Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20](Cl)=[O:21])=[CH:14][CH:13]=1)([O-:11])=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:21])=[CH:36][CH:37]=1)([O-:11])=[O:10]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1NCCCCC1C(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of ε-caprolactam (14.82 g, 0.131 mol) in 400 ml of benzene is added to the above reactor containing 0.131 mol of 3,5-bis(4-nitrophenoxy)benzoyl chloride. The mixture is heated to 80°-90° C., and after all the reactants are dissolved, 150 ml of pyridine is added. The solution is stirred at 90° C. for 3 hours and the pyridine/acid chloride salt removed by filtration, the filtrate being kept in a freezer. White crystals formed from the filtrate are collected by filtration and dried. In order to remove traces of the 3,5-bis(4-nitrophenoxy)benzoic acid, the product is further purified by chromatography using silica gel as filler and ethyl acetate as eluate to yield 65 percent of white crystals: mp 157°-158° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][N:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:16]2[CH:15]=[CH:14][C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccccc1)c1ccnc(O)c1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(C(=O)Nc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-N-phenylisonicotinamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: mp 243-245° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.88 (t, J=5.8 Hz, 1H), 8.83 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 2H), 7.36-7.19 (m, 8H), 7.10 (t, J=7.3 Hz, 1H), 6.98 (dd, J=7.6, 1.8 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.0, 161.7, 160.2, 153.5, 150.7, 139.8, 132.0, 129.1, 128.7, 127.7, 127.2, 124.7, 124.6, 123.6, 121.0, 119.5, 107.0, 106.1, 43.2, 17.5; (ES+) m/z 445.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([N+:16]([O-])=O)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl-].[Ca+2].[Cl-].C([OH:24])C>O.[Fe]>[NH2:16][C:10]1[C:11]([C:14]([NH2:15])=[O:24])=[N:12][CH:13]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:9]=1
Reactant: CCO
Reactant: Cc1cccnc1-c1cnc(C#N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: Cc1cccnc1-c1cnc(C(N)=O)c(N)c1
Yield: 94 %

Procedure:
Heat a solution of 5-(3-methyl(2-pyridyl))-3-nitropyridine-2-carbonitrile (1 g, 4.1 mmol), iron (2.3 g, 40 mmol) and calcium chloride (560 mg, 5 mmol) in ethanol (15 mL) and water (4 mL) to reflux for 1 hour. Cool the mixture, filter through Celite and wash with ethyl acetate. Evaporate the filtrate and re-dissolve the residue in ethyl acetate, wash with water and then with brine, dry (MgSO4) and evaporate to obtain the title compound as a pale yellow solid (880 mg, 94%).
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([CH:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[NH:25][CH:24]=3)[OH:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC#N.O=[Mn]=O>[C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[NH:25][CH:24]=3)=[O:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1c[nH]c2ncncc12
Agent: O=[Mn]=O
Solvent: CC#N
Product: O=C(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1c[nH]c2ncncc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a stirred solution of (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (Preparation 194, 1820 mg, 4.5 mmol) in MeCN (45 mL) was added MnO2 (1960 mg, 22.5 mmol) portionwise and the resulting mixture stirred at 50° C. overnight. Another portion of MnO2 (1960 mg, 22.5 mmol) was added to the reaction and the mixture heated to reflux for 5 hr. After cooling to room temperature, the reaction mixture was filtered through a pad of arbocel, the filter cake rinsed with DCM (100 mL) and the resulting filtrate concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 90:10) to give the desired compound as a solid in 61% yield, 1120 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:21][OH:22].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[N:21][OH:22]
Reactant: NO
Reactant: O=C1c2cc(Br)c(F)cc2C2CC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1c2cc(Br)c(F)cc2C2CC1C2
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one (4.5 g, 17.64 mmol, 1.00 equiv) in ethanol/H2O (20/20 mL), sodium carbonate (3.8 g, 35.85 mmol, 2.00 equiv), and NH2OH.HCl (2.4 g, 2.00 equiv). The resulting solution was stirred overnight at 85° C., cooled and concentrated under vacuum. The solids were collected by filtration, washed with 2×50 mL of water and dried to afford 3.5 g (73%) of 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime as a white solid.
Reaction SMILES: C(OP([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.[CH3:15]CCCCC.C([Li])CCC.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([C:39](=O)[CH2:40][CH2:41][C:42]([O-:44])=[O:43])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[Na+]>O1CCCC1>[S:14]1[CH2:13][CH2:12][CH2:11][S:10][C:9]1=[C:39]([C:36]1[CH:37]=[CH:38][C:33]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:34][CH:35]=1)[CH2:40][CH2:41][C:42]([O:44][CH3:15])=[O:43]
Reactant: O=C([O-])CCC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CCCCCC
Reactant: CCOP(=O)(OCC)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiane, 2.82 g, was dissolved in 30 ml of tetrahydrofuran and 7 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 2.8 g of 4-(4-phenoxyphenyl)-4-oxobutyrate in 10 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution followed by extraction with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 2.33 g of the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[C:19]4=[N:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[CH:26][CH:27]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a suspension of NaH (60%, 81 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.085 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-ethylphenoxy)phenyl)pyridin-2-amine (117 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 4 hr. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (20 mg) was added to a solution of 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (153 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (20 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (46.7 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of o-anisidine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:21](=[O:23])[CH3:22])[C:5]([OH:20])=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[O:8][CH3:9].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32]OS(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:21](=[O:23])[CH3:22])[C:5]([O:20][CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1CCCCc1ccccc1
Reactant: O=S(=O)(OCCc1ccccn1)C(F)(F)F
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCc2ccccn2)c1CCCCc1ccccc1
Yield: 60 %

Procedure:
Example 26a (47 mg, 0.136 mmol) was reacted with 2-(pyridin-2-yl)ethyltrifluoromethanesulphonate (0.3 mL) according to General Procedure F to give the title compound (38 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.54 (dd, 1H), 7.57 (t, 1H), 7.28-7.08 (m, 7H), 4.09 (t, J=6.3 Hz, 2H), 3.75 (s, 3H), 3.11 (t, J=6.3 Hz, 2H), 2.54 (t, J=6.9 Hz, 2H), 2.44 (t, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 1.56-1.43 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[C-:15]#[N:16].[K+].C(=O)(O)[O-].[Na+]>CCO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:15]#[N:16])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)Oc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 1-bromo-4-(bromomethyl)-2-(trifluoromethoxy)benzene (1 g, 3.0 mmol) in EtOH (20 mL) and water (5 mL) was added potassiumcyanide (390 mg, 6 mmol). The resulting mixture was stirred at 85° C. for 2 h. Sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to afford the crude title product (800 mg, 2.86 mmol). MS (ESI) m/z 279.9 M+, 281.1 [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][OH:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>CO.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][O:13][C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:21])([F:33])[F:32])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccccc1C(F)(F)F)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
2 g of 7-chloro-2-hydroxyamino-5-phenyl-3H-1,4-benzodiazepine are reacted with 1 g of 2-trifluoromethylphenyl isocyanate, analogously to Experiment 1a. Yield: 1.8 g of colorless crystals of melting point 190° C. (from methanol/dimethylformamide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=[O:12].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[N:6]=[C:5]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a solution of 5-bromo-1H-indazole-3-carboxylic acid (CXV) (59.8 g, 248 mmol) in THF (800 mL) under argon was added 3,4 dihydro-2H-pyran (50.6 mL, 558 mmol) and p-TsOH (4.72 g, 24.8 mmol). The reaction was heated to reflux at 60° C. for 16 h. An additional portion of p-TsOH (0.025 eq) and 3,4 dihydro-2H-pyran (0.56 eq) was added and the reflux continued for 5 h. The solution was concentrated under vacuum. EtOAc was added to the residue and the suspension was filtered and dried under high vacuum overnight to produce 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) as a white solid (49.07 g, 150.9 mmol, 60.8% yield). ESIMS found for C13H13BrN2O3 m/z 326.3 (M+H).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1C)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.[OH:28][CH:29](COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:55][CH:56](COC1C=CC=C(C(F)(F)F)C=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:28][CH3:29])[CH:23]=[C:22]([O:55][CH3:56])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(F)(F)F)c2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(OC)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+,0.0), 269 (16), 268 (100), 193 (9), 163 (8), 154 (7), 121 (24), 114 (46), 76 (6), 71 (11), 70 (18).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:21])[CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:12][C:11]=2[Cl:21])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(S(=O)(=O)CC)cc1Cl

Procedure:
A mixture of the product from step (iii) (0.95 g), ethyl bromoacetate (0.145 ml) and sodium acetate (0.160 g) in dry ethanol (30 ml) was heated under reflux 24 h. A further 5 equivalents of ethyl bromoacetate were added and heated for a further 48 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.44 g.
Reaction SMILES: [CH:1]1([N:5]([C:14]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)=[O:15])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])[CH2:4][CH2:3][CH2:2]1.[ClH:22].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:22].[CH:1]1([N:5]([C:14]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)=[O:15])[CH2:6][C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cnc(C(=O)N(CC(=O)OC(C)(C)C)C2CCC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cnc(C(=O)N(CC(=O)O)C2CCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-cyclobutyl-N-[(1-methyl-1H-imidazol-4-yl)carbonyl]glycinate (200 mg) in ethyl acetate (4 mL) was added 4N hydrochloric acid/ethyl acetate solution (4 mL), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to afford N-cyclobutyl-N-[(1-methyl-1H-imidazol-4-yl)carbonyl]glycine hydrochloride (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][C:15]([OH:19])=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br)([O-:28])=[O:27]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][C:15]([O:19][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=1)=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4]
Reactant: COC(=O)c1c2ccccc2nc2cc(O)ccc12
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c2ccccc2nc2cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C

Procedure:
3-Hydroxyacridine-9-carboxylic acid methyl ester (14.6 g; 57.7 mmol) was dissolved in 500 ml DMF, then potassium carbonate (25.0 g; 181 mmol) and m-nitrobenzylbromide (15.0 g; 69.4 mmol) were added and stirred at room temperature. After 4 hours the mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 and washed with HCl 1N, NaOH 1N and sodium chloride solution (10%). After drying with sodium sulfate and evaporating to dryness the residue was flash chromatographed (column: 10 cm diameter) in CH2Cl2 +1% methanol (fractions of 200 ml). Fractions 7-23 were combined, evaporated and the residue was collected on a Buchner funnel and washed with diethylether. Yield 8.7 g (39%), Fp.>250° C. 1H-NMR(CDCl3): 5,35(2H, s, CH2) and 4,22 ppm (3H, s, CH3). MS: M+ =388.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].C=O.[C:9]([O:13][C:14](=[O:36])[CH:15](P(OCC)(OCC)=O)[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH3:17])([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([O:13][C:14]([C:15](=[CH2:1])[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)[CH3:17])=[O:36])([CH3:10])([CH3:11])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Agent: C=O
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1

Procedure:
Potassium carbonate (9.16 g, 66.2 mmol) and paraformaldehyde (2.48 g, 82.7 mmol) were added to a solution of methyl 4-(4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutan-2-yl)benzoate (13.7 g, 33.1 mmol) in anhydrous THF (250 mL), respectively. The reaction mixture was heated at reflux for 20 h, then cooled, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in petroleum ether to give the title compound. MS: m/z=235.0 (M−tBu); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.5 Hz), 7.28 (d, 2H, J=8.5 Hz), 6.26-6.32 (m, 1H), 5.56-5.61 (m, 1H), 4.01 (q, 1H, J=7.1 Hz), 3.92 (s, 3H), 1.42 (d, 3H, J=7.0 Hz), 1.33 (s, 9H).
Reaction SMILES: C(Cl)Cl.C(=[N:11][N:12]1[CH2:16][CH2:15][N:14]([C@@:17]2([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[S:23][C@H:22]3[N:19]([C:20](=[O:34])[C@H:21]3[NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)[C:13]1=[O:48])C1C=CC=CC=1.[N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:11][N:12]1[CH2:16][CH2:15][N:14]([C@@:17]2([C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[S:23][C@H:22]3[N:19]([C:20](=[O:34])[C@H:21]3[NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)[C:13]1=[O:48]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NN1CCN([C@]2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CN3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3S2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
In a mixed solvent consisting of 30 ml of methylene chloride and 15 ml of methanol was dissolved 3.00 g of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane. To the solution were added 1.89 g of 2,4-dinitrophenylhydrazine and 850 mg of p-toluenesulfonic acid monohydrate in this order. The mixture was stirred at room temperature for 1.5 hours. Then, the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was mixed with a mixed solvent consisting of 30 ml of methylene chloride and 7 ml of methanol. The insolubles were removed by filtration. The filtrate was concentrate under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=100/1 to 25/1) to obtain 1.56 g (yield: 60.5%) of (3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0] heptane.
Reaction SMILES: C(N[C:6]([N:8]1[CH2:13]CC[C@@H](CNC2C(F)=CN=C(C3C4C(=NC=C(Cl)C=4)NC=3)N=2)[CH2:9]1)=[O:7])(C)(C)C.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40][NH:41][C:42]1[C:47]([F:48])=[CH:46][N:45]=[C:44]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55]([Cl:58])[CH:56]=3)[N:51](S(C3C=CC(C)=CC=3)(=O)=O)[CH:50]=2)[N:43]=1.[Cl-]>>[Cl:58][C:55]1[CH:56]=[C:57]2[C:49]([C:44]3[N:43]=[C:42]([NH:41][CH2:40][C@@H:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]4[NH:33][C:6](=[O:7])[N:8]([CH3:13])[CH3:9])[C:47]([F:48])=[CH:46][N:45]=3)=[CH:50][NH:51][C:52]2=[N:53][CH:54]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)NC(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: [Cl-]
Product: CN(C)C(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Urea 564 was prepared according to the procedure for compound 20 (Scheme 12A) using N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and dimethylcarbomoyl chloride, afforded desired product, 564, as a racemic mixture of trans isomers.