Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:7]([O:6][C:5](=[O:11])[N:4]([CH2:3][CH2:2][O:1][N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])[CH3:12])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To an ice-cold solution of tert-butyl (2-hydroxyethyl)methylcarbamate (3.0 g, 17 mmol), N-hydroxyphthalimide (2.8 g, 17 mmol) and triphenylphosphine (4.5 g, 17 mmol) in THF (90 mL) was added a solution of diethyl azodicarboxylate (3.0 mL, 19 mmol) in THF (15 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 2 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2Cl2 (40 ml) and H2O (30 mL). The organic layer was separated and washed with saturated NaCl (20 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 50:50 hexanes/EtOAc) gave tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl]methylcarbamate (4.3 g, 79%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ1.46 (9H, s), 3.03 (3H, br s), 3.62 (2H, br s), 4.34 (2H, br s), 7.74-7.85 (4H, m).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20]1>>[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: O=C(O)c1ccccc1-n1cccc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-n1cccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) mass calcd. for C25H23N5O, 409.49; m/z found, 410.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2(O)[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C:24]2[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH:23]=2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](c5ccc(=O)oc5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl) hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-(tert-butoxy carbonylamino)-3-methylbutanoate (36 mg, 0.062 mmol, 1 eq) in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to room temperature after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC(CH2Cl2:MeOH=10:1) to afford the (R)-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-amino-3-methylbutanoate. LCMS (M+H+) m/z 468.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:31]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:25][C:13]1[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 58.2 %

Procedure:
A mixture of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline-3-carboxylate (411 mg), N-bromosuccinimide (214 mg), 2,2'-azobis(isobutyronitrile)(10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave ethyl 2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (285 mg, 58%). This compound was recrystallized from ethyl acetate-hexane. Colorless prisms, mp. 135°-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1nccc2ccccc12
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nccc2ccccc12

Procedure:
The title compound (0.76 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.6 ml) and 1-chloroisoquinoline (0.8 g) according to the method used for the preparation of the compound of D8.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]3=[N:1][C:17]([OH:22])=[CH:18][C:19](=[O:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(-c2nnc(N)s2)cc1
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Yield: 96.6 %

Procedure:
A mixture of 9.3 g of 2-amino-5-(4-tert-butylphenyl)-1,3,4-thiadiazole, 20 g of 2,4,6-trichlorophenyl malonate and 50 ml of Dowtherm A was heated at a temperature of 120° to 130° C. for 2 hours. After allowing the mixture to cool, the precipitate was separated by filtration, washed successively with isopropanol and diethyl ether to obtain 11.6 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless, crystalline powder having a melting point of 265° to 268° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[CH:29][C:26]=1[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([O:33][CH3:34])[C:25]=4[O:24][CH3:23])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c(OC)c1OC

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 2,3,4-trimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(2,3,4-trimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 168-169° C.; HPLC: TRet (Grad5-40)=20.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:11]2[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)[nH]c2c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CCO[Si](C)(C)C(C)(C)C)c2c1Cl
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a mixture of Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (115.7 mgs, 291 μmol) in 2 mL of DMSO under N2 was added NaH (95%, 2 equivalents, 582 μmol, 14.0 mgs), and the reaction mixture was stirred for 20 minutes. (2-bromoethoxy)-tert-butyldimethylsilane (1.5 equivalents, 436 μmol, 94 μL) was then along with KI (1.5 equivalents, 72.4 mgs), and the reaction was stirred at room temperature overnight. The crude product was acidified with 1 M HCl, diluted with water and extracted with dichloromethane. The extracted product was concentrated en vacuo then purified by automated flash chromatography (Biotage Horizon™, gradient elution, 5 to 40% Ethyl Acetate/Hexane) to give 136.0 mgs (86%) of Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate as a oily colorless solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 2 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. Chemical shifts were reported in ppm relative to the deuterated solvent used. Coupling constants were reported in hertz. Peak multiplicity was reported using the following abbreviations: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.05 Hz, 1H), 7.73 (d, J=8.05 Hz, 1H), 7.50 (d, J=8.42 Hz, 2H), 7.24 (d, J=8.42 Hz, 2H), 4.69 (t, J=6.40 Hz, 2H), 4.17 (s, 3H), 4.12 (s, 3H), 3.95 (t, J=6.40 Hz, 2H), 2.79 (m, 1H), 1.96 (m, 6H), 1.41-1.56 (m, 3H), 1.11-1.20 (m, 1H), 0.95 (s, 9H), 0.03 (s, 6H). MS m/z 557.23 (M+H), Rf 3.05 min., 100% purity.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:22][CH2:21][C:20](=[O:23])[N:19]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:18][C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:22][CH2:21][C:20](=[O:23])[N:19]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:18][C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)Cc1ccccc1-3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)CCN1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CCC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
To a solution of methyl 15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9-tetrahydro-5H-indolo[2,1-a][2,6]benzodiazonine-12-carboxylate in DCM (0.04 M), 7 eq BBr3 (1 M solution in DCM) were added. The solution stirred at RT for 20 mins. The solvent was evaporated in vacuo. The crude was then purified by automated prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (15% over three steps).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:9]CC)([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+].O.S([O-])([O-])(=O)=O.[Al+3:20].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3]>O>[CH2:1]([O:3][P:4]([O-:9])([O-:6])=[O:5])[CH3:2].[Al+3:20].[CH2:1]([O:3][P:4]([O-:9])([O-:6])=[O:5])[CH3:2].[CH2:1]([O:3][P:4]([O-:9])([O-:6])=[O:5])[CH3:2].[Al+3:20]
Reactant: CCOP(=O)(OCC)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)([O-])[O-]
Yield: 260.7 %

Procedure:
Aluminum ethylphosphate was prepared according to a known procedure: Triethylphosphate (40 g), sodium hydroxide (17.5 g), and water (0.4 L) were refluxed for 2.5 h. A solution of aluminum sulfate hydrate (23.8 g) in water (300 mL) was then slowly added to form a white slurry. After filtration and drying, 36.7 g of aluminum ethylphosphate was obtained as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]I.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[N:1]1([C@@H:2]([CH3:5])[CH2:3][OH:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[C@H](N)CO
Reactant: ICCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H](CO)N1CCCCC1
Yield: 54 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (2.0 mL, 26 mmol), 1,5-diiodopentane (4.7 mL), and sodium carbonate (7.13 g, 67.3 mmol) in i-propanol (200 mL) was heated at reflux overnight. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) and the insoluble solid was filtered off. The solvent was removed under reduced pressure and the residue was purified on a silica gel column to yield ((S)-2-(piperidin-1-yl)propan-1-ol (2.0 g, 54%) as a clear oil. 1H NMR (CDCl3): δ 3.37 (dd, 1H), 3.30 (t, 1H), 2.78 (m, 1H), 2.62 (m, 2H), 2.33 (m, 2H), 1.40-1.70 (m, 6H), 0.86 (d, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CCNc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)cc1
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing 4-(2-aminoethyl)benzenesulfonamide (0.161 g) and N-ethyldiisopropylamine (0.5 ml) was stirred for 16 hours. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 4:6 as eluant) to give the title compound (310 mg).
Reaction SMILES: N[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)/[C:5](=[CH:13]\[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)/[C:4]=1[CH3:22].Cl[O:24]C(C)(C)C.CC(C)([O-])C.[K+].Cl>CCOCC.C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)/[C:5](=[CH:13]\[C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=1)/[C:4]([CH3:22])=[C:3]2[CH:2]=[O:24]
Reactant: CC(C)(C)OCl
Reactant: CSc1ccc(/C=C2/C(C)=C(CN)c3cc(F)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of freshly liberated amine from Step 1 (11.5 g, 37 mmol) in ether (220 mL) at 0° C. there was added a solution of t-butyl hypochlorite (4.0 g) in ether (10 mL); the mixture was stirred at 0° C. for 5 minutes as a yellow solid formed. The mixture was then allowed to warm up to room temperature and there was slowly added a solution of potassium tert-butoxide (15 g, 133 mmol) in ethanol (200 mL). The mixture was boiled on a steam bath for 10 minutes and then cooled down. There was added 1N aqueous HCl (200 mL) and after stirring for 20 minutes, the mixture was extracted with ether to afford the crude aldehyde which was purified by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate:hexane. The pure title compound was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:29]=1[CH2:30]Br>C1COCC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:29]=1[CH2:30][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reactant: Fc1cc(F)c(CBr)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(Cc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (obtained in Step 1 above; 1.30 g, 4.66 mmol) in THF (20 mL) was added t-BuOK (0.53 g, 4.66 mmol) and the mixture was stirred at room temperature for 10 min. The resulting solution was added dropwise to a stirred solution of 2,4,5-trifluorobenzyl bromide (1.20 g, 5.33 mmol) in THF (20 mL) at room temperature. After 2 h, the reaction mixture was cooled to 0° C. and partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was washed with brine (10 mL) and dried over Na2SO4. Evaporation of the solvent gave 1.82 g (96%) of the title compound as an oil which crystallized upon standing. The product can be recrystallized from tert-butyl methyl ether. HPLC purity: 94%. 1NMR and MS analyses support the stated structure.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][BH:24][O:23]1.C([O-])(=O)C.[K+]>COCCOC.Cl[Pd]Cl>[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[O:23]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3cncnc32)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cncnc32)cc1

Procedure:
As shown in FIG. 1—step iv, a mixture of compound 1004 (140 mg, 0.40 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane dimer (121 mg, 0.477 mmol), PdCl2 dppf2 (16 mg, 0.02 mmol) and potassium acetate (117 mg, 1.19 mmol) in 2 mL of DME were microwaved at 150° C. for 10 minutes. The reaction mixture was filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, 158 mg (98%) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, compound 1005: ESMS M+1=317.07.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Reactant: C1COCCN1
Product: c1cn2nc(N3CCOCC3)c3c(c2n1)CCCC3
Temperature: 0 °C

Procedure:
A mixture of 10 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine and 20.9 g of morpholine was heated at reflux for 72 hours. The mixture was then poured into about 200 ml of ice water and a solid formed immediately. This was separated by filtration and air-dried to give 6-(4-morpholinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 160°-161° C. This compound has the following structural formula ##STR3##
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([N+:35]([O-])=O)=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:38])(=[O:9])=[O:8].[Cl-].[NH4+].C([SiH](CC)CC)C.CO>C(O)C.ClCCl.FC(F)(F)C(O)=O.[Fe]>[NH2:35][C:25]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:8])=[O:9])=[C:11]([F:38])[CH:12]=2)=[CH:28][NH:27][N:26]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: [Fe]
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (310 mg, 0.434 mmol) prepared in Example 34c, an iron powder (300 mg, 5.37 mol) and a saturated aqueous solution of ammonium chloride (5.0 mL) in ethanol (10 mL) was heated under reflux with stirring for 1 hour. After allowing to cool, the reaction solution was filtered through celite, and the filtrate was subjected to extraction with dichloromethane (100 mL). The organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield crude amine. To a solution of the crude amine and triethylsilane (0.30 mL) in dichloromethane (3.0 mL), trifluoroacetic acid (3.0 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. To the reaction solution, methanol (3.0 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=90:10) to yield the title compound (41.1 mg, 21%) as a colorless solid.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (8.85 g, 24 mmol) was dissolved in DMF (100 ml), and then NaN3 (6.24 g, 96 mmol) and NaI (0.36 g, 2.40 mmol) were added, followed by stirring at 70° C. for hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:10), to give tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 92%).