)CC1C(C)(C)C2
Yield: 81 %

Procedure:
A solution of 5-isopropyl-7,7-dimethyl-bicyclo[3.2.1]octan-2-ol (18.5 g, 88 mmol) and KHSO4 (100 mg) in toluene (250 ml) was heated 36 h in a Dean-Stark apparatus. The solution was cooled and washed once with water and brine, dried (MgSO4) and concentrated in vacuo to yield 5-isopropyl-2,7,7-trimethyl-bicyclo[3.2.1]oct-2-ene (13.77 g, 81%). 13H-NMR (100 MHz, CDCl3): 140.4 (s), 118.7 (d), 52.1 (d), 51.5 (t), 46.1 (s), 46.0 (s), 39.1 (t), 37.6 (d), 37.4 (t), 31.5 (q), 26.9 (q), 24.6 (q), 18.2 (q), 18.0 (q) ppm. GC/MS (EI): 192 (M+, 17), 177 (4), 149 (22), 136 (21), 121 (15), 107 (18), 93 (100), 77 (28), 57 (17), 41 (23). IR (ATR): 2957 s, 2933 s, 2869 m, 1468 m, 1452 m, 1366 m cm−1.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([OH:26])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:34]=[N+:35]=[N-:36].[Na+]>CC(C)=O.O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([N:34]=[N+:35]=[N-:36])=[O:26])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Ethyl chloroformate (143 mL, 1.48 mol) was added to a solution of (trans)-2-(4-(benzyloxy) phenyl)cyclopropanecarboxylic acid (Intermediate S, 190 g, 0.70 mol), Triethyl amine (229 mL, 1.63 mol) in acetone (2.8 L) at −20° C. and stirred for 1 h, then a solution of NaN3 (138 g, 2.1 mol) in water (200 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, residue was dissolved in EtOAc (2 L), washed with water (2 L), brine (1 L), dried over anhydrous Na2SO4, filtered and evaporated to afford (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide (178 g, 85.9%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:13]3[N:18]=[CH:17][S:16][C:14]=3[N:15]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:13]3[N:18]=[CH:17][S:16][C:14]=3[N:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])[N:11]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COC(=O)c1cccc(-c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a stirred solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid methyl ester (0.85 g, 2 mmol) in 20 mL of THF and 20 mL of methanol was added a solution of NaOH (0.08 g, 20 mmol) in 2 mL of water at room temperature. Then the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was suspended in 50 mL of THF, then treated by 6N HCl until pH=3. The solvent was evaporated and then dissolved in 30 mL of THF, filtered. The filtrate was evaporated to give 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (0.8 g, 97.5%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.15 (s, 1H), 10.18 (s, 1H), 9.38 (s, 1H), 8.98 (s, 1H), 8.61 (d, 1H, J=8.1 Hz), 8.06 (d, 1H, J=7.5 Hz), 7.84 (d, 1H, J=2.4 Hz), 7.64 (t, 1H, J=7.8 Hz), 7.42 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.98 (d, 1H, J=8.7 Hz), 3.82 (s, 3H), 3.77 (s, 3H). LC-MS: 409 [M+H]+, 839 [2M+Na]+, tR=1.74 min. HPLC: 98.38% at 214 nm, 97.29% at 254 nm, tR=3.44 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:25][CH2:26][CH3:27])[C:13]2[C:22]3[CH:21]=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:24]=1)[CH3:8].I[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[C:34]([O:33][C:32](=[O:38])[NH:31][CH2:30][CH2:29][O:23][C:20]1[CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]3[N:24]=[C:11]([CH2:10][O:9][CH2:7][CH3:8])[N:12]([CH2:25][CH2:26][CH3:27])[C:13]=3[C:22]=2[CH:21]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCI
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2cnc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Temperature: 65 °C
Yield: 90.9 %

Procedure:
Solid cesium carbonate (18.33 g, 56.22 mmol) was added to a solution of 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (10.7 g, 37.5 mmol), prepared in Parts A-I, in DMF (185 mL). tert-Butyl 2-iodoethylcarbamate (11.17 g, 41.2 mmol), prepared in Parts J and K, was added, and the reaction mixture was heated at 65° C. for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic fraction was washed with water (4×100 mL) and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a black oil. The oil was purified by column chromatography on silica gel (eluting with 98:2 dichloromethane:methanol) to yield 14.6 g of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate as a tan, waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: Nc1ccncc1F
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4F)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-fluoro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 121. 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (d, J=6.60 Hz, 6 H) 1.62 (s, 2 H) 1.66-1.73 (m, 2 H) 2.84-2.93 (m, 2 H) 3.43-3.46 (m, 2 H) 4.23-4.31 (m, 4 H) 4.79-4.87 (m, 1 H) 4.87-4.94 (m, 1 H) 7.19 (d, J=3.30 Hz, 1 H) 8.08 (s, 1 H) 8.25 (d, J=6.05 Hz, 1 H) 8.33 (d, J=2.20 Hz, 1 H) 8.65-8.70 (m, 1 H). LRMS (ESI): 417.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:9][N:8]=1.S(Cl)(Cl)=O.O1CC[CH2:30][CH2:29]1.[O-]CC.[Na+]>O>[CH2:29]([O:13][C:11]1[N:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=1)[CH3:30]
Reactant: C1CCOC1
Reactant: O=c1[nH]c(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1nc(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-(2-pyridyl)-6-(4-trifluoromethylphenyl)-1,2,4-triazin-5-one (10.00 g, 31.4 mmol) and thionyl chloride (100 ml) was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and the solvent was distilled off. To the residue were added tetrahydrofuran (100 ml) and sodium ethoxide (10.69 g, 157 mmol, 15.0 eq.), and the mixture was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and water (300 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride (300 ml), and washed with water (200 ml), and then washed with 5% brine (200 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting solid was purified by flash silica gel column chromatography (ethyl acetate-hexane) to give the title compound (7.57 g, 70%) as pale yellow prisms.