Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C:44]1[CH:45]=[C:46]([CH:63]=[CH:64][CH:65]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]2[NH:58][CH:57]=[C:56]([C:59]([O:61][CH3:62])=[O:60])[CH:55]=2)[CH:49]=1.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([CH:63]=[CH:64][CH:65]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]2[NH:58][CH:57]=[C:56]([C:59]([O:61][CH3:62])=[O:60])[CH:55]=2)[CH:49]=1)=[O:9]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(N)c3)ccn2)c1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (490 mg, 3.88 mmol), HATU (1.71 g, 4.5 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0 g, 3.24 mmol). The mixture was stirred at 50° C. for 2 hours and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 1.30 g, 96%.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].CCOC(C)=O.[NH4+].[Cl-]>O1CCOCC1>[C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[CH:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
To a solution of (R)-tert-butyl 3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (4.44 g, 8.96 mmol) in 1,4-dioxane (54 mL) was added NaOH (2 N aqueous, 8.9 mL, 18 mmol), and the resulting mixture was heated at about 60° C. for about 3 h. The reaction was cooled to ambient temperature and EtOAc (30 mL) and saturated aqueous NH4Cl (20 mL) were added. The organic layer was separated and the aqueous layer was further extracted with EtOAc (40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous MgSO4, filtered, and coned under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford (R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.80 g, 92%): LC/MS (Table 1, Method b) Rt=1.85 min; MS m/z: 342 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:36](N(C(C)C)CC)(C)[CH3:37].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[C:27]1([CH2:26][C:25]([NH:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:5])[CH:36]=[CH2:37])[CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
{1-[4-(Phenylacetylamino-methyl)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.15 g, 0.31 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.25 ml, 1.54 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 100% DCM to 95% DCM, 5% Methanol) to give the title compound (0.025 g, 18% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[Cl:22]C1C=C(C=C(C)C=1O)C#N.CC1(C)O[C@H](CO)CO1>>[Cl:22][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:19])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: Cc1cc(C#N)cc(Cl)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@@H](CO)O1
Product: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a colorless oil (1.39 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.66 min, [M+H]+=314.96.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[N:26](CC=C)[C:25]2[C:24](=[O:30])[NH:23][C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=2[N:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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:17][C:18]1[NH:26][C:25]2[C:24](=[O:30])[N:23]([CH2:15][CH2:14][CH2:13][C:11]3[O:10][N:9]=[C:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=3)[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=2[N:19]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCc1nc(Cc2ccccc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 3 h

Procedure:
A solution of 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (88 mg, 0.4 mmol) in THF (4 ml) was treated with 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.34 mmol) and PPh3 (115 mg, 0.44 mmol) under nitrogen. DBAD (101 mg, 0.44 mmol) was added in one portion and the reaction left to react for 5 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (39 mg, 0.034 mmol) was added and the mixture degassed once more. Morpholine (294 μl, 3.4 mmol) was added and the mixture was stirred under nitrogen for 3 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The title compound was obtained as a white solid after purification by MDAP (64 mg, 42%).
Reaction SMILES: C([Li])CCC.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:8])[CH3:7].[Cl:16][CH:17]([C:20]1[O:25][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:34])([F:33])[F:32])[C:22]=2[N:21]=1)[CH2:18][CH3:19].Cl>CCCCCC.O1CCCC1.O>[Cl:16][CH:17]([CH2:18][CH3:19])[C:20]([NH:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](=[O:26])[CH2:7][C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8])=[O:25]
Reactant: CC(=O)Nc1ccccn1
Reactant: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Temperature: -70 °C
Yield: 19.4 %

Procedure:
314.3 ml of a 1.4M solution of n-butyllithium in hexane were added to a solution of 30 g of 2-acetylamino pyridine in 886 ml of tetrahydrofuran. After cooling to -70° C., a solution of 32 g of 2-(1-chloropropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared by the process of Example 10 of Belgian Pat. No. 896,941] in 230 ml of tetrahydrofuran was added and the solution was poured into 500 ml of 2N hydrochloric acid and 600 ml of water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried and concentrated to dryness under reduced pressure. The residue was taken in ethyl ether, separated and dried to obtain 9.1 g of 2-[(2-chloro-1-oxobutyl)-amino]-β-oxo-N-(2-pyridinyl)-3-trifluoromethyl benzene propanamide melting at 137° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=NN=1)=[O:5])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C(Cl)Cl>[C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:18]2[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[NH:17]2
Reactant: CCOC(=O)c1nnc(C(=O)OCC)nn1
Reactant: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: CCOC(=O)c1nnc(C(=O)OCC)c2c1[nH]c1ccccc12
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a solution of 5.71 (318 mg, 1.61 mmol) in anhydrous methylene chloride (15 mL) was added a solution of indole (100 mg, 0.85 mmol) in anhydrous methylene chloride (50 mL) dropwise over 4 h with stirring at mild reflux. Following the addition, stirring was continued for 4 h and the reaction mixture was then cooled down. After filtration, the filtrate was evaporated under (reduced pressure and the residue oil was submitted to chromatography (flash column, silica gel, methylene chloride:ethyl acetate=1:1, v/v as eluent) to afford the title compound 5.72 as an orange solid (132 mg, 52%), mp. 151-152° C. 1H NMR (200 MHz, CDCl3) δ (ppm): 11.10 (s, 1H), 8-63 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.0 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H), 4.62 (q, J=7.0 Hz, 2H), 4.47 (q, J=7-0 Hz, 2H), 1.44 (I:, J=7.0 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H). Anal. (C16H15N3O4) C, H, N.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:38]([N:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]=3)[CH2:10]2)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CCCC1

Procedure:
100 mg (0.30 mmol) of the compound from Example 183A and 75 mg (0.33 mmol) of 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid were reacted according to the General Method 7. Yield: 127 mg (78% of theory)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:11]1.[I-].[K+]>CN(C)C=O>[N:1]1([CH2:9][C:10]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:11]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(C2(CBr)OC2c2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3cncn3)OC2c2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
20.9 g of 1,2,4-triazole and 4.4 g of sodium hydride (50% strength dispersion in mineral oil) were dispersed in 150 mL of N,N-dimethylformamide, and a solution of 39.2 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) and 16.6 g of potassium iodide in 150 ml of N,N-dimethylformamide was added at room temperature. After 8 hours, the reaction solution was worked up as described in Example 2, and the product was recrystallized from diisopropyl ether. 31 g (81.9%) of 2-(1,2,4-triazol-1-ylmethyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) of melting point 119° C. were obtained (compound 3).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]1[O:16][C:15](=[O:17])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[Ca+2].[Cl-].Cl>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][CH2:15][OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC(COCc2ccccc2)O1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCC(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3.33 h
Yield: 93.1 %

Procedure:
2.3 g of sodium tetrahydroborate was added to a solution of 9.9 g of 5-((benzyloxy)methyl)oxolane-2-one in 12 mL of ethanol and 48 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and thereafter, a solution of 7.0 g of calcium chloride in 25 mL of ethanol was then added dropwise to the mixture over 20 minutes. Thereafter, 25 mL of tetrahydrofuran was added to the reaction mixture, and the obtained mixture was then stirred at room temperature for 200 minutes. Thereafter, 200 mL of ethyl acetate was added to the reaction mixture, and 1 mol/L hydrochloric acid was then added dropwise to the mixture. The organic layer was fractionated. The obtained organic layer was washed with 100 mL of a saturated sodium hydrogen carbonate aqueous solution, and then with 100 mL of a saturated sodium chloride aqueous solution twice, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 9.4 g of 5-(benzyloxy)pentane-1,4-diol in the form of a colorless oily product.
Reaction SMILES: [Al](OC(C)C)(OC(C)C)OC(C)C.[CH3:14][C:15](=[CH:18][CH2:19][CH:20]1[CH2:24][CH:23]=[C:22]([CH3:25])[C:21]1([CH3:27])[CH3:26])[CH:16]=[O:17].ClC(Cl)(Cl)C(O)=O.C(O)(C)C>CC(C)=O.C1(C)C=CC=CC=1>[CH3:14][C:15](=[CH:18][CH2:19][CH:20]1[CH2:24][CH:23]=[C:22]([CH3:25])[C:21]1([CH3:27])[CH3:26])[CH2:16][OH:17]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(=CCC1CC=C(C)C1(C)C)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
3.07 g (15 mmol) of Al(O-i-Pr)3 and 30 ml of toluene were fed into a 100 ml four-necked round bottom flask under atmosphere of nitrogen, and stirred at room temperature, and then 28.8 g (150 mmol) of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al, then 0.25 g (1.5 mmol) of trichloroacetic acid, and further 18.0 g (300 mmol) of isopropyl alcohol were added while stirring at room temperature. Reaction was conducted while fraction containing acetone generated at the solution temperature of 80° to 92° C. was distilled off. After 6 hours, the reaction solution was analyzed by GLC, 81% of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol was obtained (corresponding to 90% selectivity for conversion of the aldehyde as the starting material).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].C(O)(=O)C.C1C=CC=CC=1>O>[CH2:1]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(N)CO
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 106 g of benzaldehyde, 89 g of 2-amino-2-methyl-1-propanol, 2 ml of glacial acetic acid and 500 ml of benzene is heated for 3 hours under reflux, using a water separator. After completion of the reaction, the mixture is evaporated and the residue is dissolved in 2 liters of ethanol. After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours, continuing to stir the mixture overnight at room temperature, and working up in the usual manner, 2-benzylamino-2-methyl-1-propanol is obtained, which melts at 50°-55° C. after crystallisation from ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[C:18]([OH:22])(=O)[CH2:19]O>>[CH2:9]([O:8][C:5]1[N:4]=[C:3]2[N:16]([CH3:17])[C:19]([CH2:18][OH:22])=[N:1][C:2]2=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CO
Reactant: CNc1nc(OCc2ccccc2)ccc1N
Product: Cn1c(CO)nc2ccc(OCc3ccccc3)nc21
Yield: 46.5 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.50 g of 3-amino-6-benzyloxy-2-methylaminopyridine (prepared as described in Preparation 93) and 7.46 g of glycolic acid were reacted. After working up the product as described in Preparation 43 , the resulting crude product was purifying by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, and was then crystallized by trituration with ethyl acetate, to give 4.10 g of the title compound, melting at 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) in dichloromethane (20 ml) was added diphenyldiazomethane (0.425 g). After stirring for 4 hours at room temperature, acetic acid (0.5 ml) was added to the mixture. The reaction mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and water, and then dried over MgSO4. The solvent was distilled off and then the oily residue was subjected to a silica gel column chromatography. Crystals of diphenylmethyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.759 g, 91%) were obtained from the fraction eluted with ether-hexane (1:3, V/V). Recrystallization from ether-hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9]2)[CH:7]=1.B(F)(F)F.CCOCC.[CH3:20][C:21]([CH3:23])=[O:22]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9][C:21]([CH3:23])([CH3:20])[O:22]2)[CH:7]=1
Reactant: Brc1cncc(C2CO2)c1
Reactant: CC(C)=O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(c2cncc(Br)c2)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 5.00 mmol) in acetone (25 mL) was added BF3.OEt2 (0.950 mL, 7.50 mmol) dropwise and the reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was diluted with water (15 mL) and the resulting mixture extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (0.700 g, 54.2%). LCMS Condition B-26: retention time 2.17, [M+2]=260.0. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 3H), 1.55 (s, 3H), 3.72 (dd, J=7.6 Hz, J=8.4 Hz, 1H), 4.36 (dd, J=6.4 Hz, J=8.4 Hz, 1H), 5.08 (dd, J=6.4 Hz, J=7.6 Hz, 1H), 7.85-7.86 (m, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.C(O)C>O>[C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 123.2 %

Procedure:
The obtained phthalimide compound (13.7 g) and hydrazine monohydrate (2.5 g) are added to ethanol (34 ml) and the mixture is refluxed with stirring for 2 hours. After cooling, a small amount of water is added to the reaction mixture and the solvent is distilled off under reduced pressure. Chloroform (200 ml) is added to the residue and the insoluble substances are filtered off and washed twice with chloroform (each 50 ml). The filtrate and the washings are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated to give the desired compound (12 g). Mass spectrum m/z: 320 (M+)
Reaction SMILES: Cl/[C:2](=[N:8]/[NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.CCOC(C)=O>C1(C)C=CC=CC=1>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:18][C@@H:19]3[C@H:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][N:9]3[C:10]=2[CH:15]=1
Reactant: CCOC(=O)/C(Cl)=N\Nc1cc(F)ccc1OC/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1

Procedure:
Ethyl (2E)-chloro[(5-fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}phenyl)hydrazono]ethanoate (5-3, 3.1 g, 8.23 mmol) was dissolved in anhydrous toluene (20 mL) and treated with triethylamine (11.5 mL, 83 mmol). The reaction was heated at reflux for 24 h, and cooled. EtOAc (100 mL) was added and the organic layer was washed with 5% NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (120 g SiO2 Redisep, 0-30% EtOAc/hexanes gradient) to give pure trans-ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate (5-4). 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 6H), 6.86 (dd, J=8.9, 5.0 Hz, 1H), 6.68 (app dt, J=7.9, 3.1 Hz, 1H), 4.34-4.12 (m, 5H), 3.62 (t, J=10.7 Hz, 1H), 1.23 (t, J=7.0 Hz, 2H); MS (M+H+, C19H17FN2O3) 340.1 found 340.4 required.