Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH2:8][CH:7]1[F:22])=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:19][C:14]1[CH:15]=[N:16][N:17]([CH3:18])[C:13]=1[N:9]1[CH2:10][CH2:11][CH2:12][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:23])[F:24])[CH:7]([F:22])[CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(NC(=O)C(F)(F)F)C(F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1ncc(N)c1N1CCCC(NC(=O)C(F)(F)F)C(F)C1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a solution of Intermediate 17, 2,2,2-trifluoro-N-(3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (70 mg, 0.20 mmol) and ammonium formate (101 mg, 1.60 mmol) in MeOH (5 mL) under nitrogen was added 10% palladium on carbon (21 mg, 0.20 mmol). The mixture was heated at 70° C. for 3 hr before being cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide as a red gum (64 mg). A solution of PyBOP (146 mg, 0.28 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (78 mg, 0.22 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (65 mg, 0.20 mmol) and DIPEA (56 μL, 0.32 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature for 30 hr. Additional DCM (50 mL) was added and the mixture washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/DCM) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3-fluoro-4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a racemic mixture of four diastereoisomers in the form of a white solid (82 mg). This solid was re-dissolved in a mixture of DCM (12 mL) and TFA (2 mL) and the mixture was stirred at room temperature for 4 hr. The solvent was removed under reduced pressure. The residue was then re-dissolved in 7 N ammonia in MeOH (20 mL) and heated at 55° C. for 24 hr. The solvent was removed under reduced pressure and purification via silica gel column chromatography (0-5% 7 N ammonia in MeOH/DCM) gave two separate pairs of enantiomers of tert-butyl difluorophenyl)-4-(5-(3-fluoro-4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate. One pair of enantiomers 120 was obtained as a white solid (41 mg). 1H NMR (400 MHz, d4-MeOD) δ 7.60 (s, 1H), 7.53-7.43 (m, 1H), 7.15 (t, J=8.8 Hz, 2H), 4.48-4.30 (m, 1H), 3.83-3.72 (m, 3H), 3.57 (d, J=4.4 Hz, 1H), 3.59-3.45 (m, 1H), 3.37-3.29 (m, 2H), 3.14 (td, J=11.4, 5.2 Hz, 1H), 1.95-1.84 (m, 3H), 1.82-1.71 (m, 1H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S([O-])(=O)=O.[N:25]1([S:30](N2C=C[N+](C)=C2)(=[O:32])=[O:31])[CH:29]=[CH:28][N:27]=[CH:26]1>CC#N>[F:2][C:3]1([F:7])[CH2:6][N:5]([S:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:32])=[O:31])[CH2:4]1
Reactant: FC1(F)CNC1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(N1CC(F)(F)C1)n1ccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A solution of 3,3-difluoroazetidine hydrochloride (1.00 g, 7.72 mmol) and DIEA (1.5 mL, 8.6 mmol) in MeCN (5 mL) was stirred for about 5 min and then was added to a solution of 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.20 g, 11.6 mmol) in MeCN (10 mL) at about 0° C. The reaction mixture was stirred at about 0° C. for about 1 h, and then warmed to ambient temperature and stirred for about 16 h. The reaction mixture was then concd under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 5-100% EtOAc in DCM to give 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.95 g, 55%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.16 min; MS m/z 224 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([F:17])[CH:10]=2)=[O:8])[C:3]2[CH:18]=[N:19][CH:20]=[CH:21][C:2]1=2.B(Br)(Br)Br.CCCCCC.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:17])[CH:10]=2)=[O:8])[C:3]2[CH:18]=[N:19][CH:20]=[CH:21][C:2]1=2
Reactant: COc1ccc(C(=O)N2CCOc3ccncc32)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: O=C(c1ccc(O)c(F)c1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 31.6 %

Procedure:
In a 10 ml flask, (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methanone (30 mg, 0.104 mmol) was dissolved in dichloromethane and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (1.25 ml, 1.25 mmol) was added thereto and stirred at room temperature for 10 hours. n-hexane and water were added and then filtered to obtain solid. The resulting solid was purified by preparative LC-Mass using 0.05% TFA in acetonitrile and 0.05% TFA in water solvent. The fractions containing the product were collected and adjusted to pH 6 to 7 with saturated solution of sodium hydrogen carbonate. The organic layer was extracted with ethyl acetate. The combined organic layer was evaporated under reduced pressure to obtain the target compound 26 as white solid (9 mg, 28%).
Reaction SMILES: N1C2C=CC(C(O)=O)=CC=2N=C1.C[C@@]12C3C=CC=CC=3CC[C@@H]1NCCC2.C[C@]12C3C=CC=CC=3CC[C@@H]1NCCC2.[NH:43]1[C:47]2[CH:48]=[CH:49][C:50]([C:52]([N:54]3[C@@H:63]4[C@@:58]([CH3:68])([C:59]5[CH:67]=[CH:66][CH:65]=[CH:64][C:60]=5[CH2:61][CH2:62]4)[CH2:57][CH2:56][CH2:55]3)=[O:53])=[CH:51][C:46]=2[N:45]=[CH:44]1>>[NH:43]1[C:47]2[CH:48]=[CH:49][C:50]([C:52]([N:54]3[C@@H:63]4[C@:58]([CH3:68])([C:59]5[CH:67]=[CH:66][CH:65]=[CH:64][C:60]=5[CH2:61][CH2:62]4)[CH2:57][CH2:56][CH2:55]3)=[O:53])=[CH:51][C:46]=2[N:45]=[CH:44]1
Reactant: C[C@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Agent: C[C@@]12CCCN[C@H]1CCc1ccccc12
Agent: C[C@]12CCCN[C@H]1CCc1ccccc12
Agent: O=C(O)c1ccc2[nH]cnc2c1
Product: C[C@@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Yield: 15 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and an isomeric mixture of cis-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and trans-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 yielding a mixture of Example 10 and Example 11 which is separated by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 15% of theory; LC (method 2): tR=3.26 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CS(O[CH2:37][C:38]1[C:43]([Br:44])=[CH:42][N:41]=[C:40]([Cl:45])[CH:39]=1)(=O)=O>CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:37][C:38]3[C:43]([Br:44])=[CH:42][N:41]=[C:40]([Cl:45])[CH:39]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCc1cc(Cl)ncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(Cl)ncc1Br
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 4, 1.305 g, 4.17 mmol) in 30 mL of DMF was cooled to −20° C. NaHMDS (1.0 M, 4.17 ml, 4.17 mmol) was added and the reaction was stirred at −20° C. for 20 minutes. Next, a solution of (5-bromo-2-chloropyridin-4-yl)methyl methanesulfonate (INTERMEDIATE 28, 1.2522 g, 4.17 mmol) in 5 mL of DMF was added and the solution turned brown. The reaction was warmed to 0° C. by switching to an ice/water bath and the reaction stirred for an additional 30 minutes, at which time an LCMS aliquot confirmed the reaction was complete. It was quenched with aqueous NaHCO3. The reaction was extracted with ethyl acetate, then washed with aqueous NaHCO3 and brine, dried with Na2SO4, filtered and the filtrate was concentrated. The crude oil was purified by silica gel chromatography to give the titled compound as an off-white solid. 1H NMR (CDCl3, 500 MHz): δ 8.52 (s, 1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.36 (s, 1H), 5.81 (d, 1H), 4.78 (d, 1H), 4.34 (d, 1H), 4.17 (m, 1H), 0.82 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCc1ccc(F)cc1
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(=O)OCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[S:17][C:5]3[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=3[C:3]=2[CH3:18])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c(Br)sc2c1c(=O)n(CCCO)c(=O)n2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(Cl)c(Cl)c2)sc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 85 °C
Yield: 25 %

Procedure:
To a solution of 6-bromo-3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.15 mmol) in dioxane (2 mL) was added 3,4-dichlorophenylboronic acid (57.3 mg, 0.3 mmol), Pd(PPh3)4 (17.3 mg, 0.015 mmol) and aq. 2M K3PO4 (0.4 mL). The reaction was heated at 85° C. for 1 h, cooled to RT then diluted with EA (20 mL). The organic layer was washed with brine (20 mL) and aq. NH4Cl (20 mL), dried with Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15.0 mg, 27.4% yield) as a white solid. 1H NMR (CDCl3) δ: 7.55-7.48 (m, 2H), 7.24 (d, J=2.1 Hz, 1H), 4.27-4.14 (m, 2H), 3.60-3.50 (m, 5H), 3.27 (t, J=6.5 Hz, 1H), 2.54 (s, 3H), 2.00-1.85 (m, 2H). LCMS: MH+ 399 and TR=3.000 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[CH2:11][C:12](=O)[CH:13]([CH3:15])[CH3:14].OS(O)(=O)=O>>[CH:13]([C:12]1[C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[CH3:8])[N:9]=[C:10]([OH:17])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(C)c(NC(=O)CC(=O)C(C)C)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c(C(C)C)cc(O)nc12
Temperature: 25 °C

Procedure:
A sample of N-(2,5-dimethylphenyl)-4-methyl-3-oxopentanamide and 10.0 mL of H2SO4 was reacted at 100° C. for 1 hour. After the reaction was cooled to room temperature it was quenched into ice-H2O. The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with saturated NaHCO3 (3×15 mL), brine (lx 20 mL), dried over MgSO4 and concentrated. The residue was recrystallized in EtOAc to give 1.30 g of the desired 4-isopropyl-5,8-dimethylquinolin-2-ol. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (d, J=6.45 Hz, 6 H) 2.41 (s, 3 H) 2.77 (s, 3 H) 3.84 (quin, J=6.59 Hz, 1 H) 6.67 (s, 1 H) 6.93 (d, J=7.62 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 8.81 (br. s., 1 H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1C(OCC)=O.Cl>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@](C)(CCC(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of Example 40D (2.60, 8.22 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (1.60 g, 80%). 1H NMR (300 MHz, CDCl3): δ ppm 0.44 (m, 0.5H) 0.73 (m, 3.5H) 0.80 (m, 3H) 1.06 (m, 1H) 1.39 (m, 1H) 1.56 (s, 1.5H) 1.59 (s, 1.5H) 2.04 (m, 1H) 2.30 (m, 1H) 3.74 (s, 0.5H) 3.75 (s, 0.5H) 6.63 (s, 0.5H) 7.46 (m, 2H) 7.66 (m, 1H) 8.08 (m, 0.5H) 8.20 (m, 0.5H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]2[CH:19]=1)=[O:5])C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[S:29]([NH2:32])(=[O:31])=[O:30].[Cl-].C([Al+]CC)C.C(O)(C)C.C(O)(=O)C>CCCCCl>[Cl:14][C:13]1[C:8]2[N:9]([CH:19]=[C:6]([C:4]([NH:32][S:29]([C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[Cl:20])(=[O:31])=[O:30])=[O:5])[N:7]=2)[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:12]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCCCCl
Solvent: CC(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 84.8 %

Procedure:
A stirred slurry of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester (3.0 g, 10.3 mmol) and 2-chloro-5-methoxybenzenesulfonamide (2.39 g, 10.8 mmol, 1.05 equiv) in n-chlorobutane (45 mL) was heated to 50° C. under nitrogen. To this slurry was added neat diethylaluminum chloride (1.40 mL, 11.3 mmol). After complete addition of diethylaluminum chloride the temperature of the reaction mixture was adjusted to 65-70° C. and was held at this temperature for 4.5 h. An additional portion of n-chlorobutane (12 mL) was added and heating at 70° C. was continued for an additional 1.5 h. Iso-propanol (1.6 mL, 20.5 mmol, 2 equiv) was added at 70° C. and the resulting mixture stirred for 5 min. Aqueous 10% acetic acid (15 mL, 25.6 mmol, 2.5 equiv) was then added over a period of 10 min at 60-65° C. The reaction was allowed to cool to room temperature and then stirred overnight. The resulting solid was filtered, washed with water (12 mL) followed by n-chlorobutane (12 mL), and suction-dried. The solid product was further dried in a vacuum oven at 50-60° C. to give the title compound (4.09 g, 85.2%). Powder X-ray diffraction data conformed with Form A of Compound 1 as in Characterization Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:18]([CH3:20])[CH3:19])[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[OH-].[Na+].Cl>CC(O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:18]([CH3:20])[CH3:19])[CH:13]([OH:17])[CH:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)C(O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-methylbutan-2-one in the form in the from of its free base (4 g prepared as described in Example 49) in industrial methylated spirit (18 ml) was added dropwise to a stirred suspension of sodium borohydride (0.7 g) in industrial methylated spirit (40 ml) and the mixture was stirred for 16 hours. Sodium borohydride (0.7 g) was added and the mixture heated under reflux for 3 hours. After cooling the mixture was poured into water and acidified with concentrated sulphuric acid. 5N Sodium hydroxide solution was added with cooling and the basic aqueous liquors were extracted with ether. The extracts were washed with water and dried and the solvent was removed by evaporation to leave an oil which was converted into a hydrochloride salt by treatment with a mixture of excess concentrated hydrochloric acid and propan-2-ol. The residue was dried by azeotropic distillation with propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-methylbutan- 2-ol hydrochloride (m.p. 229°-231° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(F)c(C)c1
Yield: 83.7 %

Procedure:
To a solution of 4-fluoro-3-methylbenzoic acid (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10% sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give 4-fluoro-3-methylbenzoic acid methyl ester (4.56 g, 83.7%) as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>O1CCOCC1>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
To a mixture of 7-(benzyloxy)-4-(4-nitrophenoxy)quinoline (10.85 g, 29.14 mmol) and 1,4-dioxane (38 mL) was added concentrated hydrochloric acid (38 mL). The reaction was stirred in an oil bath at 100° C. for 9 hours, monitored by TLC and LC-MS. After the complete consumption of 7-(benzyloxy)-4-(4-nitrophenoxy)quinoline, the mixture was cooled to room temperature. The solid was collected and stirred in 95% EtOH (30 mL) for 2 hours. The title compound was collected by filtration as a beige solid (8.25 g, 88.7%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(#N)C.[CH2:25](Br)[CH:26]=[CH2:27]>C(N(CC)CC)C>[CH2:27]([N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:15][CH2:14][CH2:13]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Oc1ccc(C2(c3ccccc3)CCNCCO2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN1CCOC(c2ccccc2)(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 11.2 g of 7-(4-hydroxyphenyl)-7-phenylhexahydro-1,4-oxazepine hydrochloride, 110 ml of dry acetonitrile, 14.0 g of triethylamine and 5.05 g of allyl bromide is stirred at room temperature for 48 hours. It is evaporated and the residue partitioned between benzene and 2N aqueous sodium hydroxide. The aqueous layer is separated, combined with a further basic extraction of the benzene solution, and the combined aqueous solutions are adjusted to 9 pH of 4-6.3 with acetic acid. The solid which separates is collected, dried and converted to the hydrochloride in acetone (mp. 150°-153°). The free base is liberated again and crystalized from ethanol, to yield the 4-allyl-7-(4-hydroxyphenyl)-7-phenyl-hexahydro-1,4-oxazepine melting at 205°-207°.
Reaction SMILES: ON1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=1)([O-:11])=[O:10].[C:19](=[O:21])=[O:20].O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=C=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In this example, a solution of 0.1191 g (1.03 mmol) of N-hydroxysuccinimide, 0.5104 g (3.72 mmol) of p-nitrotoluene and 0.1330 g (0.53 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 50° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 50° C., 745 psi of CO2 was introduced into the reactor, then 120 psi of O2 was added slowly to the reactor. The mixture was stirred under pressure for one hour at 50° C., then the pressure was released, and the mixture was cooled to room temperature. The solution was extracted with ethyl acetate then washed with a saturated NaCl solution in water and, dried over Na2SO4 to yield pure white solid p-nitrobenzoic acid (90% yield) after extraction by ethyl acetate with analyses by GC-MS and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[CH:33][C:28]=2[O:27][CH2:26]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[N:12]=4)[C:36](=[O:37])[CH:35]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Nc1nc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc(-c2ccc3c(c2)OCO3)[nH]c2nc(-c3ccc(Cl)cc3)nn12
Temperature: 170 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.26 mmol) in diphenyether (2 ml) was added TsOH (2.2 mg, 0.01 mmol) and ethyl 3-(benzo[d][1,3]dioxol-5-yl)-3-oxopropanoate (81 mg, 0.34 mmol). After stirring 2 h at 170° C., the reaction was quenched by the addition of hexane (5 ml), the product was collected by filtration and washed with methanol (10 ml) and dried in an oven under reduced pressure to give 5-(benzo[d][1,3]dioxol-5-yl)-2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (23.1 mg, 24%).