Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:32]2[CH2:31][CH2:30][N:29]([S:26]([C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)(=[O:27])=[O:28])[CH2:34][CH2:33]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 1-[(3,4-dichlorophenyl)sulfonyl]piperazine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:19](=[O:20])[O:21][CH2:22][CH3:23])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liter of dichloromethane was added 4.7 ml of ethyl chloroformate and 8.9 ml of diisopropylethylamine. The mixture was stirred for 3 hours at room temperature, concentrated in vacuo to a volume of 500 ml, filtered and the solid washed with 200 ml of dichloromethane to give a tan powder, 11.4 g, mp 232°-235° C.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:7]([OH:9])=[O:8].[CH2:16](O)[CH3:17]>>[NH2:5][C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CC(N)(C(=O)O)c1cccs1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(N)c1cccs1
Yield: 86 %

Procedure:
Thionyl chloride (1 mL, 14.6 mmol) was added dropwise to 2-amino-2-(thiophen-2-yl)propanoic acid (0.500 g, 2.92 mmol) suspended in anhydrous ethanol (10 mL) at 0° then the reaction was heated at reflux for 22 hours. The reaction was concentrated by rotary evaporation, diluted with water (5 mL), adjusted pH to 9 with 6N aqueous sodium hydroxide, and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.498 g, 2.499 mmol, 86%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.17 Hz, 3 H) 1.60 (s, 3 H) 2.53 (s, 2 H) 4.11 (q, J=7.23 Hz, 2 H) 6.91-6.98 (m, 1 H) 7.00 (dd, J=3.68, 1.10 Hz, 1 H) 7.37 (dd, J=5.15, 1.10 Hz, 1 H). MS (DCI) m/z 200 (M+H)+, 217 (M+NH4)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([O:24][C:25]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:44][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[CH2:17]([O:24][C:25]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:44][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Water (0.60 mL), 2-methylphenylboronic acid (0.029 g), sodium carbonate (0.047 g), and bis(triphenylphosphine)palladium(II) dichloride (2.5 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-bromobenzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.10 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C@H:9]1[C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[F:29])C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[N:61]=[CH:62][C:63]3[CH2:69][CH2:68][NH:67][CH2:66][C:64]=3[N:65]=2)[CH2:55][CH2:54]1.C[N:71]([CH:73]=[O:74])C>O>[F:29][C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:19]=1[C@H:15]([NH:71][C:73]([N:67]1[CH2:68][CH2:69][C:63]2[CH:62]=[N:61][C:60]([NH:59][CH:56]3[CH2:55][CH2:54][O:53][CH2:58][CH2:57]3)=[N:65][C:64]=2[CH2:66]1)=[O:74])[C@H:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10]1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 322 (0.341 g, 0.813 mmol) and benzene (8 mL) cooled 0° C. was added TEA (0.154 mL, 1.11 mmol) and diphenylphosphoryl azide (0.239 mL, 1.11 mmol) and the reaction stirred at RT for 1 h then refluxed for 3 h. The reaction was then cooled to RT and a solution of 28 (0.200 g, 0.739 mmol), TEA (0.154 mL, 1.11 mmol) and DMF (3 mL) was added, and stirred at RT for 18 h. The reaction was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 0.360 g (74.9%) of (S)-tert-butyl 5-((S)-(2-fluoro-4-(trifluoromethyl)phenyl)(2-(tetrahydro-2H-pyran-4-ylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)methyl)-2,2-dimethylpyrrolidine-1-carboxylate (324).
Reaction SMILES: [NH4+].[N+:2]([C:5]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([O-:19])(=[O:18])=[O:17])([O-])=O>C(O)(=O)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:2][C:5]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)O

Procedure:
The 2-(2-nitro-4-trifluoromethylphenoxy)-4,5-dichlorobenzenesulfonic acid, ammonium salt (5 g, 11.2 mmol) was dissolved in acetic acid (75 mL). The mixture was diluted with water (75 mL), and a 20% aqueous solution of titanium trichloride (65 mL) was added. After aqueous workup the crude product was flash chromatographed (silica gel, methylene chloride/ethanol/ammonium hydroxide) to give the title compound. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 6.94 (dd, 1H),6.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][CH3:7].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][N:6]([CH3:7])[C:12](=[O:14])[CH3:13]
Reactant: CNCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of (3,4-dichlorobenzyl)-methylamine (0.50 g, 2.63 mmol) (Shapiro et al. J. Amer. Chem. Soc., (1959) 81, 3725) in a mixture of tetrahydrofuran (20 ml) and 40% aqueous sodium acetate (10 ml) was cooled to 0–5° C. (ice bath) and treated with a solution of acetyl chloride (0.3 g in tetrahydrofuran) added dropwise over 5 min. After 1 h at 0–5° C., the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and distillation of the residue in vacuo gave 0.51 g (83% yield) of the title amide as a clear oil: bp 110–120° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers: 2.36 and 2.39 (3H, 2 s, COCH3), 3.16 (3H, s, NCH3), 4.70 and 4.75 (2H, 2 s, NCH2), 7.2–7.7 (3H, m, aromatics). Anal. calcd for C10H11Cl2NO: C, 51.74; H, 4.78; N, 6.03. Found: C, 51.70; H, 4.77; N, 6.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>O>[OH:9][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[S:11]([Cl:10])(=[O:13])=[O:12].[CH2:6]([Cl:8])[Cl:10]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: ClCCl
Product: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Temperature: 24 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Molten 2,4-dichlorophenol (164.27 g) was added to 332 ml of chlorosulfonic acid at 36°-40° C. over one and one-half hours. After a 10 minute hold period at 38°-40° C. the reaction mixture was cooled to 24° C. and held for 1 hour. This solution was then pumped into 500 ml of water which had been cooled to 5° C. External cooling was required to maintain the quench slurry at 60° C. Once the quench was complete, the slurry was cooled to 45° C. and the agitation was stopped to allow the solids to settle. Using a dipstick, 380 ml of supernatent was removed. This volume was replaced with 180 ml H2O and 200 ml CH2Cl2. The organic layer was separated and a second 50 ml wash with CH2Cl2 was obtained and combined with the first to provide 340 ml, 489 g of a 40.3% solution of (C) in CH2Cl2 (81% yield).
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:52][CH2:51][C:48]3[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccncc1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccncc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 60 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with pyridin-4-ylmethanamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide was obtained as a colorless solid in 60% yield: mp 160-162° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.7-8.52 (m, 3H), 8.37 (d, J=5.1 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H), 7.31-7.15 (m, 3H), 4.60 (d, J=4.5 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.13 (d, J=6.9 Hz, 2H), 0.99-0.91 (m, 1H), 0.60-0.49 (m, 2H), 0.29-0.15 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 156.9, 153.2, 149.8, 148.5, 147.3, 142.2, 122.5, 115.8, 108.8, 48.6, 42.8, 41.6, 41.5, 9.0, 3.4; MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: O1CCCC1.[CH2:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(NCc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(NCc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 7 h
Yield: 11.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-benzylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 68-1-4 and 3-ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (190 μL, 1.37 mmol) at room temperature, which was stirred for 7 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (14 mg, 7%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CCC(=O)O)cc2OCC3)n(C(C)C)n1

Procedure:
Methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate was treated with lithium hydroxide to give 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoic acid. M/z 382.2, calc. 381.18
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH2:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:13]
Reactant: CCCCCCCO
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Cl)CC(O)CCCCCC
Yield: 94.1 %

Procedure:
58.30 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 30.00 g of heptanol, 90 g of toluene, 120 g of water and 34.35 g of zinc powder at 45° C., and then the resultant mixture was allowed to react at the same temperature for 10 hours. After the reaction finished, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and then dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 47.14 g of 2-chloroallyl-n-hexylcarbinol. The results were as follows.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:16][C:17]([NH2:19])=[S:18].II.CCO>N1C=CC=CC=1.CCOC(C)=O>[CH3:14][C:13]1[N:16]=[C:17]([NH2:19])[S:18][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: CC(=O)Cc1ccc(-n2cccn2)cc1
Reactant: NC(N)=S
Agent: II
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nc(N)sc1-c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-pyrazol-1-yl-phenyl)-propan-2-one (6.9 g, 34.46 mmol) in pyridine (30 ml) is treated with thiourea (2.6 g, 34.46 mmol) followed by iodine (8.7 g, 34.46 mmol) and heated to 80° C. After 8 hours, the reaction mixture is allowed to cool to room temperature and the resulting suspension is filtered and washed with EtOAc. The filtrate is concentrated in vacuo to afford an oil. The oil is dissolved in EtOAc (200 ml) and washed with NaHCO3 (2×100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford a sticky solid. EtOH is added to the crude residue and the resulting precipitate is filtered and dried to afford the title compound (MH+ 257.29).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:41])[C:30](=[O:40])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:41])=[O:40]
Reactant: CCCCN(C)C(=O)COCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine were added at −15° C. to a solution of 5.52 g of the product of Step B in 55 ml of methylene chloride and the reaction mixture was stirred for one hour at 0° C., then chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 6.22 g of the expected product.
Reaction SMILES: [Mg:1].[CH2:2]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:5]=1)[CH3:3].[Br:19]CCBr>O1CCCC1>[Cl:16][C:10]1[CH:11]=[CH:12][C:13]([Mg:1][Br:19])=[CH:14][C:9]=1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:2][CH3:3])=[CH:18][CH:17]=1
Reactant: [Mg]
Reactant: CCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: BrCCBr
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([Mg]Br)ccc2Cl)cc1

Procedure:
Magnesium powder (34.7 g, 1.446 mol) was charged under argon into a three-necked flask followed by the addition of a portion of a solution of 2-(4-ethylbenzyl)-4-bromo-1-chlorobenzene (122.5 g, 0.398 mol) in anhydrous tetrahydrofuran (0.4 L) and 1,2-dibromoethane (2.89 g, 1.34 mL, 0.015 mol). The mixture was heated to reflux and after reaction initiation (exothermic and consuming magnesium), the rest of the solution of 2-(4-ethylbenzyl)-4-bromo-1-chlorobenzene (245.0 g, 0.796 mol) in anhydrous tetrahydrofuran (0.81 L) was added dropwise. The mixture was then allowed to react for another 1 h under gentle reflux until most of the magnesium was consumed.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.F.F.F.C(N(CC)CC)C.[F:23]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C(N(CC)CC)C>[F:23][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cnc(CO)cn1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(CF)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)pyrazine-2-carboxylate (0.64 g) in THF (20 mL) was added triethylamine (2.30 g) and the solution was cooled to 0° C. Triethylamine trihydrofluoride (1.22 g) was then added followed by nonafluorobutanesulfonyl fluoride (2.28 g) dropwise over 5 mins. After warming to RT and stirring for 2 h, NaHCO3 (sat., aq., 100 mL) was added, and the mixture was extracted with EtOAc (2×50 mL). The combined organic portions were dried over MgSO4, evaporated, and purified by silica gel chromatography (5% to 50% EtOAc in hexane) to afford the title compound (94 mg). 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3 H), 5.67 (d, J=46.5 Hz, 2 H), 8.89 (s, 1 H), 9.28 (s, 1 H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[N:5][O:4][CH3:3])[C:7]1=[O:15])[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: CON=C1C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(=NOC)c2ccccc21)OCC
Temperature: 70 °C
Reaction time: 45 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (prepared by washing 50 g of 60% oily sodium hydride with hexane) in 1 l of N,N-dimethylformamide was added dropwise a solution of 176 g of 3-methoxyiminoindolin-2-one in 3 l of N,N-dimethylformamide at 0° C. in a nitrogen stream. To the mixture were added 1 l of N,N-dimethylformamide and 330 ml of bromoacetaldehyde diethyl acetal, and the mixture was heated to 70° C., at which it was stirred for 45 hours. The reaction mixture was concentrated, and the concentrate was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 284 g (97%) of 1-(2,2-diethoxyethyl)-3-methoxyiminoindolin-2-one.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24]([OH:32])(=[O:31])[C:25]([CH2:27][C:28](O)=[O:29])=[CH2:26]>>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:26][CH:25]([C:24]([OH:32])=[O:31])[CH2:27][C:28]2=[O:29])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Product: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N2CC(C(=O)O)CC2=O)cc1

Procedure:
The title compound was prepared from trans-N-decyl-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized twice from ethanol to give a 47% yield of material having a melting point of 214°-215° C. The infrared spectrum (KBr disc) showed absorptions at 3280, 3125, 1680 and 1625 cm-1.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].C(N(CC)CC)C>C(O)CCC>[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1cccc(O)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCCO2)c1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 3-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-butanol for 3 hours. After removal of the n-butanol by vacuum evaporation water was added to remove the n-butanol residues. The resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity >99%. 1H-NMR (400 MHZ, DMSO): 1.57m (2H); 1.70m (1H); 1.95m (2H); 2.27qq (1H, Ja=11.7 Hz, Jb=4.0 Hz); 3.66m (1H); 4.0d (1H); 4.63bs (2H); 5.67dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.58dd (1H, Ja=8.2 Hz, Jb=1.5 Hz); 6.73 (d, 1H, J=7.7 Hz); 7.07t (1H, J=7.7 Hz); 8.21 s (1H); 8.33bs (1H); 8.36bs (1H); 9.26 (1H). MS (ES): [M+H]+=326 (100).