Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([Br:11])([CH2:10][CH:4]([CH:5]3C(O)=O)[CH2:3]1)[CH2:9]2.CCN(CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:40][C:41]([O-:44])([CH3:43])[CH3:42].[K+].[N-:46]=[C:47]=[O:48]>C1(C)C=CC=CC=1.C1COCC1>[C:41]([O:44][C:47](=[O:48])[NH:46][CH:5]1[CH:4]2[CH2:10][C:8]3([Br:11])[CH2:9][C:2]([Br:1])([CH2:12][CH:6]1[CH2:7]3)[CH2:3]2)([CH3:43])([CH3:42])[CH3:40]
Reactant: O=C(O)C1C2CC3(Br)CC1CC(Br)(C2)C3
Reactant: CC(C)(C)[O-]
Reactant: [N-]=C=O
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1C2CC3(Br)CC1CC(Br)(C2)C3
Temperature: 85 °C
Reaction time: 15 h

Procedure:
A suspension of the acid 24 (2.00 g, 5.92 mmol) in dry toluene (30 mL) was treated successively with Et3N (1.0 mL, 7.10 mmol) and diphenylphosphoryl azide (DPPA, 1.6 mL, 7.10 mmol). The resulting mixture was stirred at 85° C. for 15 h. To a separated flask containing a solution of t-BuOK (1.35 g, 11.8 mmol) in dry THF (80 mL) at 0° C. was added the isocyanate solution dropwise via a dropping funnel. The resulting reaction mixture was allowed to warm to rt over 30 min, and then it was quenched with water. The THF was removed in vacuo, and the resulting material was diluted with EtOAc. The organic layer was washed with 1N HCl, sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 95:5 to 8:2, hexanes/EtOAc) afforded 1.20 g (50%, 2 steps) of the title compound as a white powder. 1H NMR (300 MHz, CDCl3) δ 4.68 (bs, 1 H), 3.76 (bs, 1 H), 2.87 (s, 2 H), 2.47-2.13 (m, 10 H), 1.46 (s, 9 H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:22](=[O:23])[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18.2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR (DMSO-d6) δ 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55 (m, 7H) and 10.32 (s, 1H).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[F:19][C:20]([F:29])([F:28])[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>CCCCCC>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:24]3([OH:27])[CH2:23][CH2:22][CH:21]([C:20]([F:28])([F:29])[F:19])[CH2:26][CH2:25]3)[CH:14]=2)[N:9]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: O=C1CCC(C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C3(O)CCC(C(F)(F)F)CC3)ccc2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) anhydrous THF solution of 2-methoxy-6-bromoquinoline (1.16 g, 4.89 mmol) was added w-BuLi (2.05 mL of a 2.5 M solution in hexane, 5.13 mmol). The mixture was stirred at −78° C. under a nitrogen atmosphere for 15 min and 4-(trifluoromethyl)cyclohexanone (0.81 g, 4.89 mmol) was added slowly to the reaction. After addition was complete, the bath was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl (aq) and extracted with EtOAc/hexanes. The organic layer was dried over Na2SO4 and evaporated in vacuo and the resultant residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-moving isomer and Isomer B as the slower-moving isomer.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])#[N:13]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([C:12]#[N:13])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
Part B. To a mixture of tert-butanol (3.50 g, 47.22 mmol), pyridine (3.72 g, 46.78 mmol) and cat. DMAP in methylene chloride (15 mL) is added dropwise 3-cyanobenzoyl chloride (6.81 g, 41.07 mmol) and pyridine (3 mL) in methylene chloride (10 mL) at 0° C. The resulting mixture is stirred at room temperature for 20 h. The solvent is evaporated, and the residue is purified by flash chromatography (1:1 methylene chloride/hexanes) to afford 3-cyano-benzoic acid tert-butyl ester (6.84 g, 82.1% yield) as white solid. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, s), 8.20 (1H, dd, J=7.9, 1.2 Hz), 7.78 (1H, dd, J=6.7, 1.1 Hz), 7.52 (1H, m), 1.58 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:30])=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32].C(=O)([O-])[O-].[K+].[K+].ClCCl.CO>CC(C)=O>[CH2:31]([NH:33][C:34]([N:16]1[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:14]([C:26]([O:28][CH3:29])=[O:27])=[C:13]([CH3:30])[N:12]=[C:11]1[S:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:35])[CH3:32]
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCNC(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 91.7 %

Procedure:
A solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.5 g, 3.5 mmole) in acetone under argon at room temperature was treated with ethyl isocyanate (0.5 ml, 0.45 g, 6.3 mmole) and powdered potassium carbonate (50 mg, 0.36 mmole). Examination of the reaction mixture using thin layer chromatography (tlc) (dichloromethane/methanol, 95:5) showed a new spot at higher Rf which did not increase after 1 to 2 hours. Volatiles were evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic fraction was washed with water, 1N hydrochloric acid, water and saturated brine. The aqueous fractions were back-extracted with fresh ethyl acetate. The combined organic fractions were dried (magnesium sulfate) and concentrated in vacuo to give 1.6 g of crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.[NH2:14][NH2:15]>>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH2:5][C:6]([NH:14][NH2:15])=[O:11]
Reactant: NN
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: O
Product: NNC(=O)Cc1cc(F)ccc1N
Temperature: 110 °C

Procedure:
Hydrazine hydrate (55%, 3000 mL) and 5-fluoroisatin (300 g) were heated to 100° C. An additional 5-fluoro-isatin (500 g) was added in portions (100 g) over 120 minutes with stirring. The mixture was heated to 110° C. and stirred for 4 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration to give crude (2-amino-5-fluoro-phenyl)-acetic acid hydrazide (748 g). The hydrazide was suspended in water (700 mL) and the pH of the mixture adjusted to <pH 3 with 12 N hydrochloric acid. The mixture was stirred for 12 hours at room temperature. The solids were collected by vacuum filtration and washed twice with water. The product was dried under vacuum to give 5-fluoro-1,3-dihydro-indol-2-one (600 g, 73% yield) as as a brown powder. 1H-NMR (dimethylsulfoxide-d6) δ 3.46 (s, 2H, CH2), 6.75, 6.95, 7.05 (3×m, 3H, aromatic), 10.35 (s, 1H, NH). MS m/z 152 [M+1].
Reaction SMILES: [CH2:1]1[O:11][C@@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@@H:6]([OH:7])[C@@:2]1([OH:5])[CH2:3][OH:4].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+]>O>[CH2:14]([O:4][CH2:3][C@:2]1([CH2:1][O:11][C@@H:10]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:8]([O:9][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:6]1[O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: OC[C@@H]1OC[C@](O)(CO)[C@H](O)[C@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O[C@]1(COCc2ccccc2)CO[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 6 h
Yield: 71 %

Procedure:
A vigorously stirred mixture of 2,5-O-methylene-L-mannitol (8.0 g.), benzyl chloride (80.0 ml.), and powdered potassium hydroxide (40.0 g.) was slowly heated to 115°-125° and kept in this temperature range for six hours. The mixture was then cooled, water (200 ml.) added, and the mixture was steam distilled for 5 hours. The solution was then cooled, the organic layer (lower) separated in a separatory funnel and the aqueous layer extracted with three 100 ml. portions of ether which were then added to the organic layer. The combined organic layer was then extracted with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated under reduced pressure to a syrup. The syrup was dissolved in methanol (35 ml.) and the solution cooled in an ice bath. Water was added until turbidity persisted and the solution was left to stand at 5° overnight. The crystalline product was removed by filtration, dissolved in isopropyl ether to which was added some methanol, and the resultant solution cooled at 5° while crystallization progressed. The filtered crystals were washed with a solution of pentane-isopropyl ether (1:2, v/v) and air dried to give pure 1,3,4,6-tetra-O-benzyl-2,5-O-methylene-L-mannitol (16.2 g. 71%) having m.p. 53°-54°, and [α]D +6.4° (c 1.09, chloroform) as compared with m.p. 55°-56°, and [α]D -6.6° (c 1.02, chloroform) which were found for the D-isomer.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([CH3:21])([CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C([O-])(=[S:48])C.[K+]>C(Cl)Cl.CC(N(C)C)=O.C(O)C>[SH:48][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([CH3:21])([CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCCC(CO)C2)cc1
Reactant: CC([O-])=S
Agent: BrC(Br)(Br)Br
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)N2CCCC(CS)C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.2 g (0.33 mol) of 2-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one and 10.5 g of triphenylphosphine are dissolved in 60 ml of methylene chloride. 13.3 g of carbon tetrabromide is dissolved in 15 ml of methylene chloride and is added dropwise to the above solution at 5 ° C. After stirring for 2 h, the resulting solution is concentrated to give a slurry. This material is purified by column chromatography on silica gel with ethyl acetate-hexane (50-50) as an eluent, and an oily product is obtained. The resulting material is used for the next reaction. 13.0 g of the above oily product is dissolved in 80 ml of dried dimethylacetamide and 4.95 g of potassium thioacetate is added. After stirring for 2.5 h at 50 ° C., the reaction mixture is poured into ice-water and extracted with ethyl acetate. The combined organic layer is washed with saturated sodium chloride solution and died over MgSO4. The solvent is removed by evaporator and the crude oil is further purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent, and an oily product is obtained. The product is dissolved in 40 ml of ethanol and the solution is bubbled by nitrogen for 10 min. to remove oxygen. To the solution are added 10 ml of 2N sodium hydroxide solution and stirred at 0° C. for 1 h. After the reaction mixture is neutralized by adding 2N hydrochloric acid solution, the resulting solution is poured into 10 ml of water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (5-95) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.02 (m, 1H), 1.26 (t, 1H), 1.29 (s, 3H), 1.30 (s, 3H), 1.43-1.55 (m, 1H), 1.61-1.66 (m, 2H), 1.87 (m, 1H), 2.06 (m, 1H), 2.23 (m, 1H), 2.40 (t, 2H), 2.52 (s, 3H), 2.69 (m, 1H), 2.88 (d, 1H), 7.22 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][N:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5]1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15]1>>[CH2:5]1[CH:6]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:12][CH2:13][CH:4]1[CH2:3][CH2:2][O:1][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)=[O:24]
Reactant: OCCC1CCN2CCCCC2C1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(OCCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12

Procedure:
eq-2-(2-Hydroxyethyl)quinolizidine (D5) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The resulting beige solid was recrystallised from ethyl acetate/petrol (60-80) to afford the title compound (E10) as a white solid mp 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[ClH:11].ClN=CC(O[CH2:18][CH3:19])=O>C(Cl)Cl>[Cl:11][CH2:18][C:19]1[O:10][C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[N:1]=1
Reactant: CCOC(=O)C=NCl
Reactant: Cl
Reactant: Nc1c(Cl)ccc(Cl)c1O
Solvent: ClCCl
Product: ClCc1nc2c(Cl)ccc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 2-amino-3,6-dichlorophenol (23.91 g, 134 mmol) in methylene chloride (270 mL), solid ethyl chloroiminoacetate hydrogen chloride (31.9 g, 202 mmol) was added. The resultant slurry was stirred at room temperature overnight, then filtered through a plug of Celite, and concentrated under reduced pressure (15 torr). The solid residue was subjected to column chromatography on silica gel (elution with chloroform). Collection and concentration of appropriate fractions yielded 26.6 g (86%) of 2-chloromethyl-4,7-dichlorobenzoxazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH3:31])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCCOC
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.84 (m, 2H) 2.36 (s, 3H) 2.91 (s, 3H) 3.04 (br. s., 1H) 3.14-3.21 (m, 3H) 7.59 (dd, J=8.1, 1.5 Hz, 1H) 7.65 (s, 1H) 7.72 (d, J=8.1 Hz, 1H) 7.95-8.04 (m, 1H) 8.05-8.09 (m, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.46 (d, J=9.9 Hz, 1H). MS m/z [M+H]+ 406.4.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](OC)=[O:26])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[NH4+:33]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:26])[NH2:33])[CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Yield: 60 %

Procedure:
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously for 132 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), and 5.65 (s, 2H). IR (KBr, cm−1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C@@H](C2C=CC=CC=2)C)[CH2:4][C@@:3]1([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.C(=O)([O-])O.[Na+].[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C.C(OCC)C>[CH2:29]([O:36][C:37]([N:5]1[CH2:6][CH:2]([OH:1])[C@:3]([CH3:22])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](c1ccccc1)N1CC(O)[C@](C)(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of tert-butyl (3R)-4-hydroxy-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (2.00 g, 6.55 mmol) in ethanol (10 mL), 1N hydrochloric acid (6.88 mL, 6.88 mmol) was added at room temperature, and the mixture was stirred for 10 minutes. After concentrating the reaction mixture under reduced pressure and dissolving the residue in ethanol (50 mL), 10% palladium-carbon catalyst (200 mg) was added, and the suspension was stirred in an oil bath at 50° C. for 14 hours in hydrogen atmosphere. After filtering the reaction mixture, the filtrate was concentrated, and the diethylether (30 mL) and saturated sodium hydrogencarbonate (30 mL) were added to the residue, and benzyloxycarbonyl chloride (982 μl, 6.88 mmol) was added in an ice bath. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (20 mL), and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 2.00 g (91.1%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].O.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]2)[C:6]2[N:22]=[C:2]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=3[O:33][CH3:34])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: C[C@@H]1CCC(N2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Temperature: 85 °C
Reaction time: 48 h

Procedure:
2-Chloro-7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (500 mg, 1.51 mmol) and 4-amino-3-methoxybenzoic acid (316.0 mg, 1.89 mmol) were weighed into a flask. 4-Methylbenzenesulfonic acid monohydrate (230.0 mg, 1.21 mmol) was weighed into a separate flask and dissolved in dioxane (15 ml). The toxic acid solution was then added to the flask containing the two starting materials. The reaction was stirred at 85° C. for 48 hours followed by 100° C. for an additional 48 hours. The dark brown mixture was cooled to room temperature and filtered through paper. The solids were washed with ethyl acetate (15 ml). m/z 462.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.C([N-]C(C)C)(C)C.[Li+].[CH:28](=[O:30])[CH3:29].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH:28]([OH:30])[CH3:29])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC=O
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)C1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
In a round bottom flask, 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.840 g, 3.0 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to −78° C., then added 2.0 M lithium diisopropyl amide in tetrahydrofuran (6.0 mmol) drop wise. After 30 minutes, acetaldehyde (1.056 g, 24.0 mmol) in 6.0 mL tetrahydrofuran was added slowly drop wise to it, continued stirring for 60 minutes. After disappearing the starting material, cooled the reaction flask to −78° C., then quenched with sat. ammonium chloride solution (3 mL). At room temperature, the resultant reaction mixture was taken into ethyl acetate (50 mL), washed with 0.1 N HCl, ammonium chloride solution and finally with water, dried over sodium sulphate and evaporated. Purified the product using column chromatography with hexane:ethyl acetate mixtures to give the product (0.842 g, 86%). [M+H] calculated for C15H21ClN4O2, 325; found 325.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:14][CH2:13]3)[C:7](=[O:15])[CH:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.[CH3:20]S(C)=O.IC.CC([O-])(C)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14]3)[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CS(C)=O
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (121 mg, 0.431 mmol), DMSO (2 ml), and iodomethane (0.032 ml, 0.517 mmol). The mixture was cooled to 0° C. and added sodium 2-methylpropan-2-olate (49.7 mg, 0.517 mmol) and allowed to stir at 20° C. for 16 hours. The reaction solution was suspended in water, and the precipitate filtered. The collected solid was washed successively with small amount of ethanol and diethyl ether. The solid was collected and dried in-vacuo to afford 2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.339 mmol, 79% yield) as a tan solid. MS [M+H] found 295.