Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]1([NH:25][CH:26]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C1C=CN=CC=1)C.ClCCl>[O:8]1[C:7]2[CH:2]=[CH:3][C:4]([CH2:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:31]([CH:28]3[CH2:29][CH2:30][CH:26]([NH:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:27]3)=[O:33])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C1CCC(Nc2ccccc2)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CCC(Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (17 mg), 3-phenylaminocyclopentanecarboxylic acid (15 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 mg), and N,N-dimethyl-4-aminopyridine (12 mg) in 5 ml dichloromethane was stirred at room temperature overnight. After addition of water (5 mL), the mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography on silica (33% ethyl acetate in hexane) gave the product as a resin: MS (m+1)=423.3; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 1.30 (m, 4H), 1.75 (m, 2H), 1.90 (m, 1H), 1.95 (m, 1H), 2.15 (m, 1H), 2.30 (m, 1H), 2.65 (m, 2H), 3.00 (m, 1H), 4.00 (m, 2H), 4.40 (m, 2H), 4.15 (m, 4H), 5.20 (s, 1H), 6.6-6.8 (m, 3H), 7.1-7.6 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
N-Acetylhomopiperazine (7.2 mL, 54.6 mmol) and DIPEA (12.3 mL, 74.4 mmol) were added to a stirred solution of 4-fluoronitrobenzene (7.0 g, 49.6 mmol) acetonitrile (100 mL) and the mixture was heated to 80° C. under nitrogen with stirring for 16 h. Volatile material was removed by evaporation and the residue was dissolved in EtOAc (150 mL) and water (150 mL) was added. The organic layer was separated and the aqueous layer was extracted again with EtOAc (2×150 mL). The organic layers were combined and dried, concentrated by evaporation then the residue was triturated with isohexane to give the title compound (5.6 g, 53%) as a solid; 1H NMR δ 8.01 (2H, qd), 6.92-6.82 (2H, m), 3.80 (1H, t), 3.70-3.56 (5H, m), 3.35 (2H, dt), 1.97-1.71 (5H, m); MS m/e MH+: 264.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C(O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:2]([OH:1])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)C(O)[C@H](O)CO

Procedure:
An alternative synthesis of D-arabinose consists in the oxidative degradation of gluconic acid, extensively described by Ruff in Berichte der Deutschen Chemischen Gesellschaft 32 (1899) 553-554. However, starting from glucose a minimum of three reaction steps are required to obtain arabinitol.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([N+:15]([O-])=O)[CH:4]=1>C(OC(=O)C)C>[NH2:15][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccccc2)c(N)c1

Procedure:
4-Methylthio-2-nitrobiphenyl (15 g) was reduced with hydrated stannous chloride (64 g) in ethylacetate (300 ml) at ambient temperature for 15 hours to give 2-amino-4-methylthiobiphenyl as a yellow oil.
Reaction SMILES: ClC1C2C=CN(CC3CC3)C=2N=CN=1.[NH2:15][C:16]1[C:17]2[C:24]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=3)=[O:26])=[CH:23][N:22]([CH:34]3[CH2:38][CH2:37][CH2:36]C3)[C:18]=2[N:19]=[CH:20][N:21]=1>>[NH2:15][C:16]1[C:17]2[C:24]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=3)=[O:26])=[CH:23][N:22]([CH2:34][CH:38]3[CH2:36][CH2:37]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: Clc1ncnc2c1ccn2CC1CC1
Product: Nc1cccc(C(=O)c2cn(CC3CC3)c3ncnc(N)c23)c1

Procedure:
The title compound was prepared from 4-Chloro-7-cyclopropylmethyl-7H-pyrrolo[2,3-d]pyrimidine by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 308.4 (MH+); HPLC Rf: 4.17 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 1-benzyl-4-(4-bromophenyl)piperidin-4-ol (3.0 g) in toluene (20 mL) was added p-toluenesulfonic acid monohydrate (1.98 g) at room temperature. The reaction mixture was stirred at 130° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at 0° C., and the mixture was extracted with ethyl acetate-THF. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.80 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)[C:4]=2[CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:12]=[C:13]([N:28]4[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]4)[CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Yield: 66.3 %

Procedure:
A solution of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (100 mg, 0.40 mmol) and 1-N-Boc-piperazine (380 mg, 2.0 mmol) in dimethyl sulfoxide (3.0 mL) was heated at 95° C. 4 h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane 25% EtOAc) to give the desired product 110 mg 66% yield. MS (ESI) m/z: 415.1 [M+H]+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:9](=[N:8][C:7]#[N:6])[S:13][CH3:14])[N:8]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 147.5 %

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine (180 mg.) in acetonitrile (2 ml.) was treated with dimethyl(cyanoimidio)dithiocarbonate (85 mg.) and the solution stood at room temperature for 18 hours. The crystalline solid which precipitated was collected to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (175 mg.), m.p. 189°-190°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.27 g (1.7 mmol) of 2,6-difluorobenzamide and 0.22 g (1.9 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-difluorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.40 g (1.7 mmol) of 2-bromo-5-chloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.54 g (Yield 76%) of the title compound as a solid.
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=C1)(C)C.[O:30]1C=CC=[C:31]1B(O)O>>[O:30]1[CH:31]=[CH:9][CH:8]=[C:7]1[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH:15]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3ccco3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-2-boronic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:9]([NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCN
Reactant: Cc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccccc1C
Yield: 91.9 %

Procedure:
According to the general procedure B, 2-chlorotoluene (73 mg, 0.58 mmol) reacted with n-hexylamine (80 μl, 0.61 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. for 8 h to give the title compound (102 mg, 92%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.20 (t, 1H, J=7.5 and 7.8 Hz), 7.12 (d, 1H, J=7.2 Hz), 6.70 (dd, 2H, J=7.5 Hz), 3.51 (bs, 1H), 3.22 (t, 2H, J=7.2 Hz), 2.21 (s, 3H), 1.74 (m, 2H), 1.48 (m, 2H), 1.41 (m, 2H). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.35, 129.94, 127.08, 121.60, 116.53, 109.52, 43.91, 31.64, 29.54, 26.90, 22.62, 17.43, 14.03. GC/MS(EI): m/z 191 (M+), 121. Anal. Calcd for C13H21N: C, 81.62; H, 11.06; N, 7.32. Found: C, 81.52; H, 11.09; N, 7.37.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:9])([CH2:6][CH:7]=[CH2:8])[CH3:5].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C)C=O>[CH2:12]([O:9][C:4]([CH3:5])([CH3:3])[CH2:6][CH:7]=[CH2:8])[CH:11]=[CH2:10]
Reactant: C=CCC(C)(C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)(C)CC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 156.9 %

Procedure:
To a suspension of sodium hydride (60%, 24 g, 60 mmol) in N,N-dimethylformamide (150 mL) at 0° C. was slowly added 2-methylpent-4-en-2-ol (20.0 g, 200 mmol). After 1 hour at 0° C., allyl bromide (48.0 g 400 mmol) was slowly added at 0˜5° C., and the reaction mixture was stirred at 0° C. for another 1 hour. The reaction was quenched with aq. ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (44 g, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[I-].ClC1C=CC=C[N+]=1C.[O:21]1[C@@H:25]2[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C@@H:24]2[NH:23][C:22]1=[O:33].CCCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:23]2[C@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@H:25]3[O:21][C:22]2=[O:33])=[O:10])[CH:2]=1
Reactant: O=C1N[C@H]2c3ccccc3C[C@H]2O1
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cccc(CC(=O)N2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of m-tolylacetic acid (8.57 g, 0.0571 mol), 2-chloro-1-methylpyridinium iodide (19.0 g, 0.0744 mol) and (3aS-cis)-(−)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one (10.0 g, 0.0571 mol) in CH2Cl2 (130 mL) were added TEA (18.0 mL, 0.129 mol) and 4-dimethylaminopyridine (DMAP, 1.39 g, 0.0114 mol) at 0° C. The reaction mixture was stirred at rt for 3 h then treated with hexane (130 mL). The resulting slurry was passed through a pad of silica gel, eluting with 3:2 EtOAc/hexane. The filtrate was concentrated to an oil and recrystallized in hot hexane to recover 13 g (74%) of the title compound as a white solid. HPLC: Rt=9.85 (Method E). MS (ES+): mass calculated for C19H17NO3, 307.36; m/z found 330.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.65 (d, J=7.6 Hz, 1H), 7.08-7.37 (m, 7H), 5.95 (d, J=6.8 Hz, 1H), 5.27-5.31 (m, 1H), 4.26 (dd, J=15.9, 39.1 Hz, 2H), 3.40 (d, J=3.5 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: COCCOC[N:7]1[C:11]2=[N:12][CH:13]=[C:14](N3CCOCC3)[CH:15]=[C:10]2[C:9](C2C=CC=CC=2OC)=[CH:8]1.C(O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C.O.[Cl-].[Na+].O>[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1
Reactant: COCCOCn1cc(-c2ccccc2OC)c2cc(N3CCOCC3)cnc21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1cnc2[nH]ccc2c1
Temperature: 65 °C

Procedure:
65 mg (0.17 mmol) of 1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine was dissolved in a mixture of 3 ml of ethanol and 2 ml of water. 500 μl of formic acid was added and the mixture heated to 65° C. for 16 h and then irradiated in the microwave to 150° C. for 40 min. The resulting mixture was neutralized by addition of sodium bicarbonate and water and the crude distributed between ethyl acetate and brine. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to afford 47 mg (0.15 mmol, 94% yield) of 3-(2-methoxy-phenyl)-5-morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine. 1H-NMR (d6-DMSO): δ11.58 (s, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.51 (dd, J=1.4 Hz, 7.3 Hz, 1H), 7.46 (s, 1H), 7.27 (ddd, J=1.5 Hz, 8.8 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.02 (dd(d), J=1.5 Hz, 7.3 Hz, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.07 (m, 4H); MS: m/z 310 [MH+].
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[C:12]1(=[CH:16][C:17](O)=[O:18])[CH2:15][CH2:14][CH2:13]1.Cl>>[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]2[C:5]=1[C:17](=[O:18])[CH2:16][C:12]1([O:11]2)[CH2:15][CH2:14][CH2:13]1
Reactant: Oc1cc(O)cc(O)c1
Reactant: O=C(O)C=C1CCC1
Agent: Cl
Solvent: O
Product: O=C1CC2(CCC2)Oc2cc(O)cc(O)c21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
8 g (49.34 mmol) of 1,3,5-trihydroxybenzene dihydrate and 6.64 g (59.21 mmol) of cyclo-butylideneacetic acid (Example 40A) are initially charged, 25 ml (197.4 mmol) of boron trifluoride/diethyl ether complex are added and the mixture is then heated to 70° C. After three hours, the mixture is cooled, poured into 600 ml of ice-water, acidified with 6 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is taken up in dichloromethane and stirred, and insoluble solid is then filtered off. Silica gel is added to the filtrate, the mixture is concentrated and the residue is purified chromatographically on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This gives 4.7 g (43% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled to 4-chloro-phenylboronic acid (775 mg, 4.96 mmol) acid using Method F to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[O:8][C:7]3[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=3[N:1]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C(=O)O)c1ccc2oc(Cc3ccc(F)cc3)nc2c1

Procedure:
A mixture of ethyl 3-amino-4-hydroxy-phenyl-propionate (4 g.), 4-fluoro-phenyl-acetic acid (3 g.), p-toluene sulphonic acid (0.1 g.) and xylene (50 ml.) was heated under reflux for 20 hours and the water which formed was removed using a Dean and Stark apparatus. The solution was evaporated to dryness and the residue dissolved in ether. The solution was washed with 2N-sodium hydroxide solution (x2) and water, then stirred with charcoal and anhydrous sodium sulphate, filtered and evaporated to dryness. The residual oil (3.7 g., ND22.5 1.5469) was dissolved in ethanol (30 ml.) and 2N-sodium hydroxide solution (30 ml) was added with stirring over 15 minutes. The reaction mixture was stirred for 21/2 hours during which time water (250 ml) was slowly added. The solution was extracted with ether (x2), acidified with concentrated hydrochloric acid and then extracted with ether (x3). These ethereal extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was purified using prep. tlc plates to give 2-[2-(4-fluorobenzyl)-5-benzoxazolyl]propionic acid as a white solid, mpt 91°-93° C., which was characterised by IR UV and NMR spectroscopy and by microanalysis which gave C 68.40%, H 3.86%, N4.64%; C17H14FNO3 requires C 68.23%, H 4.68%, N 4.68%
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:17][C@@H:5]2[C@:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])([CH3:9])[NH:7][O:8][C@@H:4]2[CH2:3]1>CCCCCCC.C(O)C>[F:18][C:2]1([F:1])[CH2:17][C@H:5]2[C@@:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])([CH3:9])[NH:7][O:8][C@H:4]2[CH2:3]1
Reactant: C[C@]1(c2ccccc2F)NO[C@@H]2CC(F)(F)C[C@@H]21
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@@]1(c2ccccc2F)NO[C@H]2CC(F)(F)C[C@H]21

Procedure:
Intermediate IX-1: The racemate of (3S,3aR,6aR)-5,5-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole was resolved on a chiral high-performance liquid chromatography (HPLC) column (Chiralpak AD) using n-heptane/ethanol (85:15) to give (3R,3aS,6aS)-5,5-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole as the faster eluting enantiomer and the desired (3S,3aR,6aR)-5,5-difluoro-3-(2-fluoro-phenyl)-3-methyl-hexahydro-cyclopenta[d]isoxazole as the slower eluting enantiomer. MS: m/z=258.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:8]1([C:6]2[N:5]=[C:4]([NH:11][CH:12]3[CH2:14][CH2:13]3)[N:3]=[C:2]([N:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)[N:7]=2)[CH2:10][CH2:9]1
Reactant: C1CSCCN1
Reactant: Clc1nc(NC2CC2)nc(C2CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C1CN(c2nc(NC3CC3)nc(C3CC3)n2)CCS1
Yield: 83.4 %

Procedure:
12.2 g of 2-chloro-4-cyclopropyl-6-cyclopropylamino-1,3,5-triazine (0.057 mole), 5.97 g of thiomorpholine (0.057 mole) and 8 g of potassium carbonate (0.057 mole) are mixed in 100 ml of isopropyl alcohol and the mixture is heated at 75°-80° C. for 2 hours. It is cooled, the salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in 200 ml of dichloromethane, the solution is washed with water and dried over sodium sulfate and the solvent is evaporated. The product obtained is crystallized from a 1:2 (v/v) mixture of ethyl acetate-hexane to give 13.18 g of 2-cyclopropyl-4-cyclopropylamino-6-thiomorpholino-1,3,5-triazine. Yield: 83.5%. M.P.: 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)cc1
Yield: 92 %

Procedure:
A mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (4.05 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionate (3.93 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 56–57° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH2:9][C:10]3[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=3[F:20])[C:7]=2[CH3:8])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 120 °C
Yield: 78.8 %

Procedure:
5-bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (1.50 g, 3.94 mmol), 1-benzyl-piperazine (5.5 mL, 31.5 mmol), and acetonitrile (1 mL) were placed in a microwave vessel and heated at 120° C. for 1.5 hr by microwave irradiation with stirring. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/2/1) and dried in a vacuum to afford the 1.48 g of the compound as a white solid (yield 79%). 1H NMR (300 MHz, CDCl3) δ 2.15 (2H, m), 2.31 (3H, s), 2.50 (2H, m), 2.78 (2H, m), 3.52 (3H, s), 3.58 (2H, m), 5.36 (2H, s), 7.19-7.41 (7H, m), 7.53 (1H, d)