Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](C3C=CNN=3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O)(=O)C>CN1C(=O)CCC1>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(-c2cc[nH]n2)nc1-c1cccc(O)c1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(N2CCOCC2)nc1-c1cccc(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Resin bound 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-pyrazolylpyrimidine-5-carboxylic acid (100 mg, 0.055 mmol, 1 eq) was suspended in NMP, and morpholine (144 μL, 144 mg, 1.65 mmol, 30 eq) was added, followed by acetic acid (31 μL, 33 mg, 0.55 mmol, 10 eq). The reaction mixture was shaken at 90° C. overnight. The resin was filtered and washed with DMF, water, MeOH, CH2Cl2, then dried. The resin was treated with 95% TFA/H2O for 1.5 h at room temperature. Filtration and evaporation under reduced pressure afforded 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-morpholin-4-ylpyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:45][C@H:46]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:47]([O:49]C(C)(C)C)=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([NH:45][C@H:46]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:47]([OH:49])=[O:48])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)N[C@@H](C(=O)O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl)amino)(phenyl)acetic acid (0.040 g, 0.065 mmol) was dissolved in CH2Cl2 (5 ml) and tert-butyl (2R)-amino(phenyl)acetate (0.016 g, 0.078 mmol) and N-methyl-morphiline (0.020 g, 0.195 mmol) were added. After 5 minutes TBTU (0.027 g, 0.084 mmol) was added. The reaction was allowed to stir at room temperature for 3 h after which the resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 25/75. Pure fractions were concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (0.5 ml). The reaction mixture was allowed to stir overnight at room temperature. The resulting acid was concentrated and the remaining trace of TFA was removed by co-evaporation with toluene (3 ml). The acid was dissolved in MeOH (3 ml) and NaBH (0.010 g, 0.260 mmol) was added. After 5 minutes, full conversion to the corresponding alcohol was obtained. The reaction was quenched by the addition of 1 ml of 0.1M NH4OAc buffer. Concentration followed by purification on preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase and freeze-drying of the pure fractions afforded the title compound (0.034 g, 70%) as a colourless solid. M/z: 750.4 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.88-2.94 (m, 2H), 4.23-4.29 (m, 1H), 4.56-4.65 (m, 2H), 4.70-4.78 (m, 1H), 4.91-5.06 (m, 2H), 5.65-5.75 (m, 1H), 6.93-7.42 (m, 22H), 8.54-8.69 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1.[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: Brc1cccc(COC2CCCCO2)n1
Reactant: CC(C)O
Product: CC(C)Oc1cccc(COC2CCCCO2)n1

Procedure:
The title-compound was prepared from 6-bromo-2-[(tetrahydropyran-2-yl)oxymethyl]pyridine prepared following the procedure given for Example 11 part a and isopropyl alcohol following the procedure given for Example 11 part b, 1H NMR (250 MHz, CDCl3), δ 1.32 (6H, d, J=6.2 Hz, 2 of CH3), 1.6-1.9 (6H, Me, 3 of CH2), 3.56 (1H, m, CH2O), 3.91 (1H, m, CH2O), 4.53 (1H, d, J=13.7 Hz, CH2O), 4.76 (1H, d, J=13.6 Hz, CH2O), 4.79 (1H, m, CHO), 5.29 (1H, septet, J=6.2 Hz, CH), 6.55 (1H, d, J=8.2 Hz, Ar—H), 6.96 (1H, d, J=7.3 Hz, Ar—H), 7.53 (1H, dd, J=8.2 and 7.3 Hz, Ar—H); MS (ES+) m/e 252 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH:11]O>C(O)(C)C>[NH2:1][C:2]1[CH2:3][S:4](=[O:11])[CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: OO
Reactant: COC(=O)C1=C(N)CSC1
Solvent: CC(C)O
Product: COC(=O)C1=C(N)CS(=O)C1
Temperature: 50 °C

Procedure:
3.2 g (0.02 mol) of 3-amino-4-methoxycarbonyl-2,5-dihydrothiophene are suspended in 30 ml of isopropanol. 2.2 ml of 35% strength hydrogen peroxide are added, with cooling. The mixture is then stirred at an internal temperature of 50° C. until starting material can no longer be detected in a thin layer chromatogram (approx. 5 hours). The mixture is then cooled in an ice bath and the precipitated crystals are filtered off with suction and washed with ice-cold isopropanol and with diethyl ether. Yield: 3.5 g (91% of theory). When recrystallized from methanol, the crystals melt at 137°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[N:6]([CH2:20][CH3:21])[N:7]=1
Reactant: Cc1ccc(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
A mixture of 4-chloro-1-(2,4-dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (100 mg, 0.365 mmol), ethyl iodide (0.032 ml, 0.40 mmol), potassium carbonate (100 mg, 0.73 mmol) and DMF (1 ml) was stirred at room temperature for 7 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 102 mg (93%) of the title compound as crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][CH:20]=3)[CH:15](O)[C:14]([CH3:30])([CH3:29])[CH2:13]2)=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:3][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:17]=2)[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[CH2:13][C:14]1([CH3:30])[CH3:29]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCOc1ccc2c(c1)C(O)C(C)(C)CC2c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CN(C)CCOc1ccc2c(c1)C(Cl)C(C)(C)CC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (3 ml) was added dropwise to a stirred solution of 4-(4-chlorophenyl)-1-hydroxy-2,2-dimethyl-7-(2-dimethylaminoethoxy)tetralin (2.0 g) in benzene (50 ml), the temperature being maintained at 5°-10°. After being stirred at room temperature for 16 hr., the solution was taken to dryness in vacuo, the residue shaken with ether-sodium carbonate solution and the ether extract dried (MgSO4). Addition of ethereal hydrogen chloride solution precipitated a viscous oil, which was separated by decantation and redissolved in ethanol. Addition of ether and cooling gave 1-chloro-4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)tetralin as the hydrochloride salt, m.p. 185°-210° approx. (0.93 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([S:20][CH3:21])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([S:20]([CH3:21])=[O:32])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(SC)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(S(C)=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-methylsulfanyl-pyridazin-3-one (60 mg, 0.16 mmol) in DCM (2 mL) at −20° C. is added mCPBA (36 mg, 0.17 mmol). After stirring for 10 min at this temperature, a yellow precipitate had appeared. The reaction was poured into a mixture of DCM (20 mL), sodium bicarbonate saturated solution (10 mL) and sodium thiosulphate saturated solution (10 mL), then stirred for 10 min. The resulting mixture was then passed through a phase separator and the DCM layer was concentrated under reduced pressure to afford the desired product 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-methylsulflnyl-pyridazin-3-one (59 mg, 0.12 mmol, 95%) as a yellow solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 23 h
Yield: 46.5 %

Procedure:
To a solution of 3-trifluoromethylaniline (11 mmol, 1.37 ml) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g), and triethylamine (11 mmol, 1.53 ml) were added. The mixture was stirred under nitrogen for 23 h. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 1.42 g of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (50%);
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][CH2:13][C:14]([CH3:28])([CH3:27])[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][CH2:13][C:14]([CH3:28])([CH3:27])[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCCC(C)(C)C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCCC(C)(C)C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyrate (1.24 g, 3.0 mmol) obtained from Example 10-(1) was reacted with anisole (1.8 g, 16.6 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutanoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 4-[bis(allyloxy)phosphoryl]oxy-2,2-dimethylbutyl chloride as a crude product.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)[C:28](O)=[O:29]>>[CH2:17]([C:11]1[CH:16]=[CH:15][C:14]([CH:28]=[O:29])=[CH:13][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCCc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
Oxidative Formylation--Allow a two-phase mixture of trifluoroacetic acid (150 mL) and hexamethylene tetramine (14.0 g, 0.100 mol), and 1-phenyl-n-nonane (20.4 g, 0.100 mol) to stand 18 hrs. at 25° C., and then reflux for 22 hrs. Concentrate the homogenous reaction mixture and pour the residue over ice and H2O (total of 600 mL). Add diethyl ether (200 mL) and stir the mixture vigorously for 30 min. Raise the pH of the mixture to pH 8 with solid Na2CO3, and add diethyl ether (200 mL). Shake the layers and separate. Extract the aqueous phase with diethyl ether. Wash the combined organic solutions with H2O and brine, dry and filter. Evaporate the solvent, and distill the residue to give 4-(n-nonyl)benzaldehyde (57% yield, 13.2 g) b.p. 136°-139° C. at 0.55 mm.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH2:10](I)[CH:11]=[CH2:12]>>[CH2:12]([O:4][C:3]1[CH:2]=[C:1]([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=1)[CH:11]=[CH2:10]
Reactant: Cc1cc(O)cc(O)c1
Reactant: C=CCI
Product: C=CCOc1cc(C)cc(O)c1

Procedure:
Orcinol and allyl iodide were processed as described in Example 88C to provide the title compound. MS (DCI) m/z 165 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:32]=[N:33][CH:34]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(Cl)c1
Product: C[C@@H](c1ccc(-c2cncc(Cl)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(c3ccc([N+](=O)[O-])cc3)C2)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (268 mg) in DMF (3 mL) was added 1-fluoro-4-nitrobenzene (91.4 mg) and N,N-diisopropylethylamine (0.376 mL). After stirring for 3 hours at 120° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-nitrophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (299 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:17])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)cnc2ccc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)cnc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinoxalinone (2.4 g, 11.77 mmol) in 1,4-dioxane (140 ml) and water (250 ml) was treated with osmium tetroxide (4% solution in water; 14.5 ml) and sodium periodate (11.9 g) and the mixture was stirred at rt for 1.5 hours. It was evaporated to dryness onto silica gel and chromatographed on a 300 g silica gel column, eluting with 1:1 ethyl acetate-hexane then ethyl acetate. The early fractions gave (7-fluoro-2-oxo-1(2H)-quinoxalinyl)acetaldehyde which was triturated with ether/DCM 3:1 to give product (1.56 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:11]([Si:15]([CH3:17])([CH3:16])[O:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(O)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 508 (1.5 g, 10.7 mmol) was dissolved in dry DMF (40 mL) under an argon atmosphere. tert-Butyl-chloro-dimethyl-silane (2.43 g, 16.1 mmol) and imidazole (1.1 g, 16.1 mmol) was added. Stirred at RT for 2 h, added EtOAc (250 mL) and then washed with water (2×100 mL), 4% MgSO4 (2×75 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product as yellow oil. Purified by chromatography using EtOAc/petroleum ether (40-60)(1:20) as the eluent, affording the title compound as an colourless, clear oil.
Reaction SMILES: [OH:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>ClCCl>[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]([O:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)[C@@H](OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(C)C)cc1

Procedure:
4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate was acylated with N-benzyloxycarbonyl-L-valine by the method described in Example A-I-1, step b. The title compound (5.74 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.70.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:9][CH:8]=[C:7]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:6]=2.[C:30](Cl)(=O)[CH2:31][CH2:32][CH3:33]>>[CH2:23]([O:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:30]([CH2:31][CH2:32][CH3:33])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCC(=O)Cl
Reactant: CS(=O)(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNS(C)(=O)=O
Yield: 69.3 %

Procedure:
The method described in Part D of Example 45 was used to treat N-[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide (15.1 g, 36.5 mmol) with butyryl chloride (4.77 mL, 46.2 mmol). The crude product was purified by column chromatography on silica gel (eluting with 96:4 chloroform:methanol containing ammonium hydroxide) to provide 11.8 g of N-[4-(7-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a tan solid.
Reaction SMILES: N1C=CC(C2C(C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=NN([CH2:12][C:13]([F:16])([F:15])[F:14])C=2)=CC=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:53]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)=[CH:52][NH:51][N:50]=2)=[C:45]([F:60])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:53]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)=[CH:52][N:51]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:50]=2)=[C:45]([F:60])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: Fc1cc(OCc2ccccc2)ccc1-c1n[nH]cc1-c1ccncc1
Product: Fc1cc(OCc2ccccc2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline but substituting 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1H-pyrazol4-yl]-pyridine provided the title compound. MS: (M+H m/z=428.4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH:14]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCC1CCCCC1
Product: CCOC(=O)c1cnc(Cl)cc1NCC1CCCCC1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and cyclohexylmethylamine in a manner similar to Example 339, the title compound was obtained as a slight yellow oil (yield 85%).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C[CH2:17][N:18](C(C)C)[CH:19](C)C.CNC>C1COCC1>[CH3:17][N:18]([CH3:19])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a mixture of 2,3-dioxoindoline-5-sulfonyl chloride (0.800 g, 3.26 mmol) in dry THF (10 ml), cooled at 0° C. under nitrogen, DIPEA (1.138 ml, 6.51 mmol) and dimethylamine 2M in THF (2.117 ml, 4.23 mmol) were added, and the mixture was allowed to stir at room temperature for 2.5 hours. The mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give N,N-dimethyl-2,3-dioxoindoline-5-sulfonamide (0.639 g, 2.51 mmol, 77% yield). MS/ESI+ 254.9 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]=1[CH3:30]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][C:22]=3[CH3:30])[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: CCOC(=O)CC(=O)CCC(=O)c1ccc(Br)cc1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(C(N)=O)cc1C

Procedure:
37C, R═Br was cyclized following step 3 of Scheme 1 with 4-amino-3-methylbenzamide with a different solvent, dioxane.