Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:10]([OH:12])[CH:11]=1.C([Al](CC(C)C)CC(C)C)C(C)C>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]2[C@@H:13]3[CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][C@H:18]3[C:19]([CH3:21])([CH3:20])[O:23][C:8]=2[CH:7]=1
Reactant: C=C(C)[C@@H]1CCC(C)=C[C@H]1c1c(O)cc(CCCCC)cc1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
To a nitrogen inerted, stirred solution of cannabidiol (21.2 g, 67.1 mmol) in dichloromethane (370 mL) was added, by syringe pump, commercial tri-isobutylaluminum solution (1 M in hexanes, 6.7 mL, 10 mol %) over 4.5 hours. The temperature of the reaction mixture was maintained at 20-25° C. and the mixture was stirred overnight. Additional charges of triisobutylaluminum solution (1 M in hexanes, 2.67 mL added, 4 mol %) were made over the next day to drive the reaction to >99% conversion by HPLC analysis. The reaction was quenched by addition of water (250 mL), stirred 30 minutes, combined with a slurry of celite in dichloromethane (10.0 g in 70 mL dichloromethane) and then clarified. The reactor and filter cake were rinsed with dichloromethane (50 mL) and the combined filtrates distilled under reduced pressure (25° C. pot temperature, 22 inches of vacuum) to about 50 mL volume. Toluene (106 mL) was added and the solvents again removed under reduced pressure. More toluene (106 mL) was added and removed under reduced pressure and then the dichloromethane-free residue was reconstituted in toluene (100 mL). HPLC analysis showed 95.6% delta-9-tetrahydrocannabinol, 1.1% cis-tetrahydrocannabinol, and no cannabinol. (Sunfire C18 5 u, 4.6 mm×150 mm, 1 ml/min, gradient 80% 0.1% TFA/water and 20% 0.05% TFA/acetonitrile to 100% 0.05% TFA/acetonitrile over 15 minutes, delta-9 tetrahydrocannabinol: rt=15.1 min). The yield was estimated at 95%. The solution was stored under nitrogen until needed for preparation of the camphorsulfonate derivative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([F:32])([F:31])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[N+](=C)=[N-].O1C=C[CH2:40][CH2:39][CH2:38]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([F:31])([F:32])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:28]4[CH2:29][CH2:40][CH2:39][CH2:38][O:30]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C1=COCCC1
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95 %

Procedure:
The difluoroester (5) (880 mg, 1.9 mmol) was treated with 2% KOH--MeOH (30 ml) at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude acid. This in ether (10 ml) was treated with etheral solution of diazomethane until the gas evolution was ceased. This solution was concentrated under reduced pressure to leave the residue. This is dioxane (10 ml) was treated with 2,3-dihydropyran (516 μl) and TsOH (10 mg) at room temperature for 3 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (200 g). Elution with n-hexane-ether (15:1) provided the THP-ester (6) (907 mg, 95%), amorphous. 1H-NMR δ: 0.70 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.53 (2H, m, THP), 3.86 (3H, s, --CO2CH3), 3.93 (1H, m, 3-H), 4.73 (1H, m, THP), 5.36 (1H, m, 6-H). 19F-NMR δ: +40.0. MS m/z: 424 (M+ -DHP), 406, 391.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1CCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[CH2:19][CH2:20][CH2:17][CH2:16]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: COC(=O)c1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then pyrrolidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane-ethanol 95:5 as eluant, affording the title compound (1.12 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1OCCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1cc(N2CCOCC2)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
The methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-(morpholin-4-yl)benzoate (2.34 g, 5.93 mmol) was diluted with ethanol (60 mL) and water (60 mL). Potassium hydroxide pellets (1.64 g, 29.2 mmol) were added, and the resulting mixture was heated to 70° C. After 2 h, the reaction mixture was concentrated in vacuo. The residue was diluted with methylene chloride (200 mL) and extracted with saturated aqueous citric acid (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the acid (2.24 g, 5.90 mmol, 99%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([O:14][C:15](=[O:21])/[CH:16]=[CH:17]\[C:18]([OH:20])=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:22]1([NH:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[CH2:11]1[CH2:10][CH2:9][CH:8]([O:14][C:15](=[O:21])[C@H:16]([CH2:17][C:18]([OH:20])=[O:19])[NH:32][CH2:31][CH2:30][CH2:29][NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][CH2:12]1
Reactant: O=C(O)/C=C\C(=O)OC1CCCCC1
Reactant: NCCCNC1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)C[C@H](NCCCNC1CCCCC1)C(=O)OC1CCCCC1
Yield: 85.2 %

Procedure:
400 ml of triethylamine are added dropwise to a solution of 433.8 g (2 mols+10% excess) of maleic acid-monocyclohexyl ester and 200 ml of dioxane, in a manner analogous to that of Example 1, and the mixture is then reacted with 310.5 g (2.0 mols) of 3-cyclohexylamino-1-propylamine for 40 minutes at 70°-90° C. The reaction mixture is further processed as in Example 1 to yield 604 g (85.2% of theory) of a white crystalline aspartic acid derivative, which decomposes at 172°-173° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]Cl)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O-])(=[O:42])[CH2:40][OH:41].[Na+].[Na]>C(O)CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:41][CH2:40][CH2:39][OH:42])[N:18]=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C([O-])CO
Reactant: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [Na]
Solvent: OCCO
Product: COc1ccc(Cl)c(Oc2c(COCCO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide was added to a sodium glycolate solution from 2.5 g of ethylene glycol and 0.12 g of sodium. The reaction mixture was stirred at 80° C. under argon for 72 hours. Thereafter, the ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with water, dried over sodium sulphate and the solvent was distilled off. The residue was chromatographed over silica gel with ether. There was obtained 0.85g of 4-tert-butyl-N-[5-(2-chloro-5methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide. m.p 162°-164° C., MS: M=606.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]>ClCCl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CNCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of N-methyl-2-morpholinoethanamine (2.1 g, 13.12 mmol, 1.00 equiv, 90%) in dichloromethane (20 mL) at 0-5° C. was added triethylamine (1.47 g, 14.55 mmol, 1.00 equiv) followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (3.3 g, 15.00 mmol, 1.20 equiv, 90%) in dichloromethane (10 mL). The resulting solution was then stirred for 3 h at room temperature. The mixture was diluted with 100 mL of dichloromethane, washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine, dried over sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (20:1) to afford 4.4 g (99%) of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate as a brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:4]([Cl:12])=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18.1 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.51 g, 18%). 1H NMR (400 MHz) δ 12.22 & 11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84 (s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[NH4+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C.CCOCC>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:26][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:24])=[CH:19][CH:18]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(C(=O)n2nc(C3CCN(C)CC3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 4-toluoyl chloride was heated at 100° C. on a steam bath for 4 hrs. Ether was added to the cooled mixture and the salt was coolected. The salt was converted to its free base by means of ammonium hydroxide solution. The base was dissolved in ethanol (90 ml)-ether (175 ml) and 1.5 g of fumaric acid was added. The mixture was stirred at ambient temperature for 16 hrs, and the resultant fumarate salt was collected. Recrystallization twice from methanol-ether yielded 3.8 g (60%) of product, mp 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.[CH:26]1([CH2:29][NH:30][CH2:31][CH3:32])[CH2:28][CH2:27]1>C(COC)OC>[CH:26]1([CH2:29][N:30]([CH2:31][CH3:32])[C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCNCC1CC1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCN(CC1CC1)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
To a stirred solution of 15.0 grams (0.05 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 4.97 grams (0.05 mole) of triethylamine in 200 ml. of dimethoxyethane was added, dropwise, 4.28 grams (0.05 mole) of N-cyclopropylmethyl-N-ethylamine at room temperature over a period of 2.5 hours. The resultant mixture was then heated under reflux for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue then dissolved in a mixture of chloroform and water. The organic layer was separated and was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate, and then water. After drying over anhydrous sodium sulfate, the organic solution was evaporated to dryness. The residue was dissolved in hexane and filtered and then evaporated to dryness to give 12.85 grams of the product as as dark, viscous amber liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CCC1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[cyclobutyl(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.74 g) in DMF (4 mL) was added potassium tert-butoxide (0.28 g) at 0° C., and the mixture was stirred for 2 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.48 g, 71%) as a pale-yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].N1C=CC=CC=1>CCO>[OH:10][NH:9][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[NH:7]
Reactant: NO
Reactant: N#Cc1nccs1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N=C(NO)c1nccs1

Procedure:
To a solution of thiazole-2-carbonitrile (0.42 g, 3.80 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.53 g, 7.60 mmol) and pyridine (0.27 g, 3.40 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 0.50 g, 91% crude yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH:19]2[CH2:21][CH2:20]2)O)=[CH:11][CH:10]=1.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2.[Cl-].[NH4+]>ClCCl>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)[CH:19]2[CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: OC1(C2CC2)CCc2ccc(Cl)cc21
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C3(C4CC4)CCc4ccc(Cl)cc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
0.03 ml (0.40 mmol) of trifluoroacetic acid was added to 70.0 mg (0.34 mmol) of the compound from Example 119A and 65.4 mg (0.37 mmol) of the compound from Example 8A in 1.6 ml of dichloromethane at 0° C., and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 52.4 mg (42% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)[N:4]=1.C(Cl)Cl>Cl.O1CCOCC1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[N:6]=2)=[CH:17][CH:18]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(N)cc2)n1
Reaction time: 18 h
Yield: 72 %

Procedure:
tert-Butyl N-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (1.20 g) was dissolved in 4M hydrogen chloride in dioxane (5 mL) and dioxane (5 mL). The reaction was stirred for 18 hour then DCM (10 mL) added to help solubilise material. The reaction was stirred at 40° C. for a further 18 hours then evaporated to dryness. The solid was suspended in DCM (20 mL) and a mixture of a saturated aqueous solution of sodium hydrogen carbonate (6 mL) and water (4 mL) was added. The organics were separated, dried (MgSO4) and concentrated in vacuo to give the desired compound (648 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].[CH3:13][C:14]1[C:19]2[NH:20][C:21](=[O:23])[O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:12][C:4]1[CH:5]=[C:6]([C:7]([C:16]2[CH:15]=[C:14]([CH3:13])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:8])[CH:10]=[CH:11][C:3]=1[C:1]#[N:2]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: N#Cc1ccc(C(=O)Cl)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
0.73 g (4.0 mmol) 4-cyano-3-fluoro-benzoic acid chloride, 0.60 g (4.0 mmol) 4-methyl-3H-benzoxazol-2-one and 2.1 g (16 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. After cooling to RT the mixture was combined with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:19][C:20]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:31]3[CH2:32][CH2:33][C:28]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[C:20]4[CH3:19])[CH2:29][CH2:30]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: CC1=Cc2ccccc2C12CCNCC2
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 77.7 %

Procedure:
In the same manner as in Example 19, step 3 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.533 g, 2.12 mmol) obtained in Example 19, step 2 and 2-methylspiro[inden-1,4′-piperidine] (0.465 g, 2.34 mmol), the title compound (0.712 g, 70%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([NH:8][C:9]([NH2:17])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Cc1cccc(N=C=S)c1N1CCOCC1
Solvent: CCO
Product: Cc1cccc(NC(N)=S)c1N1CCOCC1

Procedure:
Reaction of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methyl-2-morpholinophenyl)thiourea (m.p. 178°-179° C.).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[NH:13][C:12]([CH3:14])=[N:11][C:10]=1[N+:15]([O-])=O.[C:19]([CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])(=O)[CH3:20]>C(O)C.C(O)(=O)C.[Fe]>[OH:25][CH2:26][CH2:27][C:22]1[C:19]([CH3:20])=[N:15][C:10]2[N:11]([C:12]([CH3:14])=[N:13][C:9]=2[C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:18])[C:23]=1[OH:24]
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(C)c(-c2[nH]c(C)nc2[N+](=O)[O-])c(C)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Yield: 34.1 %

Procedure:
A solution of 5-mesityl-2-methyl-4-nitro-1H-imidazole (2.1 g, 8.56 mmol), α-acetyl-γ-butyrolactone (1.21 g, 9.42 mmol), and iron powder (2.39 g, 42.8 mmol) in ethanol (40 mL) and acetic acid (10 mL) was stirred at 80° C. for one day. The mixture was filtered through Celite and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (0.95 g) as white crystals.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)nipecotic acid (1145 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 16 hours. Triethylamine (708 mg, 7 mmol) was added thereto, and then solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (238 mg, yield of 37%).