Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][N:19]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:25]1[CH2:26][CH2:27][C:22]2([CH2:18][N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Yield: 72.9 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.640 mmol) was reacted with tert-butyl 2,8-diazaspiro[4,5]decane-2-carboxylate (169 mg, 0.704 mmol) to afford the desired product (240 mg, 73%) as a yellow foam: ESI MS m/z 514 [C26H32BrN3O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: Cc1c[nH]c(C)c1CCC(=O)O
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 60.8 mmol) in 60 ml of dichloromethane was added 1,1′-carbonyldiimidazole (11.6 g, 71.8 mmol) followed morpholine (5.5 ml, 60.8 mmol) and N,N-diisopropylethylamine (Hunig's base, 10 ml, 60.8 mmol). The dark red reaction mixture was stirred at room temperature overnight and poured into ice water. The organic layer was washed with brine until the wash had a pH of about 6, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with dichloromethane-methanol (98:2) to give 13.84 g (96%) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-morpholin-4-yl-propan-1-one.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[C:5](Cl)=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1.Cl>C1COCC1>[Cl:10][C:7]1[NH:6][C:5](=[O:1])[C:4]([F:3])=[CH:9][N:8]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Example 30A was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95° C. under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2×400 mL) and the combined organic extracts were washed with DI water (4×275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87%, 98.1% AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0° C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4×555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89%, 99.2% AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C1CCNC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCCC2)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=505.2 (M+H+), was prepared in accordance with the general method of example 52 from 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one, pyrrolidine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].O=C1[CH2:20][CH2:19][CH:18]([C:21]2[N:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.O.[CH2:39]1COCC1>>[CH2:30]([O:29][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH:18]2[CH2:19][CH2:20][C:5](=[CH:4][C:6]([O:8][CH3:39])=[O:7])[CH2:16][CH2:17]2)=[N:26][CH:25]=1)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: C1CCOC1
Reactant: O=C1CCC(c2ccc(NC(=O)OCc3ccccc3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C1CCC(c2ccc(NC(=O)OCc3ccccc3)cn2)CC1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To an ice water cooled suspension of a 60% mineral oil dispersion of sodium hydride (585 mg, 24.35 mmol) in anhydrous THF (60 mL) was added trimethylphosphonoaceate (3.1 mL, 18.73 mmol). After 10 minutes a solution of benzyl [6-(4-oxocyclohexyl)pyridin-3-yl]carbamate, prepared as above, (4.05 g, 12.49 mmol) in THF (40 mL) was added and the reaction mixture allowed to warm to ambient temperature over the weekend. Water (100 mL) was added and the volatile material was removed under reduced pressure and the mixture extracted into EtOAc (4×200 mL) the organic extracts were combined, washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to leave crude product. This was purified on a 120 g silica SiliCycle cartridge, loading in and eluting 30-50% EtOAc/isohexane to provide the title compound (3.17 g, 66.7%); 1H NMR (CDCl3) δ 1.63-1.76 (m, 2H), 2.03-2.15 (m, 3H), 2.31-2.44 (m, 2H), 2.92-2.97 (m, 1H), 3.69 (s, 3H), 3.92-3.96 (m, 1H), 5.21 (s, 2H), 5.68 (s, 1H), 6.71 (s, 1H), 7.12 (d, 1H), 7.35-7.40 (m, 5H), 8.37 (s, 1H), 8.37 (s, 1H); MS m/e MH+ 381.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=2[CH3:27])[CH:22]=O)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:29][NH:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:47]>>[ClH:47].[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:20]=[C:21]([CH2:22][N:30]([CH3:31])[CH3:29])[CH:24]=[CH:25][C:26]=2[CH3:27])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: ClCCl
Reactant: Cc1ccc(C=O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc(CN(C)C)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzaldehyde (from step 1) (0.50 g, 1.11 mmol) was dissolved in CH2Cl2 (10 ml). N,N-dimethylamine (2.0 M in THF) (1.11 ml, 2.22 mmol) was added. This mixture stirred for at room temperature for 12 hours. Next, sodium tri-acetoxyborohydride (0.47 g, 2.22 mmol) was added and the reaction stirred for two more hours. The reaction was washed with 1 N NaOH (aq.) and then extracted with CH2Cl2. The combined organic extracts were washed with water. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was taken up in diethyl ether. 1M HCl in diethyl ether (5 ml) was added and the precipitate was collected on a filter pad. This precipitate was hygroscopic. The hygroscopic solid was then taken up in hot ethyl acetate. Hexane was added until a precipitate crashed out. The precipitate was collected on a filter pad to yield a white solid (150 mg, 26%). 1H NMR (400 MHz, D2O) δ 7.42 (m, 3H), 7.17 (s, 1H), 6.86 (m, 2H), 6.53 (s, 1H), 5.20 (s, 2H), 4.18 (s, 1H), 2.72 (s, 6H), 1.85 (s, 3H), 1.82 (s, 3H); ES-MS m/z 477 (M+H). ES-HRMS m/z 477.0955 (M+H calcd for C23H24BrF2N2O2 requires 477.0984).
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:18]=[CH:17][C:6]=3[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc2nc(-c3ccc(N)nc3)oc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc3ccc(O)cc3o2)cn1
Temperature: 0 °C
Yield: 116.9 %

Procedure:
To a stirred and cooled (ice bath) solution of 5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (2.07 mmol) in CH2Cl2 (50 mL) was slowly added boron tribromide 1M in CH2Cl2 (4.15 mL) from a pressure equalized dropping funnel. After full addition the reaction mixture was stirred 5 mins in the ice bath, before it was allowed to reach room temperature and then stirred at room temperature overnight. The reaction mixture was cooled (ice bath) and diluted with CH2Cl2 (100 mL), followed by EtOAc (100 mL), water (100 mL) and sat aq NaHCO3 (100 mL) and the resulting mixture allowed to reach room temperature and stirred vigorously for 10 mins. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100 mL), the combined organic layers were dried (Na2SO4), filtered and evaporated to give 0.55 g of 2-(6-aminopyridin-3-yl)-1,3-benzoxazol-6-ol, as a pale yellow foamy solid. MS m/z 228 (M+H).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[N:21]([CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:20](=[O:31])[CH2:19]2)=[C:14]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C>C(Cl)Cl>[CH2:33]([O:32][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:2](=[O:1])[CH3:4])[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:19][C:20](=[O:31])[N:21]([CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[S:22]1(=[O:24])=[O:23])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
To a solution of 5-[4-(3-aminopropyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (124 mg, 0.26 mmol) in methylene chloride (5 mL) is added diisopropylethylamine (0.1 mg, 0.781 mmol) then acetyl chloride (21 mg, 0.267 mmol) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and 1 N HCl is added. The mixture is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 10-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[CH2:25][CH:24]=[CH:23]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:9]1[CH:24]2[CH2:25][C:26]3[C:22]([CH:23]12)=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cccc3c2CC2OC32)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A stirred solution of 47.5 g (0.234 mole) of m-chloroperbenzoic acid (85% purity) in 390 ml of chloroform was cooled to 0° C. To this was added dropwise a solution of 45 g (0.234 mole) of 7-phenyl-1H-indene (which may be prepared as in Example 1G) in 110 ml of chloroform. After complete addition, the mixture was stirred for 21/2 hours, then was allowed to stand for 21 hours at 0° C. With the temperature in the range of 0°-5° C., 100 ml of a 10% aqueous solution of sodium hydroxide, then 50 ml of a 10% aqueous solution of sodium sulfate, were added dropwise with stirring. After complete addition the two-phase mixture was stirred for 30 minutes. The organic phase was separated, washed first with a dilute aqueous solution of sodium bicarbonate, then with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 47.7 g of 1,2-epoxy-4-phenyindane as a pale yellow oil, 97% purity by gas chromatographic analysis.
Reaction SMILES: ClCCl.[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[S:6]1.C(Cl)(=O)OCC.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(N(CC)CC)C>[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=2)=[O:19])[S:6]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
To 49 mL of dichloromethane were added 6.30 g of triethylamine and 7.00 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxybenzoic acid. After 2.71 g of ethyl chlorocarbonate were added, the mixture was stirred for 10 minutes. Further, 4.59 g of 4-trifluoromethylbenzylamine were added and the mixture was stirred for 1 hour. After washed the reaction mixture with water, solvent was distilled off and to the residue were added 109 mL of water and 33 mL of ethanol, to which solution 2 mol/L hydrochloric acid was added dropwise to adjust to pH 2.0. The precipitated crystals were collected by filtration and washed with water to obtain 10.25 g of crude crystals. By recrystallizing 10.25 g of crude crystals twice from 90% ethanol, 6.49 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl] benzamide (KRP-297) were obtained (yield 61.3%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[C:5]1([CH:1]([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Agent: Cl[Ru]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CC(C)O
Product: CCC(O)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, propiophenone (0.4 mmol), i-propanol (2 mL) and a solution of sodium carbonate in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (5 atm) at 10° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylpropanol was obtained and the ee value (ee=99.2%) was measured by GC analysis.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27](O)=[O:28])[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27]([N:35]6[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]6)=[O:28])[CH2:25][CH2:26]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)O)CC4)cc2OCC3)n(C(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)N5CCN(C)CC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid (90 mg, 0.22 mmol), 1-methylpiperazine (29 uL, 0.26 mmol), HATU (108 mg, 0.29 mmol) and DIPEA (52 uL, 0.31 mmol) in DMF (3 mL) was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (MgSO4) and concentrated in vacuo affording {1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropyl}-(4-methylpiperazin-1-yl)methanone (quantitative). LCMS: RT 2.08 min [M+H]+ 492.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:38])[CH2:15][CH2:16][NH:17][C:18]([C:20]3([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH:14]([CH3:38])[CH2:15][CH2:16][N:17]3[C:18](=[O:19])[C:20]4([C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[NH:30][C:31]3=[O:33])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(CCNC(=O)C1(NC(=O)OC(C)(C)C)CCc2cc(Cl)ccc21)N1CCC(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CCN1C(=O)NC2(CCc3cc(Cl)ccc32)C1=O)N1CCC(c2ccc(F)cc2)CC1
Product: Cl
Temperature: 50 °C

Procedure:
To a solution of (+/−)N-{3-[4-(4-fluorophenyl)piperidin-1-yl]butyl}-1-tert-butoxycarbonylamino-5-chloro-indane-1-carboxamide (170 mg, 0.31 mmol) in tetrahydrofuran (4 mL) was added 60% sodium hydride/mineral oil (30 mg, 0.7 mmol) and the reaction mixture was warmed at 50° C. for one hour. The cooled reaction was diluted with ethyl acetate, washed with aqueous sat'd sodium bicarbonate, dried (anhyd. sodium sulfate), filtered, and the solvent concentrated under vacuum. The residue was triturated with methanol and the solid product collected by filtration. This material was suspended in methanol (3 mL) and 1 HCl/diethyl ether (0.25 mL) was added. Upon dilution with more diethyl ether the product salt slowly precipitated and solidified to give the title compound. By chiral HPLC this is a mixture of at least three diastereomers.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[O:3].[C:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:17]([O:16][C:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[O:3])=[CH:26][CH:27]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.3 %

Procedure:
To a solution of methyl 2-isocyanatobenzoate (0.97 g, 5.5 mmol) and Boc 1,4-phenylenediamine (1.04 g, 5 mmol) in THF (15 mL) was added DIEA (0.87 mL, 5 mmol) and DBU (0.75 mL, 5 mmol). The reaction mixture stirred at room temp for 5 hr, the off-white solid filtered and washed with ethyl ether to give desired compound (1.49 g, 85%). ES-MS (M+Na)+=376.1, (M−tBu+H)+=298.0.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:24](=[O:29])=[N:25][C:26](Cl)=[O:27].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>O1CCCC1>[O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:24]([NH:25][C:26]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)=[O:27])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC(=O)Nc1ccccc1Oc1ccccc1)Nc1nccs1
Temperature: -30 °C
Reaction time: 6 h
Yield: 55.3 %

Procedure:
To a solution of 2-phenoxyaniline (0.46 g, 2.50 mmol) in tetrahydrofuran (20 ml) was added diisopropylethylamine (0.89 ml, 5.00 mmol) and the solution was cooled to −30° C., then N-(chlorocarbonyl)isocyanate (0.3 ml, 3.75 mmol) was slowly added. The mixture was then allowed to warm up to the room temperature during 30 min. 2-Aminothiazole (0.375 g, 3.75 mmol) was added to the reaction mixture and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to afford crude product, which was purified by silica gel chromatography (hexanes:ethyl acetate from 80:20 to 30:70) to afford title compound (0.49 g, 55%) as pale yellow solid.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[N-].Cl[O:18][C:19]([CH3:22])(C)C.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][CH:3]([O:18][CH2:19][CH3:22])[C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:24]
Reactant: CC(C)(C)OCl
Reactant: CCO
Reactant: [N-]=[N+]=CC(=O)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(OCC)C(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 1-diazo-3-[4-(trifluoromethyl)phenyl]propan-2-one (53) (661 mg, 2.90 mmol) was dissolved in anhydrous ethanol (6 mL) and cooled to 0° C. To this was added tert-butyl hypochlorite (330 μL, 2.92 mmol) and stirred for an hour at the same temperature. After being concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=18/1) to give 1,1-diethoxy-3-[4-(trifluoromethyl)phenyl]propan-2-one (54) as a colorless oily substance (544 mg, 1.87 mmol, 64.7%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)cc1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 5-bromo-2,4-dihydroxy-benzoic acid (520 mg, 2.33 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (471 mg, 2.45 mmol) then HOBt (362 mg, 2.68 mmol). After 25 min, 2,3-dihydro-1H-isoindole (0.5 mL, 2.63 mmol) was added then the mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo then the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated. The residue was triturated with methanol to afford the title compound as a grey solid (328 mg, 44%). 1H NMR (DMSO-d6) 10.45 (1H, s), 10.32 (1H, s), 7.36 (1H, br.s), 7.35 (1H, s), 7.28 (3H, br.s), 6.59 (1H, s), 4.77 (2H, br.s), 4.71 (2H, br.s). MS: [M+H]+ 332/334.