Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[C:44]([F:51])=[C:45]([CH:47]=[CH:48][C:49]=1[Cl:50])[NH2:46]>>[Cl:42][C:43]1[C:44]([F:51])=[C:45]([NH:46][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]
Reactant: Nc1ccc(Cl)c(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3,4-dichloro-2-fluoro-aniline; other starting materials were prepared as example 1.
Reaction SMILES: [CH2:1]([C:4]1[C:15]([Cl:16])=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:12][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]#N)[CH2:2][CH3:3].[N-:20]=[N+:21]=[N-:22].[CH3:23][N:24](C)C(=[NH2+])N(C)C.CN(C)C=O.C(OCC)(=O)C>O>[CH2:1]([C:4]1[C:15]([Cl:16])=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:12][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:23]1[NH:24][N:22]=[N:21][N:20]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=[NH2+])N(C)C
Reactant: CCCc1c(OCCCC#N)ccc(C(C)=O)c1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCc2nnn[nH]2)ccc(C(C)=O)c1Cl

Procedure:
A solution of 0.5 g. of 4-(2-propyl-3- chloro-4-acetylphenoxy)butane nitrile and 1.3 g. of tetramethylguanidinium azide in 3 ml. of dimethylformamide was heated overnight at 125° C. The reaction was cooled, ethyl acetate and water were added, and the layers were separated. Water was added to the ethyl acetate layer, the water layer was acidified, and the layers were separated. The ethyl acetate was dried and evaporated to dryness. The residue was purified by chromatography to give the desired title product. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:26])([CH2:15][N:16]1[CH:25]=[C:19]2[N:20]=[CH:21][C:22]([Br:24])=[CH:23][C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:24][C:22]1[CH:21]=[N:20][C:19]2=[CH:25][N:16]([CH2:15][C:12]([NH:11][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:13]#[N:14])[CH3:26])[N:17]=[C:18]2[CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(Cl)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-chlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=418, RT=0.56 min.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17]([O:19][P:20]([CH2:25][C:26](Cl)=[O:27])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:20]([CH2:25][C:26](=[O:27])[NH:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])(=[O:24])[O:19][CH2:17][CH3:18])[CH3:23]
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(CC(=O)Nc1cc(Cl)ccc1C=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine (3.7 ml, 45.7 mmol) is added to a solution of 2-amino-4-chlorobenzaldehyde (6.18 g, 39.7 mmol) in 170 ml of anhydrous toluene, followed dropwise by a solution of chlorocarbonylmethylphosphonic acid diethyl ester (9.8 g, 45.7 mmol) in 15 ml of anhydrous toluene whilst maintaining the reaction mixture at a temperature of less than 30° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with a 1N HCl solution, and then again with water. Finally the mixture is washed with an aqueous saturated NaCl solution. The organic phase is dried over MgSO4, and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the following step.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:14])[C:6]1=[O:15])(=[O:3])[CH3:2].[H-].[Na+].[CH3:18][S:19][CH2:20]Cl.O>CN(P(N(C)C)(N(C)C)=O)C>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH2:18][S:19][CH3:20])[C:6]1=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2c(O)cccc2C1=O
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CSCOc1cccc2c1CC(NC(C)=O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-acetylamino-4-hydroxy-1-indanone 10.25 g (0.05 m) in 50 ml of dry HMPA under N2 is added 2.6 g (0.055 m) of a 50% oil dispersion of sodium hydride in portions. After stirring at room temperature for 1/2 hr, 5.3 g (0.055 m) of chloromethyl methyl sulfide is added, and the mixture is stirred overnight. Water is added and the mixture is extracted with ethyl acetate which is back-washed with water. After drying (Na2SO4) and concentration, the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>O1CCCC1>[CH2:15]([O:14][C:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cccc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(C)cccc2n1
Yield: 58.8 %

Procedure:
2-Amino-6-methylpyridine (5 g, 0.05 mol) was dissolved in tetrahydrofuran (100 mL). Ethyl bromopyruvate (9 g, 0.05 mol) was added and the mixture was refluxed for 4 hours. The reaction was cooled and the solid that formed was filtered to give 6 grams of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. Rf 0.45, 2% methanol/dichloromethane; MS m/z 205 (M+H).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.C(N1C=CN=C1)([N:24]1[CH:28]=[CH:27]N=C1)=O.C(N)C>>[CH2:28]([NH:24][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3])[CH3:27]
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Product: CCNC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Yield: 39.8 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 24, 3.4 g of carbonyldiimidazole and 2 ml of 70% aqueous ethylamine. The product was recrystallized from ethanol to obtain 1.3 g of the desired product, m.p. 135°-137°.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22](O)=[O:23])[CH:17]=[CH:16]3.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:26]1([C:22]([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:12]4[CH2:11][C:3]5([C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:25][C:13]=4[CH:14]=3)[N:19]=2)=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Reactant: C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21)N1CCCCC1

Procedure:
A mixture of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 12), piperidine (0.009 mL, 0.091 mmol), EDC (26 mg, 0.14 mmol), HOBT (21 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.23 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=399 (M+1). HRMS: m/z=399.1817; calculated m/z—399.1816 for C24H22N4O2.
Reaction SMILES: O.[CH3:2][C:3]1([CH3:17])[C:7]([CH3:8])=[CH:6][CH2:5][CH:4]1[CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:18]([CH:20]([CH2:24][CH2:25][C:26]1[C:27]([CH3:33])([CH3:32])[CH:28]([CH3:31])[CH2:29][CH:30]=1)[C:21]([OH:23])=[O:22])[CH3:19]>C(OCC)(=O)C>[CH3:17][C:3]1([CH3:2])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:18]([CH:20]([CH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[C:27]1([CH3:32])[CH3:33])[C:21]([OH:23])=[O:22])[CH3:19]
Reactant: CCC(CCC1=CCC(C)C1(C)C)C(=O)O
Reactant: CCOC(=O)C=CCC1CC=C(C)C1(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CCC1CCC(C)C1(C)C)C(=O)O
Product: CCOC(=O)CCCC1CCC(C)C1(C)C
Reaction time: 17 h
Yield: 36.8 %

Procedure:
To a three necked round bottom flask with a stir bar flushed with nitrogen, Degussa type palladium on charcoal Pd/C (1.5 g, 10% Pd) was added as catalyst. The catalyst was covered with distilled water (8 ml) and ethyl 4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoate/ethyl 4-(2,2,3-trimethylcyclopentenyl)butanoic acid (10.0 g, 44.9 mmol) in Ethyl Acetate (AcOEt) (200 ml) was added to the reaction flask. The flask was flushed with hydrogen and the reaction was run under hydrogen balloons that were refilled as needed. After 17 h at room temperature the reaction was found to be completed by gas chromatography and mass spectrometry (GCMS). The reaction mixture was filtered through a celite plug. The organic layers were concentrated in vacuo and purified via flash column chromatography AcOEt/Hexanes (gradient 0 to 40%) to give ethyl 4-(2,2,3-trimethylcyclopentyl)butanoate/ethyl 4-(2,2,3-trimethylcyclopentyl)butanoic acid as a colorless oil (7.48 g, 74%). The NMR data is indicated below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1Oc2ccccc2N(Cc2ccc(Cl)cc2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 0.10 g (342 mmol) ((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 1 ml dimethylformamide was added at 0° C. over a period of 20 minutes to a suspension of 0.015 g (342 mmol) sodiumhydride (55%) in 2 ml dimethylformamide. After 30 minutes 0.056 g (342 mmol) 4-chlorobenzylchloride was added and stirring was continued for 3 hours at 0° C. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane yielded 0.12 g (84%) [(6R,7S)-9-(4-chloro-benzyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester as white solid, MS m/e (%): 417.2 (M+H+, 69), 361.2 (100), 317.1 (91).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:8])[CH:3]=[N:2]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1cn[nH]c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid (1.05 g), 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (2.5 g), 1-hydroxybenzotriazole hydrate (1.6 g) and morpholine (1.2 g) in chloroform (18 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 95:5) and silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 90:10). The resulting colorless solid was washed with ethyl acetate to give the titled compound (1.00 g) as a colorless solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.C[Si]([N:19]=C=O)(C)C.C(Cl)[Cl:23]>>[ClH:23].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: ClCCl
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (35.6 g, 179 mmol) in CH2Cl2 (600 mL) was added trimethylsilylisocyanate (82.5 g, 716 mmol). After 2 h at rt, the mixture was concentrated, and the resulting white solid was dissolved in CH2Cl2 (500 mL). The solution was then treated with a solution of HCl (4.0 N in 1,4-dioxane, 135 mL). The resulting heterogeneous suspension was then stirred at rt overnight. Upon evaporation of the solvents, the desired product was isolated as a white solid (33 g), which was used directly in the next step. [Note: the mass balance was found to be 104%, which arose from additional HCl that could not be removed by standard evaporation under vacuum]. 1H NMR (500 MHz, CD3OD): 4.77 (s, 1H), 4.55 (s, 1H), 3.69 (d, J=12.1 Hz, 1H), 3.64 (d, J=12.1 Hz, 1H), 3.47 (d, J=11.3 Hz, 1H), 3.40 (d, J=11.3 Hz, 1H), 2.22 (d, J=11.5 Hz, 1H), 2.15 (d, J=11.5 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>[Cl-].[Na+].O.O.ClCCl>[CH:1]1([NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A flask was charged with 4-(3-cyclobutylureido)benzoic acid (51.3 mmol, 12.023 g), triethyl-amine (129 mmol, 18 mL, 13.07 g) and dichloromethane (75 mL) and cooled to 0° C. tert-Butyl piperazine-1-carboxylate (51.3 mmol, 9.56 g) was then added and the reagents were stirred together for 10 minutes at 0° C. before 1-propanephosphonic acid cyclic anhydride (64.2 mmol, 38.0 mL, 40.8 g, 50% solution in ethyl acetate) was slowly added. The reaction mixture was allowed to warm slowly to room temperature. After 5 hours stirring, the reaction was poured into a flask containing water (100 mL) and brine (20 ml). The mixture was then stirred and left to stand overnight. The resulting precipitate was collected by vacuum filtration, washed with cold water and dried under vacuum to yield the title compound as a white powder (19.6 g). MS (ESI) m/z 403.5 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:32]1[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]1
Reactant: COC(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: CC1(O)CCNCC1
Product: COC(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 73 %

Procedure:
In analogy to the procedure described in example 25B, (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid methyl ester (example 26A) and 4-methyl-piperidin-4-ol (intermediate 8) gave the title compound in 73% yield as colorless oil. MS: 486.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].[OH:30]O>C(Cl)Cl.C[Re](=O)(=O)=O.O=[Mn]=O>[Cl:29][C:6]1[CH:5]=[N+:4]([O-:30])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: OO
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CCOCC1)CO2
Agent: C[Re](=O)(=O)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)c2c1OCC1(CCOCC1)CO2
Reaction time: 18 h

Procedure:
To a solution 2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H),4′-tetrahydropyran]-6-yl}ethanone [127] (66 mg, 150 μmmol) in CH2Cl2 (2 mL) was added 30% H2O2 (45 μL) and methyltrioxorhenium(VII) (10 mg). The mixture was stirred for 18 h, added MnO2 (10 mg) and was stirred for another hour. CH2Cl2 (10 mL) was added and the organic phase was washed with water. The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 5.6 mg of the product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11])#[N:2].[NH2:12][OH:13].CCO>>[NH2:11][C:10]1[CH2:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[N:12][OH:13])[N:2]=1.[OH:13][NH:12][CH:10]1[CH2:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([NH2:2])=[N:11]1
Reactant: NO
Reactant: N#CCc1ccccc1C#N
Solvent: CCO
Product: NC1=NC(=NO)c2ccccc2C1
Product: NC1=NC(NO)Cc2ccccc21
Yield: 185.4 %

Procedure:
A solution of 2-cyanophenylacetonitrile (1 g, 7 mmol) and hydroxylamine (1.7 cm3, 28.1 mmol, 4 eq) in EtOH (25 cm3) were stirred under reflux for 60 hours, after which the volatiles were removed under reduced pressure. The residue was recrystallised from EtOH-water (1:4, 15 cm3) to give the cyclised product 3-aminoisoquinolin-1(4H)-one oxime or 3-(hydroxyamino)-3,4-dihydroisoquinolin-1-amine (1.15 g, 85.9%) as a solid, mp 92.5-94.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([I:16])=[CH:4][N:3]=1.[CH2:17](I)[CH2:18][CH3:19].C(OCC)(=O)C.O>CN1CCCC1=O.[H-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][CH2:18][CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([I:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ncc1I
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2-chloro-5-iodopyridin-4-yl)carbamate (S8, 239 mg) and propyl iodide (131 μL) in N-methylpyrrolidone (3 mL), sodium hydride (60% wt, 80 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours, and then stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain tert-butyl (2-chloro-5-iodopyridin-4-yl)(propyl)carbamate (S9, 155 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8](C(O)=O)[CH2:7][CH2:6]1)=[O:4].C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:19](=[O:23])[NH2:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(C(N)=O)CCCCC1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture cyclohexane-1,4-dicarboxylic acid monomethyl ester (3 g, 16.1 mmol) and triethylamine (2.24 mL, 16.1 mmol) in chloroform cooled in an icebath was dripped in of ethyl chloroformate (1.54 g, 16.1 mmol) followed by bubbling of ammonia gas for 15 min. The reaction was stirred for 1 hr, filtered, the precipitate washed with chloroform, the filtrate diluted with dichloromethane (500 mL) and washed with aqueous sodium bicarbonate (saturated, 500 mL) and brine (250 mL), dried over sodium sulfate, and concentrated to give carbamoyl-cyclohexanecarboxylic acid methyl ester (2.1 g, 72%) as a white solid. LCMS calcd for C9H15NO3 (m/e) 185, obsd 186 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Methyl 4-methoxy-3-((4-(4-(3-phenylureido)benzoyl)piperazin-1-yl)methyl)benzoate (216 mg, 0.43 mmol) was dissolved in methanol (20 mL) at room temperature. Lithium hydroxide (51.5 mg, 2.15 mmol) was added, followed by water (1 mL). The mixture was stirred at 45° C. overnight and concentrated under vacuum. The residue was dissolved in water (15 mL) and brought to pH ˜3 with 1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (×2) and with dichloromethane (×2). The combined organic phases were dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (78 mg). MS (ESI) m/z 489.1 [M+H]+