Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=[CH:10][C:9]=2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][C:20]=1[CH3:29])=[O:5])[CH3:2].[C:30]1(C)[C:31]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.Cl[CH2:42]Cl>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][O:18][S:36]([C:31]1[CH:30]=[CH:35][C:34]([CH3:42])=[CH:33][CH:32]=1)(=[O:37])=[O:38])=[CH:12][CH:11]=[CH:10][C:9]=2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][C:20]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC)cc3C)cccc2c1CCCO
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC)cc3C)cccc2c1CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 127B (2.0 g), toluene-2-sulfonyl chloride (1.16 g) in dichloromethane (30 mL) was added DMAP (0.305 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate mixture, 3% aqueous HCl, water and brine. After drying over Na2SO4 and filtering, the mixture was concentrated.
Reaction SMILES: [Cl-:1].[NH4+:2].CO[C:5]1[CH:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][N:9]=1>C(O)C>[Cl-:1].[CH2:13]([CH:6]1[CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][NH:9][C:5]1=[NH2+:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [NH4+]
Reactant: CCCC1CN=C(OC)C1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: CCCC1CNC(=[NH2+])C1Cc1ccccc1
Yield: 60 %

Procedure:
Ammonium chloride (155 mg, 2.9 mmol) was added to a solution of 4-benzyl-3-propyl-3,4-dihydro-2H-5-pyrrolyl methyl ether (0.67 g, 2.9 mmol) in ethanol (15 ml) and the mixture was heated to reflux for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The residue was crystallized from ethyl acetate to yield the title compound (440 mg) as a white crude product. 1H-NMR (DMSO-d6) δ(ppm) 0.62 (3H, t, J=7.2 Hz), 0.87-1.20 (4H, m), 2.01-2.15 (1H, m), 2.72-2.85 (1H, m), 2.88-2.98 (1H, m), 3.05-3.25 (1H, m), 3.50-3.62 (1H, m), 7.19-7.40 (5H, m)
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([C@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=O)[CH:11]=[CH2:12].Cl.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[CH2:10]([C@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:16])[CH:11]=[CH2:12]
Reactant: C=CC[C@H](CCCC)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CCCC)C(=O)NCC(=O)OC
Reaction time: 18 h
Yield: 82.5 %

Procedure:
Step B (1): DIEA (1.35 mL, 9.9 mmol) was added to a mixture of (S)-2-allylhexanoic acid (300 mg, 1.92 mmol), methyl 2-aminoacetate hydrochloride (254 mg, 2.02 mmol), EDC (387 mg, 2.02 mmol), HOBt (273 mg, 2.02 mmol) in DMF (15 mL) at room temperature. The mixture was stirred for 18 h. Poured the reaction mixture into 200 mL 1 M HCl. Extracted with EtOAc/Hex (95:5) (2×200 mL). Washed combined organic extracts with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes linear gradient) to give (S)-methyl 2-(2-allylhexanamido)acetate 360 mg (83% yield) as white solid: ESI (M+H)+=228.2; 1H NMR (500 MHz, CDCl3) δ 5.90 (s, 1H), 5.64-5.85 (m, 1H), 4.95-5.14 (m, 2H), 4.04 (dd, J=5.04, 2.29 Hz, 2H), 3.75 (s, 3H), 2.28-2.46 (m, 1H), 2.07-2.29 (m, 2H), 1.62-1.64 (m, 1H), 1.46-1.47 (m, 1H), 1.18-1.36 (m, 4H), 0.87 (t, J=6.87 Hz, 3H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][CH2:18][OH:19].N1C=CC=C[CH:21]=1>>[C:3]1([CH3:21])[C:4]([S:7]([O:19][CH2:18][CH2:17][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:12]2)(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: OCCC1CCCC1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)OCCC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A para-toluenesulfonyl chloride (16.0 g, 83.8 mmol) was added to the pyridine (250 ml) solution of (2-cyclopentyl)ethyl alcohol (8.76 g, 76.2 mmol) and then the reaction mixture was stirred at room temperature for 6 hrs. After the removement of pyridine, the residue was extracted with ethyl acetate, washed with 1N HCl, dried, filtered and separated by column chromatography to give a desirable product (15.7 g).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)(=O)=O.[CH3:18][NH:19][CH3:20]>CO.O1CCCC1>[CH3:18][N:19]([CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)[CH3:20]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (1.05 g) in methanol (20 ml) was added a 2M solution of dimethylamine in tetrahydrofuran (20 ml), followed by heating in a sealed tube at 70° C. for 40 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide the titled compound as a yellow oil (678 mg, 79.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC=Cc1ccc(Cl)c(Cl)c1
Yield: 90.9 %

Procedure:
3-(3,4-Dichlorophenyl)prop-2-en-1-ol(1.0 g)(prepared by analogy to Example 2(i) and Example 1(ii)) was oxidised using the procedure of Swern (oxalyl chloride, 0.5 ml; dimethyl sulphoxide, 0.7 ml; triethylamine 3.4 ml) to give 3-(3,4-dichlorophenyl)-prop-2-enal (0.9 g). NMR 1H: 9.76(1H,d), 7.53(3H,m), 7.41(1H,d), 6.68(2H,dd).
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[C:11]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[C:12](Br)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1Br)[CH3:2].C([Li])CCC.CN([CH:39]=[O:40])C.[O:41]1CCC[CH2:42]1>>[CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[C:11]([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[C:12]([CH:42]=[O:41])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH:39]=[O:40])[CH3:2]
Reactant: C1CCOC1
Reactant: CCCCC(CC)COc1c(Br)ccc2c(OCC(CC)CCCC)c(Br)ccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CCCCC(CC)COc1c(C=O)ccc2c(OCC(CC)CCCC)c(C=O)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
After 1.0 g of 1,5-bis-(2-ethylhexyloxy)-2,6-dibromonaphthalene (1.8 mmol) was dissolved in 20 mL of tetrahydrofuran (THF), a temperature was raised to −78° C., and n-butyl lithium was slowly added thereto for 30 minutes. The mixture was stirred at −78° C. for 2 hours, and then 0.46 g of DMF (6.3 mmol) was slowly added thereto for 10 minutes and further stirred for 30 minutes. After a temperature was raised to room temperature and the reactant was stirred for 1 hour, the reaction was terminated by cool water, and the resultant was extracted with ethylacetate, followed by distillation under reduced pressure and column chromatography, thereby obtaining 1.1 g of the title compound (45.0%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl.O>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.391 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and acetyl chloride (61 mg, 0.777 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C([Li])CCC.CCCCCCC.CN([CH:28]=[O:29])C>CC(O)=O.C1COCC1>[CH:28]([C:3]1[CH:2]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:12])[NH:8]2)=[O:29]
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=Cc1cccc2c1CCC(=O)N2
Temperature: -78 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
Following the procedure reported above for 2-ethyl-5-formyl-2H-1,2,3,4-tetrahydroisoquinolone described above, 6-bromo-1,2,3,4-tetrahydroquinol-2-one (1.07 g, 4.73 mmol), a solution oft-butyllithium in heptane (1.7M, 9.7 mL, 16.6 mmol), DMF (0.37 mL, 4.73 mmol) and THF 35 mL) were combined. The reaction mixture was stirred at −78° C. for 4 h and HOAc (1 mL) was added. The previously described workup provided crude product. Column chromatography (EtOAc:hexane::1:1, then DCM:MeOH::97:3) and removal of solvent in vacuo provided a white solid (116 mg, 14% yield): 1H NMR: 9.90 (s, 1H), 8.0 (s, 1H), 7.77–7.74 (m, 2H), 6.89 (d, 1H, J=8), 3.07 (t, 2H, J=7), 2.71 (t, 2H, J=7).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:16]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:18]=[N:19][CH:20]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:26][N:27]=[C:28]=[O:29]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:16]=[C:17]([CH:21]([NH:23][C:28]([NH:27][CH3:26])=[O:29])[CH3:22])[CH:18]=[N:19][CH:20]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3cncc(C(C)N)c3)s2)cc1
Solvent: ClCCl
Product: CNC(=O)NC(C)c1cncc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of Example 4D (0.32 g, 0.0009 mol) in methylene chloride (15 mL) was added excess methyl isocyanate (0.25 mL) and the mixture was stirred at room temperature for 0.5 hours. After quenching with methanol (10 mL), the solvent was concentrated and the residue was purified on silica gel (75˜100% ethyl acetate in hexane) to give 0.28 g of the title compound (76% yield). 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.29 (d, J=6.25 Hz, 6 H) 1.34 (d, J=6.99 Hz, 3 H) 2.51 (d, J=4.78 Hz, 3 H) 4.55-4.70 (m, 1 H) 4.71-4.85 (m, 1 H) 5.72 (q, J=4.41 Hz, 1 H) 6.48 (d, J=8.09 Hz, 1 H) 6.96-7.07 (m, 2 H) 7.28-7.39 (m, 2 H) 7.77-7.81 (m, 1 H) 7.83 (s, 1 H) 8.42 (d, J=1.84 Hz, 1 H) 8.67 (d, J=2.21 Hz, 1 H). MS (ESI), m/z 413.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:28]2[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)=[CH:30][N:29]=2)[N:18]=1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.35 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by the addition of sodium tert-butoxide (NaOtBu) (0.041 g, 0.42 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.075 g, 0.32 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 97:3) 2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.104 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH2:39]([N:47]1[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N1CCC(=O)CC1)CC1C=CC=CC=1>>[C:41]1([CH2:40][CH2:39][N:47]2[CH2:52][CH2:51][CH:50]([NH:53][C:13]([C:9]3[CH:10]=[N:11][C:12]4[C:7]([C:8]=3[NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH2:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[CH2:28][CH2:27]5)=[O:24])=[CH:19][CH:18]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:15])[CH2:49][CH2:48]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: NC1CCN(CCc2ccccc2)CC1
Agent: O=C1CCN(CCc2ccccc2)CC1
Product: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)NC3CCN(CCc4ccccc4)CC3)cnc12

Procedure:
N-[1-(2-Phenylethyl)-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)- 4piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 1-phenethyl-4-aminopiperidine as described for Example 17, Step 5. 1-phenethyl-4-aminopiperidine can be prepared from 1-phenethyl-4-piperidone as described in U.S. Pat. No. 3,875,165: mp 216°-220 ° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.51 (s, 1 H), 8.79 (s, 1 H), 8.40 (d, 5=7.7 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 7.71 (d, J=8.7 Hz, 2 H), 7.57 (d, J=8.5 Hz, 1 H), 7.41 (m, 1 H), 7.10- 7.35 (m, 11 H), 6.88 (d, J=8.7 Hz, 2 H), 3.93 (s, 3 H), 3.7-3.8 (m, 1 H), 3.4-3.6 (m, 3 H), 2.6-2.9 (m, 6 H), 2.4-2.5 (m, 2 H), 1.85-2.10 (m, 4 H, 1.7-1.8 (m, 2 H), 1.5-1.7 (m, 4 H), 1.3-1.5 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH2:2][C:3]12[CH2:8][O:9][C:10]([CH3:11])([O:7][CH2:6]1)[O:5][CH2:4]2
Reactant: CCOC(C)(OCC)OCC
Reactant: OCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC12OCC(CO)(CO1)CO2
Temperature: 125 °C
Yield: 93 %

Procedure:
To a suspension of pentaerythritol (13.6 g, 0.100 mol) in 10 mL of toluene was added freshly distilled triethyl orthoacetate (16.2 g. 18.3 mL, 0.100 mol) and p-toluenesulfonic acid monohydrate (50 mg). The mixture was slowly heated in an oil bath and ethanol was distilled from the mixture over a period of 12 hrs. After removal of the ethanol, the bath temperature was raised to 125° C. and toluene was distilled off until the solution was homogeneous (about 30 mL). The residue was sublimed (bulb to bulb, ~130--C, 2.5 mmHg) to give 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.21octane (15.0 g, 0.093 mol, 93%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncccc2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (183 mg, 0.77 mmol) in methylene chloride (4.30 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.28 g, 0.92 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.32 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 156 mg, 1.0 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1-2% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (21.9 mg, 7.6%); ES+-HRMS m/e calcd for C19H27N5O3 [M+H+] 374.2187 found 374.2187. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.72 (m, 9H), 1.05 (s, 3H), 1.06 (s, 3H), 1.92 (m, 1H, CH), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.94 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.42 (dd, Jo=9.4, Jo=3.8 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.00 (dd, Jo=3.8 Hz, Jm=1.5 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:5])[CH3:4].CCCCCC.C(OCC)(=O)C>ClCCl>[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([Br:1])[CH:11]=[C:10]1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(=O)c1cccn1CCOC(C)=O
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1cc(Br)cn1CCOC(C)=O
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
Three ml (58.3 mmole) of bromine is added in a dropwise manner to a stirred solution of 14.77 g (58.3 mmole) of ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxalate in 200 ml anhydrous dichloromethane, cooled to -75° C. After the addition, the reaction is left at -75° C. for 2.5 hours and then the temperature is allowed to increase to room temperature. The solvent is removed in vacuo, dichloromethane is added to the residue and the solution is washed successively with water, 10% sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. The crude product thus obtained (18.3 g) is subjected to column chromatography on Florisil (1 Kg) using hexane-ethyl acetate (9:1) as the eluting solvent. There is thus obtained upon removal of the solvent, 10.9 g (56%) of ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glyoxalate as an oil having the following physical constants:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1)=[CH2:2].[CH2:12](N(CC)CC)[CH3:13].S(OCC)(OCC)(=O)=O>C(OCC)(=O)C.C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([N:7]1[C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=[C:3]1[CH:1]=[CH2:2])[CH3:13]
Reactant: C=Cc1nc(C#N)c(C#N)[nH]1
Reactant: CCN(CC)CC
Agent: CCOS(=O)(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1nc(C#N)c(C#N)n1CC
Yield: 65 %

Procedure:
A flask equipped with a magnetic stirbar was charged with 6.26 g of 2-vinyldicyanoimidazole. To this, 75 ml of distilled THF and 6.1 ml of triethylamine were added with stirring. After 5 minutes stirring, 5.7 ml of diethyl sulphate was added. This mixture was allowed to stir for 2 days. Analysis by TLC (50/50 hexane/ethyl acetate, UV visualization) showed the reaction was complete (starting material rf 0.3, product rf 0.6). The THF solution was rotovapped and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with 10% aqueous sodium hydroxide. The combined aqueous layers were back extracted with methylene chloride. The combined organic layers were dried with magnesium sulphate and rotovapped to dryness. The crude residue was triturated with ether. The ether extracts were rotovapped and the residue recrystallized with ether/hexanes to yield 3.124 g of the product, mp 66-70° C. as yellow needles. A second crop yielded 1.72 g for a combined yield of 65%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[ClH:1].[CH:20]([NH:23][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)([CH3:22])[CH3:21]
Reactant: CC(C)N
Reactant: ClCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: c1ccccc1
Product: CC(C)NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: Cl

Procedure:
A mixture of 8 g. 2-chloromethyl-4,5-diphenyloxazole (prepared as described in Example 1 a), 8g. isopropylamine and 50 ml. anhydrous benzene was kept in a stoppered flask for 48 hours at room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:18]([O:27]C(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:19][B:18]([OH:27])[OH:23])=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: N#Cc1cc(OB(O)O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2-(Benzyloxy)-5-bromobenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene, and at −78° C., an n-butyllithium/hexane solution was dropwise added. This was heated up to room temperature, and 1 M hydrochloric acid was added to the reaction mixture, followed by stirring to obtain [4-(benzyloxy)-3-cyanophenyl]boric acid. ES: 254.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[CH3:64][O:65][C:66](C1C=CC(B(O)O)=CC=1)=[O:67]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([C:66]([O:65][CH3:64])=[O:67])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: COC(=O)c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and (4-methoxycarbonylphenyl)boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 26.35 min.; purity: 90%; MS (m/e): 514 (MH+).