Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28]C)=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1C(=O)N(c1ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc1)CCO2
Reaction time: 1 h

Procedure:
A stirred solution of methyl {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate (5.05 g, 12.3 mmol), from Example 1, and 1N aqueous lithium hydroxide (36.9 mL) in p-dioxane (96 mL) and water (27 mL) was stirred at 50° C. for one hour. After cooling, the reaction solution was adjusted to pH˜3.5 with 6N aqueous hydrochloric acid and the mixture was concentrated to near dryness. This residue was slurried in water (40 mL) for 1 hour, filtered, the solids washed with water (2×20 mL), ether (3×30 mL) and dried in vacuo to afford the title compound as an off-white solid, 4.58 g. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.58 (br s, 2H) 7.21 (s, 4H), 4.56 (m, 2H), 3.92 (m, 2H), 2.42 (m, 1H), 2.08 (m, 2H), 1.75 (m, 5H), 1.42 (q, 2H), 1.05 (q, 2H). m/z=397.3 (M+1). IC50 19.1 nM (range 5.2-63.6 nM).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:28])([F:27])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:27])([F:28])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.0 g), 1N aqueous sodium hydroxide solution (20 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.60 g, yield 93%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 288-290° C. (decomposition).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[NH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=3)[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Yield: 97.6 %

Procedure:
To a mixture of 5.0 g (16.2 mmole) of (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same manner as described in Preparative Example 1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which was dissolved in water and extracted with CHCl3. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to provide a liquid which was distilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the title compound as a viscous oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:16]3)[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(=O)C>C(O)(C(F)(F)F)=O>[C:21]1([NH:20][C:17]2[N:18]=[CH:19][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=3)[N:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reaction time: 16 h

Procedure:
[1.5 g, 4.03 mMol] of (4-Methoxy-benzyl)-[4-(3-phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-yl]-amine was dissolved in 25 mL of TFA and stirred at 40 C. in a sealed tube for 16 hrs. Then, 10 mL of glacial acetic acid was added and the mixture was stirred at 40 C. for an additional 24 hr. The solvent was removed under reduced pressure and the residue triturated with MTBE, The crude material was treated with water and neutralized with 11.4N ammonium hydroxide to pH 9. The resulting solid was isolated via suction filtration and washed with water. This crude product was treated with 0.25N HCl and particulates removed via suction filtration. The filtrates were neutralized with conc. ammonium hydroxide to a pH of 10 and the mixture was extracted with chloroform twice. The organics were combined and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Tan powder collected; 300 mg (33%). 1H NMR 500 MHz (DMSO-d6) ∂ 6.22(s ex, 2H), 6.88(m, 2H), 7.09d, 1H), 7.26(t, 2H), 7.67(d, 2H), 7.97(d, 1H), 9.14(s, 1H), 9.52(s ex, 1H). LC/MS [M+H+]253.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[CH:15](C(OCC)=O)[C:14](=[O:21])[C:13](=[O:22])[N:12]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.[Na+].[Cl-]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)[C:13](=[O:22])[C:14](=[O:21])[CH2:15]1
Reactant: CCOC(=O)C1C(=O)C(=O)N(Cc2ccc(OC(F)(F)F)cc2)C1c1c(OC)cccc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(OC)c1C1CC(=O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(2,6-dimethoxyphenyl)-4,5-dioxo-1-(4-(trifluoromethoxy)-benzyl)pyrrolidine-3-carboxylate (11.400 g; 23.68 mmol) and NaCl (2.767 g; 47.36 mmol) in DMSO (111 ml) and water (37 ml) was refluxed, under nitrogen, for 3 h. After cooling to rt, water (150 ml) was added, and the mixture was extracted with AcOEt (3×150 ml). The mixed organic layers were washed with brine (50 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Addition of Et2O and trituration allowed the precipitation of the product. Subsequent filtration, and drying of the obtained solid under HV afforded 5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-2,3-dione as a pink solid. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 410.15 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 90 %

Procedure:
5-Methyl-1,3-benzodioxole (8.00 g, 58.8 mmol) was dissolved in chloroform (160 ml), and the mixture was stirred under ice-cooling. To this solution was gradually added 60% nitric acid (20 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium hydrogen carbonate, and dried over potassium carbonate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (9.58 g, yield 90%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:4][C:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[NH:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:3]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:4][C:5]2[SH:9](=[O:10])([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:11][C:22](=[O:23])[NH:7][C:6]=2[CH:8]=1
Reactant: N=S(=O)(c1ccccc1)c1cc(S(N)(=O)=O)c(Cl)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(=O)N[SH]2(=O)c1ccccc1

Procedure:
A stirred mixture of 34.5 g (0.1 mole) of 5-chloro-2-(phenylsulfonimidoyl)-4-sulfamylaniline and 16.2 g (0.1 mol) of 1,1'-carbonyldiimidazole in 500 ml. of o-dichlorobenzene is heated under reflux conditions for 2 hours, filtered, and cooled, yielding the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:13][N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1)([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N)cn1
Reaction time: 16 h

Procedure:
To a solution of 42 (700 mg, 1.6 mmol) in methanol (30 mL) was added 20% Pd(OH)2 (1.25 g) and hydrogenated at 50 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluting with 5% MeOH/CHCl3) to obtain A4-13 (250 mg, 61%) as a white solid. Rf: 0.3 (10% MeOH/CHCl3), (m/z): 252 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 7.81 (1H, d, J=2.8 Hz), 7.08 (1H, d, J=8.4 Hz), 6.99 (1H, br s), 6.89 (1H, dd, J=2.4, 8.4 Hz), 5.11 (2H, br s), 1.45 (6H, s), 1.34 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:13]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>CCN(CC)CC.CS(C)=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:19][CH2:20][N:27]([OH:28])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CS(=O)(=O)OCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(O)C1)OCc1ccccc1
Temperature: 60 °C
Yield: 85 %

Procedure:
(R)-2-(Benzyloxycarbonylamino)-1,4-dimethanesulfonyloxybutane (2.0 g; 5.06 mmol) was dissolved in a Et3N/DMSO mixture (1:1, 20 ml). Hydroxylamine hydrochloride (1.4 g; 20.2 mmol) was added and the mixture was heated at 60° C. over night. The mixture was poured in aqueous HCl (the pH was adjusted to pH=6 with NaHCO3) and extracted twice with AcOEt. The organic phase was washed with water and dried over Na2SO4. The solids were filtered off and the solvent was removed. A light yellow oil (1.4 g, purity 73%) was obtained (yield: 85%). The crude title compound was used as is.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH3:38])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:43])[CH3:44])[CH3:38])=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)-thieno[3,2-c]pyridin-7-yl]-3-[(3-dimethylaminopropyl)methylamino]propionamide, and the procedure described in General Procedure F. m/z (M+H)+ 614.3.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]([O-:10])=[O:9])=[CH:6][N:7]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1ncc(C(=O)[O-])o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Next, to a solution of 2-ethyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (10 mL) is added 1N NaOH (6 mL, 6 mmol). After stirring at room temperature for 18 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-ethyloxazole-5-carboxylic acid (244 mg). 1H NMR (400 MHz, CD3OD) δ ppm 1.36 (t, J=7.7 Hz, 3H) 2.89 (q, J=7.6 Hz, 2H) 5.15 (br. s., 1H) 7.69 (s, 1H)
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[OH:18][CH2:19][CH:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21]>>[OH:18][CH2:19][CH:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21]
Reactant: CC(CO)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Yield: 20 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (530 mg, 1.8 mmol) was reacted with N-(1-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (750 mg, 2.02 mmol) to afford the desired product (150 mg, 20%) as a yellow solid: ESI MS m/z 445 [C21H20N2O5S2+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>C1COCC1.C(Cl)Cl>[OH:35][CH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methylidene-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexane (Example 165, 117 mg, 0.35 mmol) was added 9-BBN (7 mL, 0.5 N, 3.5 mmol) in THF. The reaction mixture was stirred at rt for 1 h, and then heated to 45° C. for 3 h. To the solution was then added NaOH (3 mL, 10%) and H2O2 (4 mL, 30%) and the mixture was heated at 45° C. for 14 h. The reaction mixture was poured into CH2Cl2 and washed with 2N HCl and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, EtOAc/hexane, 2:1) to give the title compound as a 2:1 mixture of two diastereomers.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])(O)=[O:18].[Na+].[Na+].P([O-])([O-])(O)=O.[K+].[K+].O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: O=P([O-])([O-])O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1C=O
Temperature: 80 °C
Yield: 35.9 %

Procedure:
A mixture of (E)-methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (10.0 g, 90% pure), sodium hydrogen orthophosphate dibasic (Na2HPO4, 5.74 g) and potassium hydrogen monophosphate monobasic (KH2PO4, 0.55 g) in DMSO (20 ml) was heated at 80° C. for 1 hour and then at 110° C. for a further hour (compare J. H. Babler, M. J. Coghlan, M. Feng and P. Fries, J. Org. Chem., 1979, 44, 1716). After cooling, the reaction mixture was poured into water and extracted with ether. The extracts were washed with brine, dried, concentrated and chromatographed using ether as eluant to give (E) -methyl 2-(2-formylphenyl)-3-methoxypropenoate (2.77 g, 40% yield) as a white crystalline solid, m.p. 67°-69° C. IR (nujol): 1710, 1634 cm-1. 1H NMR: delta 3.72 (3H, s), 3.84 (3H, s), 7.30-7.65 (3H, m), 7.69 (1H, s), 7.9 (1H, m), 10.0 (1H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1-c1ccc(Br)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(Br)cc1

Procedure:
The title compound was prepared from 5-(4-bromophenyl)isoxazole-4-carboxylic acid (13.4 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (3.8 mg). MS (pos) m/z 323.0 and 325.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[N:15]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(OC)c3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccc(OC)c4)n3n2)cc1
Yield: 30.2 %

Procedure:
Applying the Cyclization Procedure 1, 3-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 52) (41 mg, 0.11 mmol), 1,2-dichloroethane (2.2 mL) and phosphorus oxychloride (0.081 mL, 0.87 mmol), to afford 5-methyl-7-[3-(methyloxy)phenyl]-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (12 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)cc2)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 4-(1-tert-butoxycarbonyl -1,2,3,6-tetrahydropyridin-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=O)[NH:11][C:7]=2[CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10]([Cl:17])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Product: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (3.00 g, 15.6 mmol) and phosphorus oxychloride (30 mL) were combined and heated to 100° C. for 48 h. The mixture was cooled to 23° C. and concentrated under reduced pressure. The residue was cooled to 0° C., and cold, saturated aqueous NaHCO3 (60 mL) was added cautiously. After stirring at 23° C. for 15 min, the mixture was sonicated and the resulting residue was filtered to yield the titled compound (3.13 g, 95%), which was used in the next step without further purification. MS (ESI/CI): mass calcd. for C9H7ClN2O2, 210.02; m/z found, 211.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH:4]=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.[Pd]>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A suspension of 3.88 g of benzyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate in 140 ml of ethanol was treated with 0.78 g of 10 percent palladium/carbon, whereupon the mixture was hydrogenated for 16 hours. The reaction mixture was diluted with 1400 ml of water and treated with 4.18 g of sodium carbonate. The catalyst was filtered off and the filtrate was acidified with 25 percent hydrochloric acid. The separated crystals were filtered off under suction, washed with water and dried in a vacuum. There was obtained 2.85 g of 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylic acid as white crystals with a m.p. of 295° (decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C=O)C.CO>[Br:20][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[C:7](=[N:8][C:3]([NH2:2])=[N:4][CH:5]=3)[N:9]([CH3:21])[N:10]=2)[CH:17]=[C:16]([F:18])[C:15]=1[O:19][CH2:31][CH2:30][O:29][CH3:28]
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1c(F)cc(-c2nn(C)c3nc(N)ncc23)cc1Br
Temperature: 120 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in DMF (1 ml) then treated with K2CO3 (24 mg, 0.18 mmol) and 2-bromoethyl methyl ether (7.5 μL, 0.08 mmol). The reaction mixture is heated at 120° C. for 3 hours then cooled to room temperature, diluted with MeOH and concentrated in vacuo. The crude residue is dry loaded onto silica and purification by flash chromatography on silica eluting with iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) affords the title compound as an off-white soild.