Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28]O)[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[F:36][CH2:28][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:17]=2)[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]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1nc2ccccc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CF)n2Cc1cc(-c2ccc(F)cc2)no1
Temperature: -78 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
The methods described in Examples 30 and 31 were repeated on a larger scale to provide (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol. The reaction described in Example 31 was heated at reflux and was complete within three hours. Under a nitrogen atmosphere, a suspension of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol (2.31 g, 5.93 mmol) in dichloromethane (100 mL) was cooled to −78° C. (Diethylamino)sulfur trifluoride (DAST) (0.95 mL, 7.2 mmol) was added dropwise. The mixture was stirred for 30 minutes at −78° C. and then was allowed to warm to room temperature slowly and stirred for one hour. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous potassium carbonate. Additional dichloromethane and water were added to dissolve solids. The aqueous layer was separated and extracted with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 3% to 5% CMA in chloroform) followed by recrystallization from acetonitrile. The crystals were dried under high vacuum for 18 hours at 90° C. to provide 0.994 g of 2-(fluoromethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 192.0-193.0° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[C:17]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6]
Reactant: CCOC(=O)CC1CCCc2cc(OC)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
26.6 g of finely powdered aluminium chloride are added in portions to a solution of 10 g of 6-methoxy-1,2,3,4-tetrahydro-1-naphthyl-acetic acid ethyl ester in 50 ml of absolute methylene chloride whilst stirring at 5° C, and thereafter 16.9 g of benzoyl chloride are added sufficiently slowly that the reaction solution boils gently under reflux. After completion of the addition, the reaction mixture is allowed to boil for a further 30 minutes and is then allowed to cool to room temperature, after which it is poured onto 300 g of ice. The mixture is extracted with 3 times 100 ml of methylene chloride and the organic phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 500 g of silica gel, using methylene chloride as the eluting agent, gives 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-1-naphthylacetic acid ethyl ester of boiling point 190° C/0.04 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH2:21]([O:20][C:18]([C:17]1[N:15]=[CH:16][N:4]2[C:5]3[C:10](=[C:9]([Br:13])[CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=12)=[O:19])[CH3:22]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Product: CCOC(=O)c1ncn2c3cccc(Br)c3c(=O)n(C)c12

Procedure:
M.p. 272° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=2)[CH:10]=[CH:9][C:8]=1[F:14])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-3-(1-cyanocyclopropyl)-N-(2-fluoro-5-hydroxyphenyl)benzamide (6.50 g, 19.7 mmol), 2-chloro-5-nitropyridine (3.17 g, 20 mmol) and potassium carbonate (2.76 g, 20 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The 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/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (6.60 g, 74%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(I)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(Br)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[4-(2,4-Dichloro-phenyl)-2-(4-iodo-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (3.2 g, 5 mmol) was treated as described in general procedure G using 4-bromophenylboronic acid (2.0 g, 10 mmol) to give 5-{-4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:47][CH2:46][CH2:45]1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([C:46](=[O:47])[CH3:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To a solution of (±)-3-({6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) acetyl chloride (12 mg, 0.15 mmol) and TEA (20 mg, 0.2 mmol) are added at 0° C. After 30 min, the mixture is diluted with EtOAc, washed with water, brine, and the organic layer is dried over Na2SO4, filtered, and condensed. The residue is separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 638.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C>[C:23]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]2[NH:12]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Solvent: CC(=O)O
Product: CC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (207 mg) in acetic acid (2 ml) was added acetic anhydride (75 mg) with ice cooling. The solution was stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was dissolved in water (3 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was dried and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2-acetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (195 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=4)[CH2:20][NH:21][S:32]([CH3:31])(=[O:34])=[O:33])[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ncc2cnc3[nH]c(-c4cccc(CN)c4)cc3c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2cnc3[nH]c(-c4cccc(CNS(C)(=O)=O)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a flask was added (3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)methanamine (0.075 g, 0.27 mmol, Example #T.3.1), DMF (2.7 mL), DIEA (0.118 mL, 0.676 mmol) and MsCl (0.025 mL, 0.325 mmol). The mixture was stirred at rt for about 10 min. The mixture was purified directly by flash chromatography (25 g silica gel column, DCM/MeOH 1:0 to 10:1 with 2% 2.0 M NH3 in EtOH). The solid was dried under reduced pressure at about 60° C. for about 1 h to give N-(3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)benzyl)methanesulfonamide (0.057 g, 58%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z 356 (M+H)+. Syk IC50=B.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]([F:22])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:9]([F:22])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(F)c(COc2cccc(OC)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(OCc2cc(F)c(C(=O)O)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2,5-difluoro-4-[(3-methoxyphenoxy)methyl]benzoate (Preparation 28, 441 mg, 1.4 mmol) in THF (10 mL) was added aqueous lithium hydroxide (1 M, 1.6 mL) and the reaction mixture stirred under nitrogen at room temperature. After 5 hours, the reaction was evaporated in vacuo and the residue suspended in a water/EtOAc mixture (20 mL), acidified with a few drops of aqueous 1 M hydrochloric acid. The layers were separated and the aqueous layer further extracted with EtOAc (10 mL). The combined organics were dried over magnesium sulphate and concentrated in vacuo to yield the title compound as an off white solid which was used in the next step without further purification (371 mg, 88%):
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14]([C:18]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[N:20][CH:19]=2)[CH:15]=1
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
6-(5-Acetyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol) is dissolved in 20 mL of 20% TFA in DCM. The mixture is stirred at room temperature for 16 hrs. Then the solvent and the extra reagent are removed and the residue is purified by reversed phase chromatography to give 135 mg of 1-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:32])[C:30]=1[OH:31])[CH:26]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:31][C:30]1[C:29]([CH3:32])=[CH:28][C:25]([C:26]2[NH:10][C:8](=[O:9])[C:7]3[C:2](=[CH:3][C:4]([O:20][CH3:21])=[C:5]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:6]=3[O:11][CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:22]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1CN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2c(OC)c1CN1CCOCC1
Temperature: 115 °C
Reaction time: 6 h
Yield: 6.5 %

Procedure:
A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.
Reaction SMILES: [NH2:1][C:2]([NH:4][C@@:5]([CH3:18])([C:14](OC)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[I:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C@@:5]1([CH3:18])[NH:4][C:2](=[O:3])[NH:1][C:14]1=[O:15]
Reactant: COC(=O)[C@@](C)(Cc1cccc(I)c1)NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@]1(Cc2cccc(I)c2)NC(=O)NC1=O
Temperature: 110 °C
Yield: 69.7 %

Procedure:
A mixture of methyl N-(aminocarbonyl)-3-iodo-α-methyl-D-phenylalaninate (0.82 g) and potassium carbonate (624 mg) in dimethyl sulfoxide (5 ml) was heated to 110° C. for 3 h and then allowed to cool to 20° C. overnight. The mixture was diluted with EtOAc and washed with 2M HCl, brine, dried (MgSO4) and evaporated to dryness to give the title compound (521 mg) LCMS RT=2.61 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:17]([NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 121.6 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Butyl isocyanate (39 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. An addition amount of butyl isocyanate(100 μL, 0.888 mmol) was added to the reaction mixture and mixing was continued for another 6 days. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 44.4 mg (>100%) of the title compound.
Reaction SMILES: C([C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[C:17]([O:28][CH2:29][CH2:30][NH2:31])[CH:16]=2)=[O:13])=[C:10]([Cl:34])[N:9]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][CH2:30][CH2:29][O:28][C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:32]=[CH:33][CH:8]=[N:9][C:10]=2[Cl:34])[CH:20]=[CH:19][C:18]=1[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(C(F)(F)C(F)(F)F)c(OCCN)c2)c(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 500 mg (0.98 mmol) Boc-N-[3-(2-Amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 ml CH2Cl2 was added 10 ml TFA and stirred for 2 h. The reaction was concentrated down, treated with 6N NaOH, and extracted 3 times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, concentrated down, and dried under vacuum, yielding the titled compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 8.8 mL) was added dropwise over 10 min to a suspension of the product from example 22 step (iii) (0.78 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 1 h. EtOAc (10 mL) was added and then the mixture stirred for 10 min before being added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.3 g.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:17])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Yield: 79.2 %

Procedure:
To 17 g (90 millimoles) of p-azidocinnamic acid was added 53 g (450 millimoles) of thionyl chloride, and the resulting solution was refluxed with heating. When the generation of SO2 gas terminated, the reflux was stopped, after which the excess thionyl chloride was distilled off under reduced pressure to obtain 14.8 g of p-azidocinnamic acid chloride as the distillation residue.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[C:16]2=[CH:17][N:18]=[C:19]([CH:20]3[CH2:23][C:22](=[O:24])[CH2:21]3)[N:15]2[N:14]=[CH:13][N:12]=1>CN(C=O)C>[Br:8][C:17]1[N:18]=[C:19]([CH:20]2[CH2:23][C:22](=[O:24])[CH2:21]2)[N:15]2[C:16]=1[C:11]([O:10][CH3:9])=[N:12][CH:13]=[N:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncnn2c(C3CC(=O)C3)ncc12
Solvent: CN(C)C=O
Product: COc1ncnn2c(C3CC(=O)C3)nc(Br)c12

Procedure:
NBS (2.00 g, 0.01 mol) was added in one portion to a stirred, cooled solution of 3-(4-methoxyimidazo[5,1-f][1,2,4]triazin-7-yl)cyclobutanone (6.0 g, 0.027 mol) in DMF (40 mL) at 0° C. under N2. Two other portions of NBS (2.00 g, 0.01 mol) were added after 15 and 30 min respectively. The reaction was stirred with cooling for 5 h. The reaction mixture was partitioned between EtOAc (1 L) and brine (200 mL) and then 83 of 219 organic layer was washed with brine (2×150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using hexanes:EtOAc (1:1) as the eluent. 1H NMR (400 MHz, Chloroform-d) δ 3.45-3.60 (m, 3H), 3.66-3.77 (m, 2H), 4.19 (s, 3H), 8.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].[C:26]1(=O)[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.O>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:4]1[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:6]2[C:11](=[C:2]([N:1]3[C:29](=[O:30])[C:28]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]4[C:26]3=[O:31])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc(N)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(N2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Yield: 99.3 %

Procedure:
A mixture of 8-amino-6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline (I) (6.96 g, 20 mmol) and phthalic anhydride (3.25 g, 22 mmol) in xylene (100 mL) was refluxed with water removal via a Dean-Stark trap for 24 hours. After cooling, filtration gave 9.5 g (100%) of the title compound, mp 228°-30° C. Recrystallization from ethanol raised the mp to 228°-31° C.