Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1([CH3:19])[CH2:9][CH2:8][CH:7]([O:10]COCC[Si](C)(C)C)[CH2:6][CH2:5]1)=C=O.[ClH:20]>C1COCC1>[CH3:19][C:4]1([NH2:1])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[ClH:20]
Reactant: CC1(N=C=O)CCC(OCOCC[Si](C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(N)CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2-[[(4-isocyanato-4-methylcyclohexyl)oxy]methoxy]ethyl)trimethylsilane (1.5 g, 5.25 mmol, 1.00 equiv) in THF (30 mL) was added hydrochloric acid (6 N, 3.0 mL) and the resulting solution was stirred for 2 h at room temperature. Upon completion, the resulting mixture was concentrated under vacuum to give trans-4-amino-4-methylcyclohexanol hydrochloride (1.0 g, crude) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])[C:29]=2[CH:36]=[N:35]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1nsc(NC(=O)[C@@H](O)COC(C)C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (0.82 mL, 0.82 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-isopropoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate C9) (200 mg, 0.82 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) in dry THF (1.5 mL) was added dropwise over 1 minute and the reaction heated to 50° C. for 20 hours. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL). The combined aqueous extracts were acidified with 1M citric acid and extracted with EtOAc (2×20 mL), the combined organic extracts were dried (MgSO4) and evaporated. The resulting residue was purified by flash silica chromatography, eluting with an increasing gradient of 60 to 100% EtOAc in isohexane to afford (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)-3-propan-2-yloxypropanamide (300 mg, 78%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:13](Br)[CH3:14].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C@H:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCBr
Reactant: C[C@@H]1C=CCC(C)(C)[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a three necked 100 ml flask a suspension of trans-2,6,6-trimethyl-3-cyclohexene-1-carboxylic acid obtained in example 2 a) (0.800 g, 4.8 mmol), ethylbromide (0.616 g, 5.7 mmol) and K2CO3 (0.787 g, 5.7 mmol) in DMF (20 ml) was stirred at 40° C. for 2 h. The cooled reaction mixture was next poured onto cold 5% aqueous HCl and extracted twice with pentane. The organic phases were washed (three times with H2O and brine), dried (Na2SO4), filtered and concentrated. A bulb-to-bulb distillation (100°/4 mbar) afforded 0.870 g of ethyl trans 2,6,6-trimethyl-3-cyclohexene-1-carboxylate in the form of a trans/cis=96:4 mixture (yield=84%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[S:23][C:24]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[C:25]([NH2:27])[N:26]=2)=[CH:17][CH:16]=1)=O)(C)(C)C>Cl.C(OCC)C>[NH2:27][C:25]1[N:26]=[C:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:20][CH:19]=2)[S:23][C:24]=1[C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)cc1
Agent: Cl
Solvent: CCOCC
Product: Nc1nc(Nc2ccc(OCC3CCCN3)cc2)sc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-2-[4-[4-Amino-5-(3fluoro-benzoyl)-thiazol-2-ylamino]-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 2, 200 mg, 0.39 mmol) was suspended in 1N HCl in diethyl ether and the mixture was stirred at room temperature overnight. The solid was filtered and passed through a C18 column eluting with aqueous ammonia in acetonitrile. The mixture was concentrated and the solid was filtered and dried to give a yellow solid. 120 mg, 75%. MS (ES) MH+=413.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[C:6]([C:22](=[O:25])[CH2:23][CH3:24])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.O.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]3[NH:38][N:37]=[N:36][N:19]=3)=[CH:16][CH:15]=1)[C:6]([C:22](=[O:25])[CH2:23][CH3:24])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C#N)cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
To a suspension of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzonitrile (1.89 g) in toluene (80 ml) was added trimethyltin azide (2.47 g) and the mixture was stirred at 110° C. for 4 days. Water (50 ml) and methanol (50 ml) were added at room temperature, and the precipitated crystals were collected by filtration to give the title compound (1.19 g, 58%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH2:3][CH2:2]1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[N:12][C:9]2[N:10]([N:11]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:8]=2)[CH:17]=1
Reactant: Nc1cc(C2CCOCC2)n[nH]1
Reactant: O=CC(Br)C=O
Product: Brc1cnc2cc(C3CCOCC3)nn2c1

Procedure:
The title compound, light brown solid, MS: m/e=284.0 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from 5-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-ylamine (example 26, step 1) and 2-bromomalonaldehyde.
Reaction SMILES: C([O:9][CH:10]([C@@H:12]1[CH2:16][C@@H:15]([N:17]=[N+:18]=[N-:19])[C@H:14]([N:20]2[C:24]3[N:25]=[C:26]([NH2:30])[NH:27][C:28](=[O:29])[C:23]=3[S:22][C:21]2=[O:31])[O:13]1)[CH3:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:30][C:26]1[NH:27][C:28](=[O:29])[C:23]2[S:22][C:21](=[O:31])[N:20]([C@H:14]3[C@H:15]([N:17]=[N+:18]=[N-:19])[CH2:16][C@@H:12]([C@@H:10]([OH:9])[CH3:11])[O:13]3)[C:24]=2[N:25]=1
Reactant: CC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](N=[N+]=[N-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)[C@@H]1C[C@@H](N=[N+]=[N-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.5 %

Procedure:
To a solution of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]ethyl benzoate (compound 25l, 600 mg, crude) in MeOH (8 mL) was added K2CO3 (187 mg, 1.4 mmol). After being stirred at room temperature for 5 hours, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 30 mg of 5-amino-3-[(2R,3R,5S)-3-azido-5-(1-hydroxyethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 25) as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(C=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(CO)cnc21
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a stirred and cooled (0° C.) solution of crude 13 (2.77 g, 10.6 mmol) in EtOH (100 mL) was added NaBH4 (0.48 mg, 12.7 mmol) in a single portion. The mixture was allowed to warm to r.t. After 20 h the mixture was concentrated and partitioned between CH2Cl2-brine. The organic layer was dried (MgSO4) and concentrated. The residue was purified by SGC with CH2Cl2:MeOH as eluent (gradient up to 5% MeOH) to afford alcohol 14 (0.67 g, 24%). 1H NMR (400 MHz; CDCl3) δ 0.31 (s, 6H), 0.94 (s, 9H), 2.97 (t, J=8.2 Hz, 2H), 3.65 (t, J=8.2 Hz, 2H), 4.39 (s, 2H), 7.19 (s, 1H), 7.69 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][C:14]=2[CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=4)=[CH:15][C:14]=3[CH3:30])[N:3]=2)=[CH:33][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Cl)nc4c3ncn4C)c(C)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Nc4ccc(C#N)cc4)nc4c3ncn4C)c(C)c2)cc1

Procedure:
A degassed solution of methyl 4′-(2-chloro-9-methyl-9H-purin-6-yloxy)-3′,5′-dimethylbiphenyl-4-carboxylate (180 mg, 0.43 mmol), 4-aminobenzonitrile (105 mg, 0.89 mmol), Pd(OAc)2 (10 mg, 0.044 mmol), BINAP (57 mg, 0.092 mmol), and Cs2CO3 (280 mg, 0.88 mmol) in toluene (2 mL) was heated at 80° C. overnight. The desired product was precipitated with EtOAc (2 mL) and saturated NaHCO3 (2 mL) and the resulting precipitate was collected by filtration (210 mg). NMR (DMSO-d6): δ 10.10 (s, 1H), 8.25 (s, 1H), 8.10 (d, 2H), 7.95 (d, 2H), 7.68 (s, 2H), 7.60 (d, 2H), 7.34 (d, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.18 (s, 6H); MS (ESI): m/z 505 (M+1)+.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28]
Reactant: COCCOCCOCCOCCO
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (13 mmol), dry THF (30 mL), purged with argon and cooled to 0° C. in an ice bath. Tetraethyleneglycol monomethyl ether (10 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (13 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 24 h under argon. Deionized water (2 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite and then concentrated in vacuo to yield clear/light yellow oil (47%). 1HNMR (400 MHz, CDCl3): δ=5.90 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.3 Hz, 2JHHgem=1.7 Hz), 5.15 (dd, 1H, 3JHH=10.4 Hz, 2JHHgem=1.5 Hz), 4.00 (dd, 2H, 3JHH=5.89 Hz, 4JHH=1.5 Hz), 3.65 (m, 12H), 3.59 (m, 2H), 3.53 (m, 2H), 3.36 (s 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=134.8, 117.0, 72.2, 71.9, 70.6, 70.6, 70.6, 70.5, 69.4, 59.0 ppm. HRMS-ESI: Calculated [M+Na]+: 271.1516. found: 271.1516.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=2)=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=4)[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccc(F)c(Cl)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′R,5′S)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (0.2 g, 0.32 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid as a off white powder (Yield, 0.16 g, 82%).
Reaction SMILES: CC1C(C#N)=NC=C(C)C=1.C(C1C=C(Cl)C=CN=1)(=O)C.Br.Br[CH2:23][C:24]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=1)=[O:25]>>[C:24]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=1)(=[O:25])[CH3:23]
Reactant: Cc1cnc(C(=O)CBr)c(C)c1
Agent: Br
Agent: CC(=O)c1cc(Cl)ccn1
Agent: Cc1cnc(C#N)c(C)c1
Product: CC(=O)c1ncc(C)cc1C

Procedure:
The title compound was prepared from 3,5-dimethylpyridinecarbonitrile (K. Takahashi et al., J. Heterocycl. Chem., 1978, 15, 893) according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33. 1H-NMR (CDCl3) δ: 8.32 (1H, s), 7.37 (1H, s), 2.69 (3H, s), 2.56 (3H, s), 2.36 (3H, s). 2-Bromoacetyl-3,5-dimethylpyridine hydrobromide:
Reaction SMILES: C([O:4][C@@:5]1([CH2:41][CH3:42])[C:38]2[CH:37]=[C:36]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([CH2:26][O:27]C(=O)C)=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:39])[C:9]=2[CH2:8][O:7][C:6]1=[O:40])(=O)C.NN.Cl>CO>[CH2:41]([C@:5]1([OH:4])[C:38]2[CH:37]=[C:36]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([CH2:26][OH:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:39])[C:9]=2[CH2:8][O:7][C:6]1=[O:40])[CH3:42]
Reactant: CCCCCN1C(COC(C)=O)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCCN1C(CO)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of (9S)-9-acetoxy-2-acetoxymethyl-9-ethyl-1-pentyl-1H, 12H-pyrano[3″,4″:6′7′]indolizino[1′2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (34 mg, 0.059 mmol) in methanol (3 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl) and the mixture was stirred for 2 hr. at room temperature. Aqueous 1 N hydrochloric acid solution (5 ml) was added dropwise to acidify the reaction mixture, and the mixture was stirred for 1 hr. at room temperature. The mixture was extracted with dichloromethane (50 ml) and the dichloromethane layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=25/1) to give pure product (19 mg, 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]1[N:15]=[C:16]([N+:19]([O-:21])=[O:20])[NH:17][CH:18]=1>CC(C)=O>[CH3:13][C:14]1[N:15]=[C:16]([N+:19]([O-:21])=[O:20])[N:17]([CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH:18]=1
Reactant: CC(C)=CCBr
Reactant: Cc1c[nH]c([N+](=O)[O-])n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCn1cc(C)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3,3-Dimethylallyl bromide (14.08 g, 94.49 mmol) was added to a suspension of anhydrous K2CO3 (13.0 g, 94.20 mmol) and 4-methyl-2-nitroimidazole (10.0 g, 78.74 mmol, D. P. Davies et al, J. Heterocyclic Chem., 1982, 19, 253-256) in dry acetone (100 mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. The insoluble inorganic material was removed by filtration and the filtrate was evaporated to afford a brown paste which was loaded onto a silica gel column and eluted with hexane-ethyl acetate (8.5:1.5). The fractions containing the compound with Rf 0.51 (silica gel TLC, hexane-ethyl acetate, 7:3) were collected and evaporated to afford a solid which was recrystallized from ethyl acetate-hexane to provide 1-(4-methyl-2-nitro-1H-imidazol-1-yl)-3-methyl-2-butene as a light yellow crystalline solid in 60% (9.21 g) yield; mp. 53-54° C.; 1H NMR (CLCl3) δ 1.80[s, 6H, C(CH3)2], 2.26(s, 3H, imi-CH3), 4.97(d, 2H, J=7.26 Hz, NCH2), 5.36 (t, 1H, J=7.26 Hz, CH2CH) and 6.90(s, 1H, imi-CH). 13C NMR (CDCl3)δ 13.80 (imi-CH3), 18.16 & 25.70 [C(CH3)2], 47.76 (NCH2), 117.35(CH2CH), 122.77 (imi-CH), 138.09[C(CH3)2], 139.97 (imi-CCH3) and 143.53 (CNO2). MS m/e 196 (M+H)+.
Reaction SMILES: [N:1]1([CH:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)Cl.[F:39][C:40]([F:50])([F:49])[CH:41]([N:46]=[C:47]=[O:48])[C:42]([F:45])([F:44])[F:43].C1(C)C=CC=C(C)C=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[C:34]([CH2:33][C:9]1([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:8][CH:7]([N:1]2[CH2:2][CH2:3][N:4]([C:47]([NH:46][CH:41]([C:40]([F:39])([F:50])[F:49])[C:42]([F:44])([F:43])[F:45])=[O:48])[CH2:5][CH2:6]2)[CH2:10]1)#[N:35]
Reactant: O=C=NC(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(N5CCNCC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)c1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(N5CCN(C(=O)NC(C(F)(F)F)C(F)(F)F)CC5)C4)c3)ncnc21
Reaction time: 8 h

Procedure:
To a solution of {3-piperazin-1-yl-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (0.10 g, 0.20 mmol) in methylene chloride (5 mL, 80 mmol) was added. 0.21M 1,1,1,3,3,3-hexafluoro-2-isocyanatopropane in m-xylene (1.2 mL, 0.24 mmol) was added, followed by N,N-diisopropylethylamine (71 μL, 0.41 mmol). The reaction was stirred overnight. The reaction was rotovaped and ethyl acetate was added, washed with sat. NH4Cl (×2), sat. NaHCO3, and sat. NaCl. The extracts were dried and the solvent removed by rotary evaporation to give 164 mg of an orange oil. The crude oil was purified by column chromatography on 40 g silica gel using a gradient of 0-8% MeOH/DCM, 0-0.8% NH4Cl. The product was collected as 82 mg of a glass (59% yield). LCMS (M+1): 586.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8](F)[CH:7]=2)#[N:2].[N:22]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].C(O)(=O)C>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8]([O:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:7]=2)#[N:2]
Reactant: OCCCN1CCOCC1
Reactant: N#Cc1cnc2cc(F)cc(OC3CCOCC3)c2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1O
Temperature: 60 °C
Yield: 43.6 %

Procedure:
A mixture of 3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (864 mg), 3-morpholin-4-ylpropan-1-ol (876 mg) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 9.0 ml) in anhydrous dimethyl sulphoxide (30 ml) was heated at 60° C. for 8 hours. The solution was cooled and then diluted with water (120 ml). Acetic acid was added until pH5 was reached. The solution was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml). The product was eluted off the column with methanol containing triethylamine (1%). The fractions containing the product were combined and evaporated. The residue was further purified by chromatography on a Redisep silica cartridge (40 g) eluting with a gradient of methanol in dichloromethane (5–20%). This gave the title compound as an white solid (540 mg, 44%); NMR spectrum: (DMSOd6; 373° K) 1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.10 (t, 2H), 4.64 (m, 1H), 6.46 (d, 1H), 6.60 (d, 1H), 8.24 (s, 1H); Mass spectrum: M+H+ 414.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]>CC1CCCO1>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([NH2:2])=[O:23])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC1CCCO1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Temperature: 80 °C

Procedure:
Concentrated ammonium hydroxide (8.0 mL of 29%) was added to a solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (5.1 g, 16 mmol) in 2-methyltetrahydrofuran (10 mL), and the mixture was heated overnight in a sealed high-pressure vessel at 80° C. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the reaction was incomplete. The solvents were evaporated under a stream of nitrogen, and ammonium acetate (10 g) was added. The vessel was sealed and heated overnight at 135° C. The reaction was allowed to cool to ambient temperature, and water (50 mL) was added. The mixture was filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate (25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 2.95 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a light brown solid.