Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)OB([C:24]2[CH:29](C)[CH2:28][CH:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH:25]=2)O1.[F-].[Cs+]>O1CCOCC1.O.[Cl-].[NH4+]>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]=1[C:34]1[CH2:35][CH2:36][CH:31]([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)[CH2:32][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(c2ccccc2)CC=C1B1OC(C)C(C)(C)O1
Reactant: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)[nH]1
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(C2=CCC(c3ccccc3)CC2)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 140 °C
Yield: 31.7 %

Procedure:
A mixture of 5-benzyl-6-chloro-1H-pyrimidine-2,4-dione (WO06014394) (1.0 g), 4,4,5,6-tetramethyl-2-(4-phenylcyclohex-1-enyl)-[1,3,2]dioxaborolane (1.4 g), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.06 g) and cesium fluoride (1.92 g) in 1,4-dioxane (18 mL) and water (2 mL) was heated at 140° C. in a microwave reactor for 20 minutes. The resulting mixture was diluted with saturated aqueous ammonium chloride and filtered to remove the precipitate. The filtrate was extracted with dichloromethane and the combined organic layers washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (0:1 to 1:20 by volume) to afford the title compound 2a as an off-white solid (0.48 g). LCMS (Method A): Rt=3.56 min. (M+H)+=359. 1H NMR (DMSO-D6): δ 11.06 (1 H, s), 10.69 (1 H, s), 7.23-7.21 (10 H, m), 5.84-5.79 (1 H, m), 3.61 (2 H, s), 3.57 (1 H, s), 2.77-2.67 (1 H, m), 2.19-2.16 (3 H, m), 1.84-1.81 (1 H, m), 1.68-1.67 (1 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H+].[B-:11]([F:15])([F:14])([F:13])[F:12].[N:16]([O-])=O.[Na+].C(OCC)C>CCO>[F:12][B-:11]([F:15])([F:14])[F:13].[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:16]
Reactant: Nc1ccc(Cl)cc1Br
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: N#[N+]c1ccc(Cl)cc1Br
Yield: 96 %

Procedure:
A solution of 2-bromo-4-chloroaniline (10.0 g, 48.4 mmol) and HBF4 in EtOH (60 mL) kept at 0° C. was treated with an aqueous solution (20 mL) of NaNO2 (3.34g, 48.4 mmol). After completion of the addition, diethyl ether (200 mL) was added to the mixture. The solid was collected by filtration, washed with water and dried under high vacuum affording the title compound (14.2 g, 96%) as white crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:24])=[O:25]
Reactant: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 39.8 %

Procedure:
Method E. Reaction of oxalyl chloride (56 λL, 0.64 mmol) and benzoic acid 32 (158 mg, 0.43 mmol) with subsequent coupling to 3-pyridinylmethylamine (48 λL, 0.47 mmol) gave benzamide 33 (79 mg, 40%) as a white powder: mp (EtOAc) 179-181° C.; 1H NMR δ 9.20 (t, J=5.8Hz, 1 H, CONH), 8.57 (d, J=1.8Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.5Hz, 2 H, H-2, H-6), 7.90 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (dt, J=7.9, 1.9Hz, 1 H, H-4′), 7.63 (br s, 1 H, H, H-2″) 7.53-7.60 (m, 2 H, H-4″, H-6″), 7.50 (t, J=7.6Hz, 1 H, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.5Hz, 1 H, H-5′), 4.65 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.37 (s, 3 H, CH3), 2.16 (s, 3 H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 139.0, 138.3, 135.3, 135.1, 134.8, 134.3, 128.9, 128.7, 128.3, 128.0 (2), 125.8, 125.3 (2), 125.2, 123.3, 52.8, 40.4, 20.6, 9.67; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 64.06, 5.02; N, 9.10. Found: C, 64.76; H, 5.06; N, 9.05%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:7][C:8]1[N:13]=[C:12]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)[C:11]([Cl:15])=[CH:10][N:9]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccon1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2ccon2)n1

Procedure:
The mixture isoxazol-3-amine (36 μL, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (53 mg, 0.5 mmol) in 3 mL of EtOH is heated at 60° C. for 48 hrs. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford N-(2,5-Dichloropyrimidin-4-yl)isoxazol-3-amine; ESMS m/z 231.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.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>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (100 mg, 0.22 mmol) in DMF (10 mL) was added 2,4-dichlorophenyl boronic acid (63 mg, 0.33 mmol) and Na2CO3 (58 mg, 0.55 mmol, in 0.4 mL of H2O). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(PPh3)4 (35 mg, 0.03 mmol) and the mixture was stirred at 100° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 29% yield) MS [M+H]+517.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>C1(C)C=CC=CC=1>[O:19]=[C:13]([CH2:11][C:10](=[O:12])[C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(C)cc(C)cc1C
Yield: 66.7 %

Procedure:
To a solution of 2', 4', 6'-trimethylacetophenone (15 g, 92.6 mmol) and diethyl oxalate (20 g, 139 mmol) in 500 mL of anhydrous toluene was cautiously added 7.4 g of NaH (60% dispersion in mineral oil). The reaction mixture was slowly heated to reflux under N2. It was refluxed for about 20 minutes, then cooled, poured into ice-cold aqueous HCl solution, and extracted with ether. The extracts were washed with brine, dried over Na2SO4, filtered through a short silica gel pad and concentrated to give 16.2 g of a red oil which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:23]([O:24][CH3:25])=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH3:27])(=[O:3])[CH3:2].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[C:1]([O:4][C:5]1[C:23]([O:24][CH3:25])=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH3:27])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC(C)=O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: COc1cc(C(=O)NCc2ccc(N)cc2)cc(OC)c1OC(C)=O
Yield: 82 %

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A colourless oil is obtained with a yield of 82%. The product is used directly in the following stage without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>COCCO>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:18][CH:17]=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1ccc2c(O)ncnc2c1
Temperature: 130 °C
Reaction time: 15.25 h
Yield: 89.8 %

Procedure:
Step 1 A mixture of 2-amino-4-methoxybenzoic acid (0.5 g, 2.99 mmol) and formamidine acetate (0.623 g, 5.98 mmol) in 2-methoxyethanol (4 mL) was heated at 130° C. After 15.25 h, the mixture was cooled to rt. The resulting precipitate was collected by filtration, washed with methanol and dried to provide 7-methoxyquinazolin-4-ol as a tan solid (473 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (1H, br. s.), 8.06 (1H, s), 8.03 (1H, d, J=9.5 Hz), 7.03-7.14 (2H, m), 3.90 (3H, s).
Reaction SMILES: C([NH:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:8]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])=[C:8]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2.8 h
Yield: 39.8 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (13.70 g, 26.5 m mol) in methanol (65 ml) was added dropwise conc. HCl (11.0 ml) at room temperature and the mixture was stirred at the same temperature for 2.8 hours. The mixture was poured into a mixture of ethyl acetate and ice water and adjusted to pH 7 by addition of 5N NaOH aq. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ethyl acetate to give diphenylmethyl 7β-amino-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (5.16 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH:14]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:13]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1C=CCC1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 81.8 %

Procedure:
This compound was prepared in the same manner as for Intermediate 2, using 5-cyanoindole (4.26 g, 30 mmol) and 2-cyclopenten-1-one (2.95 g, 36 mmol) to give 5.5 g (82%) of the desired product: mp 136–138° C.; MS (ESI) m/z 224 [M]+.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 350 mg, 1.62 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (322 mg, 1.62 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 10 min. Na(AcO)3BH (412 mg, 1.94 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc-IH, 1:1) gave the title compound: m/z (ES+)=400.0 [M+H]+.
Reaction SMILES: CC1(C)[O:7][C:6]2[C:8]([CH2:12][C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4][O:3]1.Cl.C>O>[NH:16]1[CH:17]=[C:13]([CH2:12][C:8]2[C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=[CH:10][CH:9]=2)[N:14]=[CH:15]1
Reactant: CC1(C)OCc2cccc(Cc3c[nH]cn3)c2O1
Agent: C
Agent: Cl
Solvent: O
Product: OCc1cccc(Cc2c[nH]cn2)c1O
Temperature: 120 °C
Yield: 804.1 %

Procedure:
82.83 g (0.0339 mole) of 4-[(2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole (prepared in Example 5.2.) are suspended in 1645 ml of water (pH 7.9) and dissolved by the addition, over the course of 80 minutes, of 349 ml of a 1N aqueous solution of hydrochloric acid. When this addition is complete, the pH of the solution is 2.5. The reaction mixture is subsequently heated for 1 hour on an oil bath at 120° C. The solution is then cooled, treated with 5 g of Norit and filtered on Hyflo-cel. The solution is subsequently rendered alkaline by the addition of 242.5 ml of a 1N aqueous solution of sodium hydroxide (pH 8.5). The precipitate obtained is filtered off, washed with water and dried. This precipitate is then dissolved in 3.3 liters of ethyl acetate in the presence of Norit and of a few grams of sodium sulfate. The mixture is then filtered, concentrated to a volume of 400 ml and left to crystrallize. There are obtained 55.67 g of 3-[(1H-imidazol-4-yl)methyl]-2-hydroxybenzenemethanol. Yield: 80.4% of theory; M.P.: 152°-155° C.
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:33](=[O:44])[C:32]2(O)[C:45]1[C:46]([OH:54])=[CH:47][C:48]2[O:52][CH2:51][CH2:50][C:49]=2[CH:53]=1>>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:33](=[O:44])[CH:32]2[C:45]1[C:46]([OH:54])=[CH:47][C:48]2[O:52][CH2:51][CH2:50][C:49]=2[CH:53]=1
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [5-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (94%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 5.05 (s, 1H), 4.53-4.46 (m, 4H), 4.21 (q, 2H), 3.14-2.94 (m, 2H), 1.25 (t, 3H); MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(CC)CC.[Na+].[Cl-]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCOCC2)cn1
Temperature: 45 °C
Yield: 90.4 %

Procedure:
A mixture of 4.9 g (28 mmol) 5-chloro-pyrazine-2-carboxylic acid methyl ester (commercially available), 3.2 g (37 mmol) morpholine and 7.37 g (73 mmol) NEt3 in 50 mL dioxane was heated to 45° C. for 16 h. Water and NaCl aq. was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with NaCl aq., dried with MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate to yield 5.65 g (89%) of the title compound as white solid. m/z (ES+): 224.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[C:57]([C:59](O)=[O:60])[CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:57]2[CH:58]=[N:54][NH:55][CH:56]=2)=[O:60])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1cn[nH]c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2cn[nH]c2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-4-carboxylic acid as the starting materials in 66% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH3:22])[C:3]=1[F:23].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH3:22])[C:3]=1[F:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Solvent: c1ccncc1
Product: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
1.21 g (3.77 mmol) of Compound 80 obtained in Example 80 (3) was dissolved in 10 mL of pyridine, 0.46 mL (3.77 mmol) of pivaloyl chloride was added under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water and the precipitated crystals were collected by filtration to give 1.48 g of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one (yield: 97%).
Reaction SMILES: Cl.Cl.C[C@H]1CCCN1[C@@H]1CCNC1.C([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][C@@H:28]2[CH3:32])[CH2:23][CH2:22]1)(OC(C)(C)C)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C[C@H]1CCCN1>>[CH3:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH:24]1[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]1
Reactant: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[C@H]1CCCN1
Agent: C[C@H]1CCCN1[C@@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H]1CCCN1C1CCNCC1
Yield: 95 %

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2S,3′R)-2-Methyl-[1,3′]bipyrrolidinyl dihydrochloride by acid hydrolysis of BOC-4-((S)-2-Methyl-pyrrolidin-1-yl)piperidine which was synthesized by condensation of tosylate with (S)-(−)-2-methylpyrrolidine to get 1.28 g (95% yield) of the title product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 163) (200 mg, 0.44 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (99 mg, 44%).
Reaction SMILES: [C:1]([NH:3][C:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)#[N:2].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[C:1]([NH:3][C:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)#[N:2]
Reactant: O=Cc1ccccc1
Reactant: N#CNC(=NCCc1ccc(N)cc1)c1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CNC(=NCCc1ccc(NCc2ccccc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.20 g, 0.75 mmol) was dissolved in methanol (15 ml), and benzaldehyde (0.12 g, 1.13 mmol) and sodium cyanoborohydride (0.10 g, 1.59 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue thus obtained was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.12 g, 0.34 mmol, yield: 75%) as colorless needles.