Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=[C:37]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:54]([C:37]1[CH:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of Intermediate 81d (240 mg, 0.64 mmol), Intermediate 108b (325 mg, 0.64 mmol) and DIPEA (221 μL, 1.27 mmol) in dioxane (6 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to afford the title compound (377 mg, 80%). LCMS (Method 4): Rt 3.48 min, m/z 737 [MH+].
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.8 g (14.7 mmoles) 3-chlorolactic acid and 3.4 g p-chlorophenol in 15 ml 3.3N sodium hydroxide was stirred under reflux for two hours. The mixture was cooled to room temperature and acidified to pH=3, with concentrated hydrochloric acid. The resulting white crystals were filtered and dissolved in hot water and the hot solution was adjusted to pH=1 with concentrated sulfuric acid. Upon cooling the product, 3-(p-chlorophenoxy)-lactic acid was collected as clear crystals, 0.7 g, m.p. 135° to 136° C.; Edelson, et al., Biochem Pharmacol 18, 2331 (1969) reported m.p. 137° to 138° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([I:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([I:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Temperature: 50 °C
Yield: 69.4 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.413 g, 1.5 mmol) from Example 1A, 4-chloro-6-iodoquinazoline (0.436 g, 1.5 mmol), and Cs2CO3 (0.489 g, 1.5 mmol) in isopropanol (10 mL) was heated at 50° C. for 2 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea as solid (0.551 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.08 (s, 1H), 8.84 (s, 1H), 8.78 (m, 1H), 8.40 (dd, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.09 (d, 1H), 6.55 (s, 1H), 1.35 (s, 9H); LC-MS (ESI) m/z 530 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[S:18]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([C:22]3[S:18][CH:19]=[N:20][CH:21]=3)=[O:24])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1cncs1
Product: C[C@]1(c2cc(NC(=O)c3cncs3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and thiazole-5-carboxylic acid (CAS 14527-41-4) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=353.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[OH:25])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:25][C:16]2[C:15]([O:26][CH3:27])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:11]3)=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(C(=O)OC)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.89 g (0.002 mole) of the compound from Example 31, 0.69 g (0.003 mole) of 4-carbomethoxybenzyl bromide (Aldrich), 5.0 g of powdered anhydrous sodium carbonate, and 5 mL of DMF is heated at reflux, with stirring, for 5 minutes. The cooled mixture is treated with 50 mL of ice water. The precipitated product is extracted into 150 mL of ether. The solution is dried (magnesium sulfate) and concentrated; wt. of amorphous solid 1.20 g; mass spectrum (CI) 594 (M+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Sn](C)(C)[C:46]1[CH:47]=[CH:48][C:49]2[C:50](=[O:61])[C:51]3[C:56]([C:57]=2[CH:58]=1)=[CH:55][CH:54]=[C:53]([CH2:59][OH:60])[CH:52]=3.C(Cl)(Cl)Cl>CN1CCCC1=O.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([C:46]4[CH:47]=[CH:48][C:49]5[C:50](=[O:61])[C:51]6[C:56]([C:57]=5[CH:58]=4)=[CH:55][CH:54]=[C:53]([CH2:59][OH:60])[CH:52]=6)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Sn](C)(C)c1ccc2c(c1)-c1ccc(CO)cc1C2=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CO)cc3C4=O)CS[C@H]12
Yield: 61.2 %

Procedure:
Benzhydryl 7β-phenylacetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate (1.26 g) was dissolved in N-methylpyrrolidone (NMP) and treated with 3-trimethylstannyl-7-hydroxymethyl-9-fluorenone (0.742 g). Zinc chloride (4.0 ml, 1.0M solution in ether) was added followed by Pd2 (dba)3.CHCl3 (60 mg) and the reaction mixture was stirred under nitrogen for 45 min. The reaction mixture was diluted with ethyl acetate and washed with water five times, then with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from hot ethyl acetate/hexane to give 0.844 g of the desired product in the first crop and a further 0.170 g in the second crop of crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29]OS(C3C=CC(C)=CC=3)(=O)=O)[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:48].[Li+].CN(P(N(C)C)(N(C)C)=O)C>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][Br:48])[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O[C@H]2NC(=O)[C@H]2NC(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)c2ccccc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CBr)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
A mixture of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(p-toluenesulfonyl)oxy-1 -phenylethoxy}azetidin-2-one (160 mg, 0.244 mmol), lithium bromide (133 mg, 1.525 mmol) and HMPA (4 ml) was stirred at 60° C. for 1.5 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:2) as eluent and 100 mg (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-bromo-1-phenylethoxy)-azetidin-2-one as white foam was obtained in 72% yield.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:35]([O:34][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (50 mL of a 10% solution in dichloromethane) was added to tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (2.07 g, 4.50 mmol), and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was recrystallized from methanol to provide 2.2 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine trifluoroacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH2:8][C:9]1[N:10]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:11](=[O:37])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][N:26]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C.O1CCCC1>[C:1]([O:5][C:6](=[O:42])[NH:7][CH2:8][C:9]1[N:10]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:11](=[O:37])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1=O
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 125.5 %

Procedure:
A mixture of tert-butyl{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate (0.85 g, 1.5 mmol), and hydrazine monohydrate (0.6 mL, 12 mmol) in ethanol (20 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 17 h. The reaction mixture was filtered, and the filtrate was concentrated. After the residue was dissolved in ethyl acetate (50 mL), the solution was filtrated to remove insoluble material. The filtrate was concentrated to give tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.82 g) as a crude pale yellow oil. To a solution of the crude oil (0.16 g) in tetrahydrofuran (2 mL) was added acetic anhydride (0.034 mL, 0.36 mmol), and then the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl{6-[(acetylamino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.090 g, 63%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:42]([O:44]C)=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:22]=3)[N:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([C:42]([OH:44])=[O:43])[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:22]=3)[N:16]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 240 mg (0.39 mmol) of methyl 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylate and 3 ml of 1 M aqueous solution of lithium hydroxide in 20 ml of methanol and 10 ml of tetrahydrofuran was stirred for 18 hours at room temperature and 2 hours at 60° C. The mixture was concentrated in vacuum, neutralized to pH 5 by careful addition of 1 N aqueous HCl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to afford 150 mg (43%) of 4-(tert-Butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid over two steps. ESI MS m/z 600.2 (M+1).
Reaction SMILES: O1CCCC1.P(Br)(Br)[Br:7].CC1C=CC(S(O[C:21]2[CH2:25][CH:24]([C:26](=[O:43])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[C:35](=[O:42])[NH:36][CH:37]([CH:39]3[CH2:41][CH2:40]3)[CH3:38])[N:23]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:22]=2)(=O)=O)=CC=1>O>[Br:7][C:21]1[CH2:25][CH:24]([C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35](=[O:42])[NH:36][CH:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])=[O:43])[N:23]([C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[N:22]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 235.1 %

Procedure:
A tetrahydrofuran (1 ml) solution comprising 0.16 g of phosphorus tribromide was dropwise added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 9 ml of tetrahydrofuran under cooling with ice. After stirring for 5 minutes, the reaction liquid was heated to 45° C. 5 hours later, the reaction liquid was poured to 50 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.73 g of the desired product in the form of a paste.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3]>[Pd].C(O)(C)C>[CH2:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)CNC(=O)NCC(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Charge benzyl 2-(isobutylcarbamoylamino)acetate (200 g; 98.1% assay), dry Pd/C (20 g; 10% w/w), and isopropyl alcohol (2000 ml) into an autoclave. Degas under vacuum and purge with hydrogen three times. Stir at 60° C. under 50-60 psi of H2 for 4 hours. Cool the mixture to 20-30° C. and filter through diatomaceous earth and concentrate the filtrate under reduced pressure at 45-50° C. to 1-2 Vol. Add acetonitrile (1000 ml) and concentrate under reduced pressure at 45-50° C. to 2-3 Vol. Cool the mixture to 5-10° C. and filter. Dry the cake under reduced pressure at 45-50° C. to give of 2-(isobutylcarbamoylamino)acetic acid (112 g; 95.2% assay; 82.5% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A suspension of NaH in mineral oil (55-60%)(712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115,2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:24]1([CH3:33])[C:25]([N:30]=[C:31]=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:31]([NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:33])=[O:32]
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg) was dissolved in chloroform (10 ml), and o-toluyl isocyanate (59 mg) was added to the solution. The mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal. The crystal was collected by filtration to give 59 mg (yield 34%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C2=CCNCC2)nc1

Procedure:
A solution of tert-butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 hours. This resulted in the product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][OH:24])=[C:17]([CH2:25][OH:26])[CH:16]=1.C(N(CC)CC)C>C(Cl)Cl.CO>[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:25]=[O:26])[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:23]=[O:24]
Reactant: COc1cc(CO)c(CO)cc1OCCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C=O)c(C=O)cc1OCCCl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with mechanical stirrer, thermometer and addition funnel is added 100 mL dry methylene chloride and 8 mL of oxalyl chloride under nitrogen. This is cooled to −78° C. in a dry ice/acetone bath, then 13.6 mL DMSO in 25 mL dry methylene chloride is added dropwise. After complete addition it is further stirred for 5 minutes. Then 9.87 g of [4-(2-chloroethoxy)-2-(hydroxymethyl)-5-methoxyphenyl]methanol in 10 mL of dry methylene chloride (with enough DMSO added to dissolve the solid) is added dropwise. The reaction mixture is stirred for an additional 30 minutes, then 100 mL of triethylamine is added slowly at −78° C. The solution is stirred for 10 minutes, allowed to warn to room temperature and then 200 mL of ice/water is added. The aqueous layer is extracted with methylene chloride (2×100 mL). The organic layer is dried over MgSO4, filtered and evaporated to give the crude product as a solid. This solid is slurried with cold methanol and filtered, washed with cold methanol, then dried to give 6.37 g of 4-(2-chloroethoxy)-5-methoxyphthalaldehyde as a yellowish solid, m.p. 113–4° C.