Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][OH:16].[CH2:18]([C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)=[N:28][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][O:16][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[N:26]=[CH:25][C:24]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:29][N:28]=2)=[CH:35][CH:34]=1
Reactant: C[C@H](Cl)CCO
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCc1cnc(-c2ccc(OCC[C@H](C)Cl)cc2)nc1
Reaction time: 24 h

Procedure:
26.3 g of (S)-3-chlorobutyl-1-tosylate, preparable from p-toluenesulfonyl chloride and (S)-3-chlorobutan-1-ol, and 27.2 g of 4-(5-n-hexylpyrimidin-2-yl)phenol are added to a suspension of 40 g of potassium carbonate in 200 ml of acetone. After 24 hours' boiling under reflux, the reaction mixture is filtered, the filtrate is freed from solvent and the residue is twice recrystallized from ethanol. (S)-2-[p-(3-Chlorobutyloxy)phenyl]-5-n-hexylpyrimidine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([F:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=417.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:22]([NH:24][NH2:25])=[O:23])[CH:3]=1.CN([CH:29]=[O:30])C>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:13]2)[CH:5]=[C:4]([CH:22]2[N:24]=[N:25][C:29](=[O:30])[O:23]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(=O)NN)cc(Cl)n2)CC1
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N′-Carbonyldiimidazole (0.12 g, 0.82 mmol) was added to a solution of tert-butyl 1-[6-chloro-4-(hydrazinocarbonyl)pyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 49, 0.15 g, 0.41 mmol) in DMF (3 ml). The mixture was stirred at room temperature overnight and was purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to afford the title compound (0.125 g).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[O:20][C@@H:19]5[C@@H:21]([C:22]([O:24]CC)=[O:23])[C@@H:18]5[C:17]=4[CH:27]=3)[C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.CO>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[O:20][C@@H:19]5[C@@H:21]([C:22]([OH:24])=[O:23])[C@@H:18]5[C:17]=4[CH:27]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(Oc4ccnc5c4CCC(=O)N5)cc3[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCc2c(Oc3ccc4c(c3)[C@@H]3[C@H](O4)[C@H]3C(=O)O)ccnc2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a stirred solution of ester product of Step A (360 mg, 0.98 mmol) in THF (3 mL) and methanol (3 mL) was added sodium hydroxide aqueous solution (1 mL, 2 M, 2 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hrs. The solvent was removed under reduced pressure and the residue was dissolved into water (5 mL). The solution was neutralized with HCl (2 mol/L) to pH=7 and white solid precipitated out of solution. The white solid was collected by filtration and dried in air to give the title compound (230 mg, 69.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cc(F)ccc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cc(F)ccc2F)O3)nc1

Procedure:
2-(2,5-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 200 mg of 2-(2,5-difluorophenyl)chroman-4,6-diol (Example 14(b)). The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate (4:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.03 (d, 1H, J 2.8 Hz), 8.50 (dd, 1H, J 9.1, 2.8 Hz), 7-36-7.33 (m, 2H), 7.08-6.95 (m, 5H), 5.50 (d, 1H, J 11.1 Hz), 5.09 (m, 1H), 2.53 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)=[O:14])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1)=[O:14]
Reactant: CCOC(=O)c1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(NC(=O)c2cc3ccccc3[nH]2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
By carrying out the procedure according to Example 10 which is described above, the compound 2-[(1-acetyl-2-indolyl)carbonylamino]-4-phenyl-5-ethoxycarbonylthiazole (1.5 g) is prepared and dissolved in 100 ml of ethanol in the presence of 0.6 g of Na2CO3. The mixture is stirred at room temperature for 48 hours and then concentrated under vacuum. The residue is triturated in water and then in a minimum amount of dichloromethane, filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a solution of 1-[8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-5-yl]propan-1-ol (150 mg, 0.365 mmol) and pyridine (0.15 mL, 1.85 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (0.113 mL, 1.20 mmol) at room temperature. The mixture was stirred at room temperature for 5 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 16 hr. Acetic anhydride (0.113 mL, 1.2 mmol) and pyridine (0.30 mL, 3.71 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at 45° C. for 20 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (116.5 mg, 0.257 mmol, 60%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].C([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26]C=2N=N1)CC#C>>[N:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[N:6]=[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]2=[N:9]1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: C#CCCn1nnc2ccccc21
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 8 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(C), from 90 mg (0.53 mmol) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg (42 mmol, 8%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil with a purity of 82%. Another fraction yielded after SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH4OH 95:4:1 to 94:4:2) 19 mg (76 μmol, 14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1c1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
2-(3,5-Dichloro-phenyl)-cyclohexanone (50 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.5 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (75 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])[CH3:13]>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:12]([O:14][C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C)(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
31 ml of 90% chloroformic acid benzyl ester are slowly added, at 0°-5° C., to 29.04 g of 3-amino-2,2-dimethylpropionic acid ethyl ester in 500 ml of ethyl acetate and 250 ml of 1M sodium hydrogen carbonate solution. The reaction mixture is stirred for 2 hours at 0°-5° C. and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and then concentrated. The evaporation residue is purified by FC (1 kg of silica gel; eluant: ethyl acetate/hexane=1:3). The title compound is obtained: Rf (ethyl acetate/hexane=1:3)=0.28.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[N:20]([C:2]1[C:3](=[O:13])[N:4]([CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:19][CH2:18]2
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-methylpropyl-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 150° C.; 1H NMR (300 MHz, CDCl3): δ 7.32 (d, J=1.8 Hz, 1 H), 7.26 (d, J=1.9 Hz, 1 H), 6.85 (s, 1 H), 4.97-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 1.77-1.70 (m, 2 H), 1.36 (d, J=7.0 Hz, 3 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C16H17N3OBrCl2 (M+H)+: 415.9932; Found m/z 415.9943.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:12]([CH3:25])=[N:13][N:14]([CH3:24])[C:15]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])O.COCCN(S(F)(F)[F:36])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]1[N:14]([CH3:24])[N:13]=[C:12]([CH3:25])[C:11]=1[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[F:36]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1C(F)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of α-(2,4-difluorophenyl)-5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole-4-methanol (i.e. the product of Example 4) (70 mg, 0.20 mmol) in dichloromethane (2 mL) at −78° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) (40 μL, 0.24 mmol). The reaction mixture was stirred overnight at room temperature, and then cooled to −78° C. and saturated aqueous sodium bicarbonate solution (3 mL) was added dropwise. The resulting mixture was extracted with dichloromethane (3×) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (50% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (30 mg)
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([N:10]=[C:11]([CH:23]3[CH2:25][CH2:24]3)[C:12]=2C(OCC2C=CC=CC=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:1]([C:4]1[C:5]2[N:6]([N:10]=[C:11]([CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccn2nc(C3CC3)c(C(=O)OCc3ccccc3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cccn2nc(C3CC3)cc12
Reaction time: 3.5 h
Yield: 79.1 %

Procedure:
The compound of Example 40 (5.57 g) was dissolved in ethanol (30 mL) and water (30 mL). To this solution, potassium hydroxide (3.70 g) was added and the mixture was stirred for 3.5 hours under reflux. Subsequently, the mixture was neutralized with concentrated hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting solid product was dissolved in toluene (150 mL). This solution was stirred for 6 hours under reflux. Subsequent removal of the solvent and purification by silica gel column chromatography (hexane:ethyl acetate=4:1 then 1:1) afforded the title compound as a yellow powder (2.64 g) (Process D).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@@H:22]([O:25][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1

Procedure:
Combine 10.8 g (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one, 5.4 g tert-butyldimethylsilylchloride, and 2.7 g imidazole in 50 mL dry dimethylformamide and stir at ambient temperature over night. Pour into 300 mL brine and extract twice with 200 mL diethyl ether. Wash the combined extracts with brine, dry over magnesium sulfate and concentrate to dryness under vacuum. Purify by silica gel chromatography using 10-15% ethyl acetate in hexanes to recover 11.5 g of the product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-fluoro-6-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 127. 1H NMR(CDCl3) δ 7.42 (d, 1H, J=7.7 Hz), 7.33 (app q, 1H), 7.23 (d, 1H J=8.0 Hz), 6.45 (d, 1H, J=2.2 Hz), 6.26 (d, 1H, J=1.8 Hz), 4.52 (ABq, 2H, JAB=14.3 Hz), 4.33 (s, 2H), 4.12 (app d, 1H, J=12.4 Hz), 3.65 (app t, 1H), 3.25-3.00 (m, 4H), 2.95-2.85 (m, 2H), 2.57 (app t, 1H), 2.42 (app t, 1H), 1.92-1.82 (m, 2H). LRMS (ES)+: 422.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][CH3:14])[N:4]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])([O:17][CH3:18])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:29]([NH:28][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:27])=[O:26])=[O:30])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][CH3:14])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)c([N+](=O)[O-])c(OC)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)c1[N+](=O)[O-]
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A solution of 0.2 g (1.0 mmol) of 2,6-dimethoxy-5-nitro-4-pyrimidinamine and 0.6 g (2.4 mmol) of 2-carbomethoxybenzenesulfonyl isocyanate in 15 ml of methylene chloride was stirred at ambient temperature and pressure for 12 hours under anhydrous conditions. The solvent was then evaporated under reduced pressure. The residue was stirred in n-butyl chloride (70 ml). The solid was then collected by filtration, washed with ether and then dried in an oven to afford 0.4 g of the title compound, m.p. 150°-152° dec.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][S:12][C:13]1[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:11][S:12][C:13]1[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:21][CH:20]=2)=[N:17][CH:18]=1
Reactant: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CSc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Reaction time: 8 h
Yield: 80 %

Procedure:
The phenyl chloroformate (0.84 ml, 6.68 mmole, 2.5 eq) was added to a mixture of 4-(5-(methylthio)-4morpholinopyrimidin-2-yl)benzeneamine (0.84 g, 2.18 mmole, 1 eq), NaHCO3(aq) (1M, 6.3 ml, 6.3 mmole 2.2 eq) and ACN (13 ml) at 0□. The reaction mixture was stirred for 8 hrs and then dried. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 2:1) to give a yellow solid (80%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Br[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(OCCCCSc3ccccn3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
14.4 gm (0.13 mol) of 2-mercapto-pyridine and 17.9 gm (0.13 mol) of potassium carbonate were stirred into 360 ml of dimethylsulfoxide which had been dried over a molecular sieve, and the solution was admixed with 36 gm (0.12 mol) of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.; prepared from 6-hydroxy-carbostyril and 1,4-dibromo-butane). The mixture was stirred for 15 hours at about 25° C., then poured into 3.6 liters of water, and the aqueous mixture was stirred for 30 minutes. The precipitate formed thereby was collected by suction filtration, thoroughly washed with water, dried and recrystallized from xylene in the presence of activated charcoal, yielding 32 gm (81.2% of theory) of a light yellow crystalline product having a melting point of 123°-124.5° C. It was identified to be the compound of the formula ##STR9##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]>C1COCC1>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:22]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1CCNc1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCN(C(=O)n1ccnc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a 50 mL round-bottomed flask was added 2-(2-(4-fluorophenylamino)ethyl)-isoindoline-1,3-dione (204 mg, 718 μmol, from step 1), 1,1′-carbonyldiimidazole (175 mg, 1076 μmol, Aldrich), THF (2 mL). The reaction mixture was stirred at 80° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1H-imidazole-1-carboxamide. MS (ESI pos. ion) m/z: 379 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].[N+:20]([O-])([OH:22])=[O:21]>O>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:20]([O-:22])=[O:21])[C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-4'-methoxy-2'-methyl-benzophenone (0.75 g; 2.5 mmol) is added to nitric acid (10 ml; 65%). The mixture is stirred at 80° C. for 1 hour. After addition of water the reaction product crystallises and is chromatographically purified (flash column filled with 30 g of silicagel, elution with toluene). White crystalls (0.35 g; 41% y); mp. 156°-160° C.