Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>C1COCC1>[CH2:12]([NH:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1)[CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Solvent: C1CCOC1
Product: CCNc1nc(F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 2,6-difluoro-3-nitropyridine (45.7 g, 285 mmol) in THF (500 mL) at −40° C. was added drop-wise a solution of ethylamine (25.7 g, 570 mmol) in THF (250 mL). After 30 min, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The resulting yellow solid was purified by flash chromatography (15% EtOAc in hexane) to give the title compound (43.2 g, 82% yield) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O>[Cl:22][C:20]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[N:21]=1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1ccccc1Nc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: O
Product: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine (0.4 mmol) are stirred at RT in N-methylpiperazine (0.3 ml) for 12 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:1) as mobile phase. The product containing fractions are combined and evaporated. A pale oil with Rf=0.25 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Yield: 59.7 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (37 mg, 0.062 mmol) and NaOH (0.312 mL, 0.312 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then filtered and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acid (21 mg, 0.037 mmol, 59.6% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 7.29 (d, J=7.7 Hz, 1H), 7.26-7.19 (m, 2H), 7.17-7.11 (m, 1H), 6.53 (s, 1H), 5.71 (s, 1H), 4.74-4.58 (m, 4H), 4.50-4.42 (m, 1H), 3.68-3.20 (m, 4H), 2.82-2.75 (m, 1H), 2.66 (d, J=8.4 Hz, 2H), 2.51 (s, 3H), 1.90-1.81 (m, 2H), 1.71-1.51 (m, 8H), 1.19 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=565.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].ClC1C=CC=CC=1C=O.F[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][C:20]=1[Cl:28]>>[Cl:28][C:20]1[CH:21]=[C:22]([C:25](=[O:27])[CH3:26])[CH:23]=[CH:24][C:19]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Sc1ccccc1Cl
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Agent: O=Cc1ccccc1Cl
Product: CC(=O)c1ccc(Sc2ccccc2Cl)c(Cl)c1

Procedure:
The title compound was prepared by the procedures described in Example 1A substituting 2,4-dichlorothiophenol with 2-chlorothiophenol, and 2-chlorobenzaldehyde with 4'-fluoro-3'-chloroacetophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:6][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cc(Cl)cc(Cl)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.13 (s, 2H), 7.42 (s, 1H), 7.78 (t, J 7.8, 1H), 7.89 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.51 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:6]2[C:7]3[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:5]2[C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:18][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)c1nc2c([nH]1)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of Intermediate 52 (325 mg), 1-(bromomethyl)-4-chlorobenzene (417 mg) and tetrabutylammonium bromide (272 mg) in toluene (8 mL) at ambient temperature was added aqueous sodium hydroxide 20% wt (3.25 mL). The reaction was stirred at ambient temperature for 2.5 hr. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the title compound. (126 mg). LC/MS MH+ 317, Rt 2.10 mins (5 min run).
Reaction SMILES: C1([O:6][C:7](=[O:33])[C@@H:8]([NH:29][C:30](=[O:32])[CH3:31])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[NH:25][OH:26])=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>O>[C:30]([NH:29][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[NH:25][OH:26])=[CH:12][CH:11]=1)[C:7]([OH:33])=[O:6])(=[O:32])[CH3:31]
Reactant: CC(=O)N[C@@H](Cc1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)O
Reaction time: 4 h

Procedure:
Stage 6 resin loaded with Compound 1 (0.3 g, 1.14 mmol/g) was treated with sodium hydroxide (0.068 g), in water (2 ml, 0.85 M) and the reaction shaken for 4 hrs. The resin was washed, DCM, DMF (×2), DCM, MeOH (×2), MeOH, TBME and dried. The required product was cleaved with 2% TFA/DCM to give crude compound 2, which was further purified by preparative HPLC. m/z 394 [M++H]+, 1H NMR (400 MHz, d4-MeOH) δ: 1.39-1.44 (4H, m, 2×CH2), 1.63-1.71 (4H, m, 2×CH2), 1.90 (3H, s, CH3CO), 2.11 (2H, t, CH2), 2.37 (2 H, t, CH2), 2.92 (1 H, dd, ArCH), 3.17 (1 H, dd, ArCH), 4.65 (1 H, q, NHCH), 7.19 (2 H, 2 d, Ar), 7.48 (2 H, d, Ar).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:43])[CH2:12][CH2:13][N:14]([C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH3:40])[C:28]([CH2:30][NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[NH4+:50].[NH4+]>C(O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:12][CH2:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH3:40])[C:28]([CH2:30][NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:50])=[CH:36][CH:37]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])=[O:43]
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCNC(=O)OC(C)(C)C)c3ccccn3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)NCCN)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of 2b (1.34 mmol) was added to a saturated HCl solution in dry ethanol (30 mL). The solution was stirred at room temperature for 5 hours, then evaporated to dryness at 30° C. Ethanol (30 mL) and ammonium carbonate (13.0 mmol) were added and the mixture stirred at room temperature over night. The solvent was then evaporated, the residual material was triturated 5 times with ca. 4 mL of a mixture of dichloromethane/methanol (30:1), filtered and evaporated in order to separate the product from inorganic salts.
Reaction SMILES: FC1C=CC=CC=1C1C=CN(C)N=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:22]1[CH:23]=[N:24][N:25]([CH3:26])[C:21]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14]
Reactant: Cn1nccc1-c1ccccc1F
Reactant: BrBr
Agent: Cn1ccc(-c2ccccc2F)n1
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1ccccc1F
Reaction time: 0.83 h
Yield: 27.6 %

Procedure:
To a solution of a mixture of 3-(2-fluorophenyl)-1-methyl-1H-pyrazole and 5-(2-fluorophenyl)-1-methyl-1H-pyrazole (6.77 g, 38.4 mmol, 1.0 eq.) in chloroform (10 mL) under nitrogen at 0° C. was added a solution of bromine (2.0 mL, 39.0 mmol, 1.0 eq.) in chloroform (5 mL) over 10 min. After 50 min, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (10:1) as eluent afforded 4-bromo-5-(2-fluorophenyl)-1-methyl-1H-pyrazole as a white solid (2.70 g, 28% yield), a mixture (0.65 g, 7% yield) and 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole as a white solid (5.94 g, 61% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:34]2[C:30](=[N:31][O:32][N:33]=2)[CH:29]=[CH:28][C:27]=1[S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>>[Cl:25][C:26]1[C:34]2[C:30](=[N:31][O:32][N:33]=2)[CH:29]=[CH:28][C:27]=1[S:35]([N:22]1[CH2:21][CH2:20][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:24][CH2:23]1)(=[O:36])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc2nonc2c1Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc5nonc5c4Cl)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7 carboxamide (32 mg, 0.1 mmol), 4-chloro-2,1,3-benzoxadiazole-5-sulfonyl chloride (38 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (8.0 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:33])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([N:16](C)[C:17](=O)OC(C)(C)C)[C@H:12]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][CH3:17])[C@H:12]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:11]2)[C:3]=1[Cl:33])[C:8]#[N:9]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 86.5 %

Procedure:
(+/−)-tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)(methyl)carbamate (Example 186B, 78 mg, 0.158 mmol) was treated with TFA (25% in 1,2-dichloroethane, 0.012 mL, 0.158 mmol) at rt for 1 h. LCMS showed completion of reaction. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 1-10% 2 N ammonia in methanol/dichloromethane) to give (+/−)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(methylamino)piperidin-1-yl)-4-chlorobenzonitrile (54 mg) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>ClCCl>[NH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][N:17]=[CH:16]3)(=[O:27])=[O:28])[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCNCC1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5.02 g of 4-aminomethylpiperidine and 22 g of triethylamine in 50 ml of dichloromethane. Add dropwise over 30 minutes 5.0 g of 5-isoquinoline sulfonyl chloride dissolved in 50 ml of dichloromethane while cooling the mixture in an ice bath. Stir at room temperature for 72 hours. Filter the reaction mixture and evaporate the filtrate. Chromatograph the residue over 400g of silica gel eluting with dichloromethane/methanol (9/1). Obtain the title compound by evaporating the appropriate fractions, as determined by thin layer chromatography. Dissolve the product in ethanol saturated with HCl and evaporate to obtain the title compound as the dihydrochloride salt. FAB MS (M+1)e =306.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH2:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH:23][C:12](=[O:14])[CH2:11][C@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@H](CC(=O)Nc1c(F)cc(F)cc1F)c1cccc2c1OCO2
Reaction time: 8 h
Yield: 86.8 %

Procedure:
In the same manner as in Example 1, 0.86 g (3.25 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid was converted into its acid chloride. This acid chloride was dissolved in 5 ml of methylene chloride and added dropwise to a solution of 571 mg (3.88 mmol) of 2, 4, 6-trifluoroaniline and 0.54 ml (3.9 mmol) of triethylamine in 15 ml of methylene chloride. The reaction mixture was stirred overnight, washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) and recrystallized from a mixed solvent of hexane and a trace of ethyl acetate to give 1.11 g of (R)-N-(2, 4, 6-trifluorophenyl)-3-(2, 3-methylenedioxyphenyl) octanamide as white crystals. Yield, 87%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:12][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[S:11])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cccc(NC(N)=S)c1
Product: CN(C)C=NC(=S)Nc1cccc(C#N)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 3 g (16.9 mmol) 1-(3-Cyanophenyl)-2-thiourea and 20 ml N,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1 h. After evaporation of the volatiles the precipitate was suspended in DCM, filtered and dried to yield 3.56 g (91%) of the title compound.
Reaction SMILES: [OH:1][CH:2](C(O)C)[CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6].I([O-])(=O)(=O)=O.[Na+]>CO.O.C(OCC)C>[CH:2]([CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6])=[O:1]
Reactant: COC1C(OC(=O)C=CC(O)C(C)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC1C(OC(=O)C=CC=O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 6-(4,5-dihydroxy-2-hexenoyloxy)-5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (412 mg) in a mixture of methanol (4 ml) and water (4 ml) was added sodium periodate (215 mg) in several portions at 5° C. The mixture was stirred for half hour at the same temperature and diluted with diethyl ether (30 ml). The mixture was washed with brine, dried, and concentrated in vacuo to give a crude oil, which was purified by column chromatography on silica gel (elution by diethyl etherln-hexane =1/1) to yield 6-(3-formylacryloyloxy)-5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (251 mg) as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=O)(=[O:3])[CH3:2].[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2>O=P(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: Nc1cccc2c1CCC2
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCN=C1Nc1cccc2c1CCC2
Reaction time: 40 h
Yield: 34.6 %

Procedure:
140.9 g (1.1 moles) of 1-acetyl-2-imidazolidinone (melting point 186°-187° C.) are introduced into 1,320 ml of POCl3 and 133.2 g (1 mole) of 4-amino-indan are added dropwise, with vigorous stirring, under conditions such that the internal temperature does not rise above 50° C. After completion of the addition, stirring is continued for 40 hours at 50° C. The excess POCl3 is then distilled off as completely as possible under reduced pressure on a rotary evaporator and the distillation residue is added to 5 l of ice water whilst keeping the temperature at ≤15° C. by further addition of ice. The pH is brought to 11 by means of 25% strength sodium hydroxide solution, whilst cooling with ice, the mixture is repeatedly extracted with chloroform, the combined chloroform phases are again washed with 1 liter of 2 N sodium hydroxide solution and are then washed neutral with water and dried over anhydrous sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from isopropanol. 84.3 g of pure 1-acetyl-(4-indanylamino)-2-imidazoline of melting point 180.5°-182° C. are obtained.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:5]
Reactant: NCCCN1CCCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCCN1CCCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 1-(3-aminopropyl)pyrrolidine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then concentrated. The resulting residue was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(3-(pyrrolidin-1-yl)propyl)acetamide (13.7 mg, 0.025 mmol, 53.5% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.28 Hz), 7.50-7.81 (7 H, m), 5.14 (1 H, s), 3.33-3.41 (2 H, m), 2.90 (4 H, br. s.), 2.78 (2 H, t, J=7.65 Hz), 1.74-2.01 (6 H, m); Analytical LC/MS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.2 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-9H-purine (1.2 g, 6.35 mmol) in N,N-dimethylformamide (5 mL) was added morpholine (553 mg, 6.35 mmol) followed by diisopropylethyl amine (1.2 mL, 6.87 mmol), dropwise via a syringe. The solution was stirred at room temperature for 1 hour until precipitate formed. The reaction mixture was then poured into water and the precipitate was filtered. Upon drying under high vacuum, 2-chloro-6-morpholin-4-yl-9H-purine was isolated as an off-white solid. (1.5 g, 99%) LC/MS analysis method 7, mass (ES+) m/z 240.2 1H NMR (DMSO-d6): 13.21 (1H, brs), 8.15 (1H, s), 4.18 (4H, brs), 3.72 (4H, t)
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])#[N:6]>>[C:5]([C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:3])=[O:11])#[N:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C#N)cccc1C(=O)O
Product: Cc1c(C#N)cccc1C(=O)Cl

Procedure:
75 cc of thionyl chloride and 30 g of 3-cyano-2-methyl-benzoic acid [prepared by process in C. R. Acad. Sci., Vol. 235(1952), p. 1660] were refluxed for 11/2 hours and after cooling, excess thionyl chloride was removed under reduced pressure. The last traces of thionyl chloride were removed by addition of benzene and distillation under reduced pressure. The residue was purified by rectification under reduced pressure to obtain 27.4 g of 3-cyano-2-methyl-benzoyl chloride in the form of colorless crystals melting at 62° C.