Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[O:10][CH:11]=1)=[O:6].[OH-].[Na+]>C1COCC1>[CH3:21][C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][C:9]2[O:10][CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=2)[O:20][CH2:19][CH2:18][O:17]1
Reactant: COC(=O)c1coc(CCCCC2(C)OCCO2)n1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(CCCCc2nc(C(=O)O)co2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carboxylic acid methyl ester (713 mg, 2.65 mmol) in THF (15 mL) was treated at rt with 1N NaOH (6.7 mL, 6.70 mmol) and the reaction mixture was stirred for 1 h at rt. The solvents were removed under reduced pressure. The residue was treated with sat. aq. NH4Cl, and acidified to pH 4-5 with 1N HCl. The aq. layer was extracted with CH2Cl2 and the combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a white solid. TLC: rf (4:1 CH2Cl2-MeOH)=0.5. LC-MS-conditions 02: tR=0.75 min [M+H]+=256.31.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:28].CN(C=O)C.C(O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[CH:2][CH:7]=1
Reactant: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CO
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 129.1 %

Procedure:
A vial was charged with 1-(2-bromo-4-chlorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (202.5 mg, 0.320 mmol) and tetrakis(triphenylphosphine)palladium(0) (37.0 mg, 0.032 mmol). The vial was flushed with Ar (g), then DMF (1.6 mL) and formic acid (123 μl, 3.20 mmol) were added. The vial was sealed and placed in an 80° C. heating bath for 27 hrs. The mixture was cooled to rt and was loaded onto a 4-g silica gel loading column with the aid of MeOH/DCM, and the column was dried was dried under vauum. The column was then eluted onto a 25-g SNAP Ultra column with 0-50% of a 3:1 EtOAc/EtOH in heptane with 10% DCM to give 166 mg of 1-(4-chlorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide contaminated with some DMF and starting material. m/z (ESI) 402.2 (M+H)+.
Reaction SMILES: Cl.[N:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]([C:25]2[C:33]3[CH:32]=[N:31][CH:30]=[N:29][C:28]=3[N:27]([CH:34]([CH3:36])[CH3:35])[CH:26]=2)=[O:24])[CH:20]=[N:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[N:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[C:19]([C:23]([C:25]4[C:33]5[CH:32]=[N:31][CH:30]=[N:29][C:28]=5[N:27]([CH:34]([CH3:36])[CH3:35])[CH:26]=4)=[O:24])[CH:18]=3)=[O:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)CN1CCc2cccnc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)CN3CCc4cccnc4C3)c2)c2cncnc21
Temperature: 50 °C
Yield: 26 %

Procedure:
To a DMF solution of (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid hydrochloride (Preparation 235) (34.2 mg, 0.18 mmol) were added (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95) (50 mg, 0.18 mmol), HATU (136.4 mg, 0.36 mmol) and Hunig's base (0.092 ml, 0.54 mmol). The mixture was heated at 50° C. for 20 hours and then diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude solid was purified over preparative TLC eluting with 5% MeOH/EtOAc to afford the title compound as off white solid in 26% yield, 21 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.55 (d, 6H), 2.85-2.92 (m, 4H), 3.45 (s, 2H), 3.80 (s, 2H), 5.10 (m, 1H), 7.19 (dd, 1H), 7.56 (d, 1H), 8.32 (d, 1H), 8.53 (s, 1H), 8.56 (t, 1H), 8.73 (d, 1H), 8.99 (s, 1H), 9.07 (d, 1H), 9.45 (s, 1H), 10.31 (s, 1H); LCMS (system 9): Rt=1.77 min; m/z 456 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:14])[C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52]C(=O)C)=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH:51]=2)[C:48]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=2[Cl:14])=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: Nc1c(Cl)cc(OC(F)(F)F)cc1Cl
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3c(Cl)cc(OC(F)(F)F)cc3Cl)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.1 %

Procedure:
2,6-Dichloro-4-trifluoromethoxyaniline (0.395 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) and then recrystallized from ether to obtain the titled compound (0.099 g, 0.177 mmol, 33%).
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>>[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16]([O:5][C@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][I:1])=[CH:15][CH:14]=1
Reactant: O[C@H](CCI)c1ccccc1
Reactant: Oc1ccc(F)c2c1SCC2
Product: Fc1ccc(O[C@@H](CCI)c2ccccc2)c2c1CCS2

Procedure:
using (R)-1-iodo-3-phenyl-3-propanol with 4-fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 242 mg of the title compound as a colorless solid: δH (300 MHz, CDCl3) 7.32-7.12 (5H, m, 3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H, m, CH2CH2HI and SCH2CH2), 2.50-2.31 (1H, m, CHHCH2I) and 2.27-2.09 (1H, m, CHHCH2I).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][OH:48])[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO)CC5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 54d (210 mg, 0.261 mmol) and TBAF (1M in THF, 0.31 mL, 0.31 mmol) in THF (5 mL) was stirred at RT for 1.25 h. The mixture was diluted with water and extracted with DCM (3×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (134 mg, 79%). LCMS (Method 5): Rt 4.24 min, m/z 649.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.38-2.16 (9H, m), 2.36 (3H, s), 2.85-2.97 (2H, m), 3.28-3.49 (4H, m), 4.52 (1H, t, J 5.2), 4.78-4.85 (1H, m), 5.55 (1H, t, J 4.3), 6.32 (1H, s), 7.07 (1H, d, J 8.6), 7.15 (1H, dd, J 9.7, 2.1), 7.25-7.41 (8H, m), 7.60 (1H, d, J 9.7), 7.64 (1H, d, J 1.6), 8.04 (1H, s).
Reaction SMILES: Br[C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.C([Li])CCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH4+].[Cl-]>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-4-chloropyrrolo[2,3-d]pyrimidine (Example 35) (232 mg; 1 mmol) in anhydrous THF (5 mL) was cooled to -78° C. under argon and a solution of n-butyl lithium (1.3 mL of 2.31M) was added at such a rate that the temperature of the reaction mixture remained below -72° C. After stirring the reaction mixture at -78° C. for 45 minutes, a solution of ethyl chloroformate (0.15 mL) in THF (2 ml) was added slowly, maintaining the reaction temperature below -72° C. The reaction mixture was stirred at -78° C. for 2 hours then allowed to warn to room temperature. A saturated solution of NH4Cl (20 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried and evaporated to a white solid, yield 210 mg (92%): m.p. 140°-141° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>O1CCOCC1.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[CH:25]=[C:24]([CH3:33])[CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)csc2n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4scc(-c5ccc(F)cc5)c34)CC2)c1
Reaction time: 8 h

Procedure:
To a solution of Example 1 (115 mg, 0.35 mmol) in 1,4-dioxane (15 mL) was added m-tolyl isocyanate (0.38 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and the organic layer was extracted several times with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 1% methanol in dichloromethane), yielding the title compound as a white powder. MS (m/z) 463 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:35])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:13]2[S:12][CH:16]=[CH:15][N:14]=2)=[O:35])=[CH:24][C:23]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc2cc(Br)ccc12
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc2c(C)noc2c1
Yield: 7.5 %

Procedure:
Example 8 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-(thiazol-2-yl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 18, 17 mg) followed by purification via mass directed autoprep to give the title compound as an oil (1.3 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[N:32]1([C:19]([C:18]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)O)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxylic acid (125 mg, 0.426 mmol) and 1-hydroxybenzotriazole (57.6 mg, 0.426 mmol), morpholine (0.0743 ml, 0.852 mmol) in DMF (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (163 mg, 0.852 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give the desired product (130 mg, 84.4%) as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])C.[NH4+:23].[OH-]>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][C:7]([N+:19]([O-:21])=[O:20])=[C:6]([CH2:5][C:4]([NH2:23])=[O:3])[CH:11]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(CC(N)=O)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[5-(4-Methyl-piperazin-1-yl)-2-nitro-phenyl]-acetic acid ethyl ester (1.54 g, 5.01 mmol) is suspended in a 33% aqueous NH4OH solution (400 mL), and stirred for 3 days at RT. The volume is carefully reduced under vacuum until the title compound remains as a yellow solid, which is further dried under high vacuum. ES+-MS: 279 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OC(=O)C)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][C:5]2[NH:4][N:3]=[N:2][N:1]=2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cc2nnn[nH]2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of tetrazole (0.17 g) in dimethylformamide (2 ml) at ice-bath temperature under nitrogen was stirred with 60% sodium hydride (0.1 g) for 5 mins and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.73 g) in dimethylformamide (8 ml) was added to it. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethylacetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (30 g). Elution with 10% to 20% ethylacetatedichloromethane gave 1-hexyl-3-(1-tetrazolylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone (0.37 g). That this compound was obtained was confirmed by the spectral data: MS: m/e 355 (M+); NMR (CDCl3): δ4.18 (s, 3H, OCH3), 5.68 (s, 2H, CH2), 9,14 (s, 1H, CH= ).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>FC(F)(F)C(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH2:13][C:15]([F:18])([F:17])[F:16])[C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)F)[C@H](C)CO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 195.9 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3 ,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (4 mg, 0.01 mmol) and NaBH4 pellets (large excess, >10 equiv) in 2.5 mL trifluoroacetic acid (0.005 M) stirred at rt for 12 h, to afford 4 mg (80%) of (R)-3,4-dihydro-8-isopropoxy-3-methyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (4 mg, 0.01 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 2 mL acetic acid and 2 mL concentrated HCl (0.003 M) and heated at 90° C. for 4 h to afford 3.2 mg (71%) of Compound 104, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 12.00 (bs, 1H), 7.16 (s, 1H), 7.11 (d, J=9.3, 1H), 7.00 (d, J=8.8, 1H), 4.20 (d, J=10.7, 2.9, 1H), 4.09 (dd, J=10.7, 2.4, 1H), 3.82 (m, 2H), 3.60 (m, 1H), 1.26 (d, J=6.8, 3H).
Reaction SMILES: Cl.[CH:2]12[NH:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([NH2:14])=[CH:4][C:3]2=1.[Cl:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>>[CH:2]12[NH:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([NH:14][C:29]3[N:28]=[C:27]([NH:26][C:17]4[C:16]([Cl:15])=[CH:25][CH:24]=[CH:23][C:18]=4[C:19]([NH:21][CH3:22])=[O:20])[C:32]([Cl:33])=[CH:31][N:30]=3)=[CH:4][C:3]2=1
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl

Procedure:
Following a procedure analogous to 61e, 12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine hydrochloride salt (83 mg, 0.39 mmol) and 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (see Example 312a-b for preparation) (100 mg, 0.30 mmol) were converted to the title compound isolated as an ivory solid (85 mg, 18%). 1HNMR (400 MHz, DMSO-d6) δ 9.2-9.0 (m, 2H), 8.4 (bs, 1H), 8.1 (s, 1H), 7.7 (d, 1H, J=7.3 Hz), 7.6 (d, 1H, J=7.6 Hz), 7.4 (m, 1H), 7.1 (s, 1H), 7.0 (d, 1H, J=7.6 Hz), 6.7 (d, 1H, J=8.1 Hz), 3.8-3.6 (m, 2H), 3.3 (bs, 1H), 2.9 (dd, 1H, J=16.2, 4.3 Hz), 2.6 (s, 3H), 2.3 (d, 1H, J=16.2 Hz), 1.9-1.8 (m, 2H), 1.6-1.4 (m, 2H); MS (m/e) 469 (M+1); mp 150-154° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:6]3[C:12]([C:13]#[CH:14])=[N:11][N:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]3)=[C:6]3[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Pd]
Solvent: CO
Product: CCc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-ethynyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.4 mmol) was placed in MeOH (2 mL). Pd/C (175 mg, 0.08 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then filtered and concentrated to give tert-butyl 4-(5-cyclopropyl-3-ethyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (150 mg, 74% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[C@@H:16]([C:17]#[N:18])[NH:15][C:14]1=[O:19].C(N(CC)CC)C.Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])([CH3:46])[CH3:45])[C:39](Cl)=[O:40])[N:37]=1)=[O:31]>O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=2)=[O:48])([CH3:45])[CH3:46])[C:39]([NH:12][C@H:13]2[C@@H:16]([C:17]#[N:18])[NH:15][C:14]2=[O:19])=[O:40])[N:37]=1)=[O:31]
Reactant: CC(C)(ON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N#C[C@H]1NC(=O)[C@H]1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
In 12 ml of tetrahydrofuran was dissolved 0.30 g of (3S, 4S)-3-amino-4-cyano-2-azetidinone p-toluenesulfonate. To the solution were added, under ice-cooling, 0.12 g of triethylamine and, subsequently 0.60 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was purified on a silicagel column [ethyl acetate-chloroformmethanol (3:3:1)] to yield 0.27 g of (3S, 4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone.