Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.Cl.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.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:3]2[C:2](=[N:7][C:6]([CH3:8])=[CH:5][CH:4]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(O)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2oc([C@@H]3CCCN3C(=O)OC(C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.10 g (13.2 mmol) sample of 6-iodo-2-picoline-5-ol (Aldrich Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.377 g, 1.98 mmol) and triethylamine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 1 mL of DMF, was added carefully. The reaction was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with 2 N HCl and extracted with ether. The aqueous layer was adjusted to pH 10 with K2CO3, then extracted with CH2Cl2. The extract was washed with 20% NaOH, brine, dried over MgSO4, and the solvent was removed. The residue was repeatedly dissolved in toluene and distilled to azeotropically remove the DMF. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 521 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.33 and 1.47 (2 s, 9H), 1.90-2.30 (m, 4H), 2.63 (s, 3H), 3.45-3.65 (m, 2H), 4.95 and 5.10 (2 s, 1H), 5.58 (s, 1H), 7.02 (d, 1H), 7.55 (d, 1H); MS m/z: 303 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(CC)CC.[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH2:42])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH:42][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:24])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
Ethyl bromoacetate (167 mg) and Et3N (101 mg) were added to the solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (530 mg) in toluene (3 mL). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by Mass Directed Auto Prep to afford ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycinate (D86) (132 mg) as a yellow solid. MS (ES): C25H27ClN4O4 requires 482; found 483.2 (M+H+).
Reaction SMILES: C(OC[N:11]1[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:13])(=O)C1C=CC=CC=1.[OH-].[Na+]>N1C=CC=CC=1.O>[C:22]([O:21][CH2:20][N:14]1[C:15](=[O:16])[C:17]([F:19])=[CH:18][NH:11][C:12]1=[O:13])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCn1cc(F)c(=O)n(COC(=O)c2ccccc2)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCn1c(=O)[nH]cc(F)c1=O)c1ccccc1
Reaction time: 4 h

Procedure:
In a mixture of 10 ml of pyridine and 10 ml of water was dissolved 4 g (0.01 mol) of 1,3-bis(benzoyloxymethyl)-5-fluorouracil. A 5% aqueous caustic soda solution was slowly added dropwise to the solution under agitation while maintaining the pH value of the liquid at 10~11. The mixture was kept for 4 hours at 60° C. whereby alkaline hydrolysis of the starting 1,3-bis(benzoyloxymethyl)-5-fluorouracil was effected. After completion of the hydrolysis reaction, the reaction liquid was concentrated under reduced pressure and cooled. Any remaining unreacted 1,3-bis(benzoyloxymethyl)-5-fluorouracil was then precipitated out and filtered off and the filtrate was subjected to a column chromatographic treatment using a column packed with silica gel. Using a mixture (3:1 in mixing ratio) of benzene and ethyl acetate as eluent, 1-benzoyloxymethyl-5-fluorouracil aimed at was separated as a first elution component. 3-Benzoyloxymethyl-5-fluorouracil formed as by-product was also separated as a second elution component. The yields of 1-benzoyloxymethyl-5-fluorouracil and 3-benzoyloxymethyl-5-fluorouracil were 0.92 g (yield: 35%) and 0.65 g, respectively. After recrystallization from benzene of the crude product, the desired 1-benzoyloxymethyl-5-fluorouracil was obtained as white crystals melting at 179°~180° C.
Reaction SMILES: [OH:1][C:2]([P:8]([OH:10])[OH:9])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][CH2:13][CH2:14]O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CCOCC>[OH:1][C:2]([PH:8](=[O:10])[O:9][CH2:14][CH2:13][O:12][CH3:11])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COCCO
Reactant: CCCCC(C)(O)P(O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)[PH](=O)OCCOC
Reaction time: 3 h

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid prepared as described in Example 8 (0.166 g. 0.001M), 2-methoxyethanol (0.076 g. 0.001M) and dimethylaminopyridine (0.01 g.) are stirred in THF (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0.001M) is added portionwise and the mixture is stirred for 3 hours. Ether (10 ml.) is added and the dicyclohexylurea is filtered off. The filtrate is evaporated and the residue is dissolved in chloroform and washed with water. Evaporation of the chloroform gives an oil which is purified on silica using ethyl acetate as eluant. There is obtained 2-methoxyethyl (1-hydroxy-1,4-dimethylbutyl)phosphinate.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]([CH2:20][O:21][P:22]([O:29]C(C)(C)C)([O:24]C(C)(C)C)=[O:23])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)(C)(C)C.[ClH:35].C(O[C:39](=N)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][CH3:48])[CH:41]=1)C>CO>[ClH:35].[NH2:7][C@:8]([CH3:19])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][C:39]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][CH3:48])[CH:41]=3)=[N:18][C:13]=2[CH:12]=1)[CH2:20][O:21][P:22](=[O:23])([OH:24])[OH:29]
Reactant: CCOC(=N)c1cccc(OCC)c1
Reactant: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(O)c(N)c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCOc1cccc(-c2nc3cc(CC[C@@](C)(N)COP(=O)(O)O)ccc3o2)c1
Temperature: 25 °C

Procedure:
A solution of [(R)-3-(3-Amino-4-hydroxy-phenyl)-1-(di-tert-butoxy-phosphoryloxymethyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (157.5 mg, 0.313 mmol) and 3-ethoxy-benzimidic acid ethyl ester hydrochloride in dry methanol (2 mL) was stirred for 20 minutes at 120° C. in a closed vial (microwave reactor). After cooling to RT the precipitate was filtered off, washed 2× with MeOH, 3× with water and 3× with diethyl ether. After drying in vacuum, the precipitate was dissolved in a mixture of diethyl ether/HCl (4 mL, 2M) and methanol (1 mL). After evaporation of the solvents the title compound was obtained as colorless crystals. 1H-NMR (CD3OD): δ=7.76 (d; 1H), 7.71 (s; 1H), 7.61 (bs; 2H), 7.47 (m; 1H), 7.37 (m; 1H), 7.14 (d; 1H), 4.24-4.00 (m; 4H), 2.89 (m; 2H), 2.10 (m; 2H), 1.47 (s; 6H); MS (ESI+): 421.4 [M+H]+
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[C:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([C:47](O)=[O:48])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:47]([CH:43]4[O:44][CH2:45][CH2:46][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]4)=[O:48])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(C(=O)OC(C)(C)C)CCO3)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of EDC (125 mg, 0.54 mmol) and HOAt (74 mg, 0.54 mmol) in DMF (2 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (117 mg, 0.45 mmol) (Example 15B) and (rac)-BOC-2-carboxymorpholine (125 mg, 0.54 mmol) and the mixture stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was then washed successively with saturated aqueous sodium bicarbonate, brine and then dried (MgSO4). The solution was evaporated to dryness in vacuo and the residue purified by flash column chromatography [SiO2, gradient elution: EtOAc-hexanes (1:1)-EtOAc-MeOH (80:20)] to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-BOC-2-morpholine carboxamide (65 mg) as a colourless solid. (LC/MS (acidic method): Rt 2.65 min, [M+H]+ 473).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)#[N:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: N#Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-cyanobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37](=[O:41])[C:38](Cl)=[O:39])=[CH:29][CH:28]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:15])([F:16])[F:17])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:38](=[O:39])[C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([O:26][CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[O:41])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(F)(F)F
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1C(F)(F)F

Procedure:
5-tert-Butyl-2-methoxy-3-trifluoromethyl-phenylamine (32 mg, 0.165 mmol) was dissolved in 2 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.232 mmol), prepared as described before, and DIEA (0.02 mL, 0.50 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=558. Observed mass=559
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>O>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C(C)=NNc1ccc(O)cc1[N+](=O)[O-]
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=NNc1ccc(OCCCOC)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a mixture of ethyl 2-[(4-hydroxy-2-nitrophenyl)hydrazono]propanoate (6.81 g), potassium carbonate (3.52 g) and N,N-dimethylformamide (100 mL) was added 1-bromo-3-methoxypropane (3.90 g) at 60° C., and the mixture was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (3.67 g, yield 42%) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:4]([OH:21])[CH:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]2[N:12]=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[O:21][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2nc(-c3ccncc3)oc2cc1Cl
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a mixture of 1.01 g of N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 10 ml of tetrahydrofuran and 0.92 g of triphenylphosphine, 1.53 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant crystals washed with methanol to give 0.66 g of 6-chloro-2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 80”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)cc(F)c1C=O
Temperature: 0 °C
Yield: 57.3 %

Procedure:
3,5-Difluoroanisole (50 g, 0.35 mol) was charged to a 3-neck flask fitted with thermometer, dropping funnel and argon bubbler. Dichloromethane (200 mL) was added and the solution was cooled in ice-water. Titanium (IV) chloride (61.5 mL, 0.56 mol) was added dropwise (15 min), followed by dropwise addition of α,α-dichloromethyl methyl ether (31.5 mL, 0.35 mol) so that the temperature was maintained <10° C. (approx 20 min). The reaction was stirred in ice-water for a further 140 min, poured into ice-water (1 L), then extracted thrice with DCM. The organic solutions were washed with water, brine then dried (MgSO4) and evaporated. The crude product was purified using the Versaflash (80×300 mm SiO2 cartridge, gradient from DCM to 5% EtOAc) in 7 separate batches to give the title compound (34.5 g, 57%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:30][CH3:31].Br[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:33]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:25]([NH:28][CH3:29])(=[O:26])=[O:27])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:30][CH3:31])([CH3:35])[CH3:34]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(O)c(OC)cc23)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OC(C)C)c(OC)cc23)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A solution of 3-{[7-hydroxy-6-(methyloxy)-4-quinazolinyl]amino}-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (170 mg, 0.37 mmol) in DMF (5 mL) was treated with 2-bromopropane (181 mg, 1.48 mmol) and K2CO3 (154 mg, 1.11 mmol) and stirred at 60° C. for 16 hours before being poured into water. The precipitate that formed was collected by filtration, washed with MeOH, and dried to give 3-(7-isopropoxy-6-methoxy-quinazolin-4-ylamino)-N-methyl-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (80 mg, 43%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C(Cl)Cl>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 126 (150 mg, 0.346 mmol) in DCM (7 mL) was added isopropyl isocyanate (265 mg, 3.11 mmol) and the reaction mixture was heated to reflux for 8 hours. The mixture was cooled to RT and concentrated. Purification by column chromatography (EtOAc) afforded the title compound 128 which was further triturated with Et2O (90 mg, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.50 (d, J=5.28 Hz, 1H), 8.49 (s, 1H), 7.93 (d, J=8.41 Hz, 2H), 7.70 (m, 1H), 7.63 (d, J=8.41 Hz, 2H), 7.35 (t, J=9.19 Hz, 1H), 7.11 (m, 1H), 6.60 (d, J=5.48 Hz, 1H), 6.15 (d, J=7.63 Hz, 1H), 3.74 (m, 1H), 3.59-3.40 (m, 4H), 1.88-1.79 (m, 4H), 1.09 (d, J=6.46 Hz, 6H). MS (m/z)=519.65 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH:12]3[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]([CH3:26])[CH3:25])=[O:22])[C:16]4[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=4[N:14]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:13]3=[O:44])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46]>>[C:45]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH2:11][CH:12]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:24]([CH3:25])[CH3:26])=[O:22])[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:13]2=[O:44])=[N:7]1)(=[O:47])[CH3:46]
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1nc(CC2C(=O)N(CC(=O)N(c3ccc(F)cc3)C(C)C)c3ccccc3N(c3ccccc3)C2=O)c2ccc(F)cc21

Procedure:
300 mg (0.505 mmol) 2-[3-(6-Fluoro-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-fluoro-phenyl)-N-isopropyl-acetamide, prepared as in Example 63, is dissolved in 15 mL Acetic anhydride and heated at reflux 1 h. The solvent is removed in vacuo and the residue purified by preparative HPLC on a Delta-Pak C-18 column eluted from 35% to 60% CH3CN in H2O with 0.1% TFA buffer over 30 minutes at 150 mL/min. The appropriate fraction is frozen and lyophilized to give 144 mg (0.226 mmol) of the title compound as a white lyophilizate: 1H NMR (CDCl3, 300 MHz) δ8.04 (m, 1H), 7.76 (m, 1H), 7.50 (d, 1H, J=8.0), 7.39-7.08 (m, 12H), 6.98 (d, 1H, J=7.8), 5.02 (m, 1H), 4.32 (d, 1H, J=16.6), 4.30 (t, 1H), 4.10 (d, 1H, J=16.6), 3.75 (m, 1H), 3.57 (m, 1H), 2.63 (s, 3H), 1.08 (m, 6H); low resolution MS (FAB) m/e 636.1 (MH+); TLC Rf =0.30 (EtOAc/Hexanes, 1:2).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.S(Cl)([Cl:13])=O>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([Cl:13])=[O:10])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cn(C)nc1C(=O)O
Product: Cc1cn(C)nc1C(=O)Cl

Procedure:
1,4-Dimethyl-1H-pyrazole-3-carboxylic acid (190 mg) was weighed to a round bottom flask and thionyl chloride (1 ml) was added. The reaction was heated to reflux for 6 h then overnight at RT. After this time thionyl chloride was evaporated and the residue azeotroped with toluene to afford the title compound, 200 mg.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[CH3:1][CH:2]([CH3:25])[CH:3]([N:8]([CH3:26])[C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Reaction time: 0.08 h

Procedure:
To methyl 3-methyl-2-(5-(4-nitrophenyl)thiazole-2-carboxamido)butanoate (Intermediate 2, step C, 1 g) in DMSO (10 ml), to this cesium carbonate (1.346 gm) was added and the reaction mixture was stirred for 5 minutes. To this, methyliodide (0.258 ml) was added and the reaction mixture was stirred for 1 hour. Reaction mixture was quenched using water. The residue obtained was filtered and dried to obtain the title compound. Yield: 0.870 gm (83%); 1H NMR (DMSO-d6, 300 MHz): δ 8.65 (s, 1H), 8.33 (d, 2H), 8.08 (d, 2H), 6.18-4.75 (d, 1H), 3.68 (s, 3H), 3.46-2.96 (s, 3H), 2.38 (m, 1H), 1.03 (d, 3H), 0.91 (d, 3H); MS (ESI) m/z 378 [M+H]+, 400 [M+Na]+
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS(O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.C(O)CCCCCCCCC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOS(C)(=O)=O
Reactant: CCOC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCO
Solvent: CCO
Product: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Ethyl 1-piperazinecarboxylate (77.3 g, 0.28 mole), 1-decanol methanesulfonate (77.3 g, 0.28 mole) from the condensation of 1-decanol with methane sulfonyl chloride, K2CO3 (39.0 g, 0.28 mole), and 500 mL of EtOH were combined and refluxed for 2 days under N2. After cooling to room temperature, the reaction was partitioned between water and Et2O. The organic layer was separated, washed 3 times with water, dried over Na2SO4 and stripped of all solvent under reduced pressure to yield the crude product oil. Chromatographic purification of the crude oil gave 53.4 g of ethyl 4-decyl-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([F:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([F:12])[CH2:7][CH2:8][N:9]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1(F)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
4-Fluoro-piperidine-4-carboxylic acid ethyl ester (1.263 g), synthesis described in patent application US2004/10013, was dissolved in pyridine (70 ml) and p-toluenesulfonyl chloride (1.512 g) was added and the mixture was stirred at RT for 48 h under an argon atmosphere. Then the solvent was evaporated off, the residue partitioned between AcOEt and aqueous HCl, the organic layer was separated, washed with brine, dried over sodium sulphate and concentratedin vacuo to give a brown oil which was purified by flash chromatography (AcOEt/Heptane, gradient from 0 to 25%) to give the desired 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.086 g) as a white solid. MS (ESI): 330.0 (MH+).