Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([OH:7])=O.[NH2:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([NH:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1cccc(O)c1
Yield: 38.6 %

Procedure:
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.33 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give powder of 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.447 g.).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[O:20]=[C:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[C:17]=2[N:16]=[C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 16.14 ml of BOC-L-proline in 150 ml of methylene chloride, 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethylbenzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted for 20 hours. The mixture was extracted with methylene chloride and the residue was chromatographed on silica gel and was eluted with methylene chloride to obtain 16.4 g of 1,1-dimethylethyl (2S) 2-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-1-pyrrolidine carboxylate having a specific rotation of [α]D =-75°±2.5° (c=0.6% in CH3COOH).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:15])[NH:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: NC1CCOCC1
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a room temperature mixture of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (96.0 mg, 0.177 mmol) (prepared according to the method described for the preparation of compound 17e, HOBT (29.0 mg, 0.215 mmol), 4-aminotetrahydropyran (19.6 mg, 0.194 mmol), methylene chloride (2 mL), and water (2 mL) was added EDCI (39.0 mg, 0.203 mmol) in one portion. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with methylene chloride, washed with water, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate to afford 77.1 mg (69%) of the title compound as an amorphous white solid. mp: 78.6° C. Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[C:13]=2[Cl:20])[CH2:7][CH2:6]1.[CH3:22][C:23]1[NH:27][N:26]=[N:25][C:24]=1[C:28](O)=[O:29]>>[Cl:20][C:13]1[C:14]([CH3:19])=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:21])[CH2:2][NH:1][C:28]([C:24]2[N:25]=[N:26][NH:27][C:23]=2[CH3:22])=[O:29])[CH2:6][CH2:7]1
Reactant: Cc1c(Cl)ccc(OC2CCN(C[C@H](O)CN)CC2)c1Cl
Reactant: Cc1[nH]nnc1C(=O)O
Product: Cc1[nH]nnc1C(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(C)c2Cl)CC1

Procedure:
Prepared as Example 1 using (2R)-1-amino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]propan-2-ol (0.158 g) and 5-methyl-1H-1,2,3-triazole-4-carboxylic acid to yield the title compound as a colourless solid (0.037 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:8](O)=[O:9])=O.[CH2:16]([O:18][C:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22])[CH3:17]>>[Cl:1][CH2:2][C:3]1[N:22]([C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]([O:18][CH2:16][CH3:17])=[O:27])[C:8](=[O:9])[C:7]2[C:6](=[CH:14][CH:13]=[C:12]([Cl:15])[CH:11]=2)[N:5]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Reactant: CCOC(=O)c1ccccc1N
Product: CCOC(=O)c1ccccc1-n1c(CCl)nc2ccc(Cl)cc2c1=O

Procedure:
2-Chloromethyl-3-(2-ethoxycarbonyl-phenyl)-6-chloro-4H-quinazolin-4-one (melting point: 195°-197° C., recrystallised from toluene) was prepared from N-chloroacetyl-5-chloroanthranilic acid and anthranilic acid ethyl ester analogously to the method in J. Amer. Chem. Soc. 68 (1946), 542.
Reaction SMILES: O=O.[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:7]([CH3:19])[N:6]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:19])=[CH:8][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(C)nc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)nc(OC)c1N
Reaction time: 17 h

Procedure:
To an oxygen free solution of the nitro ester 1-2 from step B (2.5 g, 10.4 mmol) in 50 mL of EtOAc was added 520 mg of 10% Pd on charcoal. Hydrogen gas was added and the reaction mixture was stirred for 17 h. The solution was filtered through a pad of Celite, concentrated and chromatographed (2:3 EtOAc/Hexane) to give the desired amine 1-3 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C@@H:11]3[C@@H:6]([N:7]([C:15]([C:17]4[CH:25]=[CH:24][C:20]5[NH:21][CH:22]=[N:23][C:19]=5[CH:18]=4)=[O:16])[CH2:8][CH2:9][CH2:10]3)[CH2:5][C:4]=2[C:3]=1[OH:26].C(OCC)(OCC)O[CH2:29][CH3:30]>>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:7]3[C@H:6]4[C@H:11]([C:12]5[CH:4]=[C:3]6[O:26][C:29]([CH3:30])=[N:1][C:2]6=[CH:14][C:13]=5[CH2:5]4)[CH2:10][CH2:9][CH2:8]3)=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: Nc1ccc2c(c1O)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: CCOC(OCC)OCC
Product: Cc1nc2cc3c(cc2o1)[C@@H]1CCCN(C(=O)c2ccc4[nH]cnc4c2)[C@@H]1C3
Temperature: 25 °C
Yield: 64 %

Procedure:
(cis-7-Amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol-5-yl)-methanone (0.10 g) in triethyl orthoformate (0.5 mL) is stirred at 60° C. for 2 h. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0→7:3) to afford the title compound. Yield: 64% of theory; LC (method 1): tR=2.28 min; Mass spectrum (ESI+): m/z=373 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[H-].[Na+].CS(C)=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Yield: 14 %

Procedure:
2-Amino-4-chloropyridine (2.0 g), 5-hydroxyindole (4.1 g), sodium hydride (60% in oil, 1.25 g) and dimethylsulfoxide (20 ml) were stirred at 160° C. for 9.5 hours. Water was added, extraction was performed with ethyl acetate, and purification was performed by silica gel column chromatography (hexane:ethyl acetate=1:1, ethyl acetate). The solvent was distilled off under reduced pressure, a small amount of ethyl acetate was added to the residue and the solid was filtered out to obtain 490 mg of a light brown solid.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=[CH:5][N:4]=1>C(O)(=O)C>[Br:1][C:13]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:8]=2[C:9](=[O:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=1
Reactant: BrBr
Reactant: O=c1c2ccccc2ccc2ccncc12
Solvent: CC(=O)O
Product: O=c1c2ccccc2cc(Br)c2ccncc12

Procedure:
Bromine (4.18 ml.) in acetic acid (50 ml.) is added dropwise to a stirred solution of benzo[5,6]cyclohepta[1,2-c]pyridin-11-one (12.35 g.) in acetic acid (250 ml.). The resulting mixture is heated on the steam bath for 24 hours and the acetic acid is removed under reduced pressure. Saturated Na2CO3 solution (500 ml.) is added to the residue and the deep yellow solid that forms is collected, washed with water, and dried. This crude product is recrystallized from 1-chlorobutane to give 9.3 g., m.p. 167°-169° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([OH:24])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a stirred solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (5 g) in methanol (10 ml) is added dropwise a solution of sodium hydroxide (2.6 g) in water (20 ml) at room temperature. After completing addition, the mixture is stirred for 30 minutes, diluted with water (300 ml) and extracted with ethyl ether (50 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (3.5 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].S(Cl)(Cl)=O.[Cl:17][S:18](O)(=[O:20])=[O:19]>O>[Cl:17][S:18]([C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25° C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring was continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116° C. was obtained by crystallisation from hexane:toluene. Found: C, 41.02; H, 3.27. C9H9ClO5S requires C, 40.84; H, 3.43%. δ (CDCl3): 1.64 (3H, t), 4.45 (2H, q), 7.26 (1H, d), 8.20 (1H, dd), 8.80 (1H, d).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[CH:7](Cl)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28]>O.C(OCC)C>[Cl:22][C:20]1[C:19]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:18][C:17]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:16]([F:15])[CH:21]=1
Reactant: O=C(C(Cl)Cl)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 5.3 g of sodium acetate dissolved in 100 ml of water was added 4.4 g of 1,1-dichloro-3,3,3-trifluoroacetone under ice cooling, and the reaction was allowed to proceed at 90° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 5.8 g of 2-fluoro-4-chloro-5-isopropoxyphenyl-hydrazine dissolved in 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed once with 10 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and evaporated to remove the diethyl ether to give 6.5 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[N:15]=[C:14]([NH:16][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:29])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2ncc(N)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)CCCCn1ncc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([O:20]CC)=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[OH-].[K+]>C(O)C.O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([OH:20])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CCOC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 2 g. of ethyl 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylate, 2 g. of potassium hydroxide and 50 ml. of ethanol:water (9:1) is refluxed for 4 hours. The mixture is concentrated, diluted with water and the solid 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid isolated. The preceding compound is heated neat at 190° C. to give the product of the example.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][C@H:8]2[NH2:13].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([NH:35][C:36]2[N:41]=[C:40](SC#N)[C:39]([N+:45]([O-:47])=[O:46])=[CH:38][N:37]=2)[CH:22]=1>CS(C)=O.C(#N)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([NH:35][C:36]2[N:37]=[C:38]([NH:13][C@H:8]3[C:7]4[C:12](=[C:3]([F:2])[CH:4]=[CH:5][CH:6]=4)[O:11][CH2:10][CH2:9]3)[C:39]([N+:45]([O-:47])=[O:46])=[CH:40][N:41]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
A solution of the (R)-8-fluorochroman-4-amine hydrochloride (104 mg) in DMSO (2 mL) and potassium carbonate (141 mg) were added to a stirred solution of tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (140 mg) in ACN (10 mL). The mixture was stirred for 15 hr at room temperature then partitioned between brine and EtOAc and separated. The aq. layer was washed with additional EtOAc, the combined organics were evaporated and purified via column chromatography, elution with 20-30% EtOAc/H gave the titled product in 83% yield. 1H-NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.7 (m, 1H), 8.2 (br s, 1H), 7.7 (m, 1H), 7.3 (m, 1H), 7.3-6.8 (m, 4H), 6.5 (s, 1H), 5.5 (br s, 1H), 4.4 (m 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H); MH+=515, 459 (-tBu).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Yield: 97 %

Procedure:
Add 20% palladium hydroxide on carbon (0.772 g) to a solution of (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-cyclohexyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.772 g, 1.023 mmol) in ethanol (10.2 mL). Stir vigorously under 1 atmosphere of hydrogen gas for 60 hours. Filter through a filtering agent, wash with ethanol and concentrate to give the desired compound (0.481 g, 97.1%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[C:11]1([N:17]2[C:21]3[C:22]4[C:27]([CH2:28][C:20]=3[C:19]([C:29](Cl)=[O:30])=[N:18]2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCOCC1>[C:1]([CH:3]([C:29]([C:19]1[C:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)=[O:30])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Ethyl cyanoacetate (1.4 g) is treated with 50% sodium hydride (0.58 g) in anhydrous dioxane (20 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazole-3-carbonyl chloride (3 g), prepared according to Example 5, dissolved in anhydrous dioxane (50 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 20 hours, then it is dilusted with ice water and acidified to pH 3 with 37% HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with water and then evaporated to dryness in vacuo. The residue is purified over a SiO2 column, using hexane-ethyl acetate 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl) -3-oxo-propanoic acid, ethyl ester (2.2 g), which is reacted with aniline (3.4 g) in xylene (100 ml) at the reflux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloro-methane/methanol to give 1.2 g of 2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 273°-277° C.
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][CH3:13])=[CH:4][C:5]=2[O:6]1
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
Homopiperonyl alcohol (1) (7.03g, 42.4 mmol)1,2,3 and triethylamine (8.59 g., 85.0 mmol) were dissolved in methylene chloride (100 ml). The mixture was cooled to 0°-5°, then methanesulfonyl chloride (7.31 g., 63.6 mmol) was added slowly dropwise to the vigorously stirred solution. The mixture was stirred an additional 30 mins., then transferred to a separatory funnel where it was washed with water (3 × 50 ml), 4% hydrochloric acid (3 × 50 ml), saturated sodium bicarbonate solution (25 ml), saturated brine (25 ml) and dried over sodium sulfate. Filtration and evaporation of the methylene chloride yielded 9.76 g of a brown oil (94%); NMR--(CDCl3) 6.72 (m, 3H), 5.92 (S, 2H), 4.34 (t, J=7, 2H), 2.95 (t, J=7), lying under 2.89 (s) giving a total integration of 5H. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7](=[O:16])[C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]=2[O:4]1.[CH3:21][NH:22][CH3:23].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)(C)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH:10]1([N:8]2[C:7](=[O:16])[C:6]3[CH:17]=[CH:18][CH:19]=[N:20][C:5]=3[O:4][CH:3]([CH2:2][N:22]([CH3:23])[CH3:21])[CH2:9]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CNC
Reactant: O=C1c2cccnc2OC(CCl)CN1C1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Product: CN(C)CC1CN(C2CCCCC2)C(=O)c2cccnc2O1

Procedure:
Utilizing the procedure of Example 10, 2-(chloromethyl)-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one (Intermediate 35) is reacted with 40% aqueous dimethylamine and reacted with oxalic acid in isopropyl alcohol.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (30.7 g, 93.7 mmol) in IPA (300 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (26.9 g, 112.5 mmol) and DIPEA (48 mL, 281.2 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (600 mL). The solution was washed with water and the organic fraction separated. The organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to yield the title compound as a yellow oil (30 g, 70%) 1H NMR 400 MHz (CDCl3) δ 8.25 (1H, s), 7.96 (1H, s), 7.70 (1H, qn, J=4.1 Hz), 7.37-7.58 (5H, m), 6.98-6.82 (1H, m), 6.52-6.66 (1H, m), 5.60-5.77 (2H, m), 4.12-4.19 (1H, m), 3.76 (1H, td, J 11.3, 2.5 Hz), 1.91-2.13 (4H, m), 1.68-1.84 (2H, m), 1.60-1.68 (3H, m)