Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]SC1C=CC(Cl)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](C(OO)=O)[CH:19]=1.[S:28]([O-:31])([O-])=[O:29].[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:28]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)(=[O:31])=[O:29]
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCCCCCCCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 1 -bromo-7-(4-chlorophenylthio)heptane (1.19 g) in dichloromethane (20 ml) at −20° C. was added metachloroperbenzoic acid (60%, 2.23 g) portionwise over 15 min. The mixture was allowed to warm to room temperature over 1 h and was shaken with aqueous sodium sulfite/sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using 50:50 hexane:dichloromethane as eluent to give 1-bromo-7-(4-chlorophenylsulfonyl)heptane (1.17 g). 1H-NMR (CDCl3) δ 1.2-2.0 (10H, m), 3.07 (2H, m), 3.38 (2H, t), 7.5-7.6 (2H, m) and 7.8-7.9 (2H, m).
Reaction SMILES: C(O)C1C=CC=CC=1.[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([O-])=O>CCOCC.C(O)C.[Pt]=O>[NH2:21][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: O=C(OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCOCC
Solvent: OCc1ccccc1
Product: Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Benzyl alcohol (10 g, 92.6 mmole) was treated with a solution of m-nitrobenzoyl chloride (17.5 g, 94.5 mmole) in ether (50 ml) added dropwise. The mixture was stirred at room temperature for eighteen hours, then washed twice with aqueous sodium bicarbonate, dried over sodium sulfate, and filtered. The filtrate was evaporated to dryness in vacuo and the residue chromatographed on silica gel eluted with 1:1 CH2Cl2 :hexane. The product fractions were combined and evaporated to dryness in vacuo. A portion (5.2 g, 20.2 mmole) of the resulting benzyl m-nitrobenzoate was dissolved in ethanol and hydrogenated over platinum oxide (70 mg) at 50 psi of H2. The resulting mixture was filtered and evaporated to dryness in vacuo to give benzyl m-aminobenzoate.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14](S(N2CCC(C3C4C(=CC=C(F)C=4)N(S(CC[Si](C)(C)C)(=O)=O)C=3)CC2)(=O)=O)[CH:13]([C:45]([OH:47])=O)[CH2:12]1)=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:54]O.CO>C(Cl)Cl.CN(C=O)C>[NH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:45]([NH2:54])=[O:47]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)O)CC2)c2cc(F)ccc21
Reactant: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C1CNCCN1
Temperature: 25 °C
Reaction time: 14 h
Yield: 483.9 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-(4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl)piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacua, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trithylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-j4-[5-fluoro-1-2-trmethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl ) piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[S:7][CH:6]=1)=[O:4].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(C=O)c1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1csc(C(O)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A solution of 5-formyl-thiophene-3-carboxylic acid methyl ester (0.504 g, 2.96 mmol) in Et2O (30 mL) at 0° C. is treated with neopentyl magnesium chloride (7.1 mL, 0.5 M in Et2O, 3.6 mmol) and stirred for 15 min. Solution warmed to rt and additional Et2O (10 mL) added. The reaction mixture is stirred overnight at rt. after which it is poured into H2O (30 mL) and extracted with EtOAc (3×50 mL). Combined extracts washed with brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 50%. The resulting mixture is then loaded onto C18 and eluted using H2O and a MeCN gradient from 15% to 100% giving (±)-5-(1-hydroxy-3,3-dimethyl-butyl)-thiophene-3-carboxylic acid methyl ester (0.316 g, 44%) as a light yellow syrup.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]([C:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:15](C(OC(C)(C)C)=O)[CH:14]=1)=O.C(=O)(O)O.[C:35]1([NH:41][C:42]([NH2:44])=[NH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>COCCO>[C:35]1([NH:41][C:42]2[N:44]=[C:11]([C:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[NH:15][CH:14]=3)[CH:10]=[CH:9][N:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)C#C[Si](C)(C)C)c2cnccc21
Reactant: N=C(N)Nc1ccccc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: c1ccc(Nc2nccc(-c3c[nH]c4ccncc34)n2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.2 104 mg (0.75 mmol) of potassium carbonate are added to a solution of 103 mg (0.30 mmol of tert-butyl 3-(3-trimethylsilylpropynoyl)pyrrolo-[3,2-c]pyridine-1-carboxylate and 148 mg (0.75 mmol) of phenylguanidine carbonate in 1.5 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 68 hours. After cooling, 10 ml of water are added, and the mixture is stirred at 40° C. for 1 h. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving phenyl-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl]amine (“A1”) as pale-brown solid; ESI 287;
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH:24]1([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:38]([C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:29]([C:27]([CH:24]2[CH2:25][CH2:26]2)=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(C1CC1)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Diisopropylethylamine (0.33 ml, 2.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.2 g, 1.0 mmol) in DCM (5 ml) at room temperature. To this mixture was added 1-cyclopropanecarbonyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (0.29 g, 1.0 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, dried with diethyl ether and dried under vacuum give the title compound (0.36 g, 73% yield) as a pale yellow solid. Tr=2.02 min m/z (ES+) (M+Na+) 472.
Reaction SMILES: BrC1C=C(Br)C2N(C(C(=O)C)=C(C3C=CC(F)=CC=3)N=2)C=1.[Br:22][C:23]1[CH:24]=[C:25]([Br:46])[C:26]2[N:27]([C:29]([C:39](=O)/[CH:40]=[CH:41]/N(C)C)=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:31]=2)[CH:28]=1.[CH:47]1([NH:52][C:53]([NH2:55])=[NH:54])[CH2:51][CH2:50][CH2:49][CH2:48]1>COC(OC)N(C)C>[CH:47]1([NH:52][C:53]2[N:55]=[C:39]([C:29]3[N:27]4[CH:28]=[C:23]([Br:22])[CH:24]=[C:25]([Br:46])[C:26]4=[N:31][C:30]=3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:40]=[CH:41][N:54]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nc2c(Br)cc(Br)cn12
Agent: CC(=O)c1c(-c2ccc(F)cc2)nc2c(Br)cc(Br)cn12
Agent: COC(OC)N(C)C
Product: Fc1ccc(-c2nc3c(Br)cc(Br)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 54 %

Procedure:
In a similar manner as described in Example 1 treatment of 1-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethanone (850 mg, 2.1 mmol) with N,N-dimethylformamide dimethyl acetal (30 mL), followed by condensation of the resulting (2E)-1-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one with cyclopentyl guanidine gave N-cyclopentyl-4-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (600 mg, 54% for two steps) as a yellow solid. 1H NMR (CDCl3): δ 9.98 (broad s, 1H), 8.13 (d, 1H), 7.71 (d, 1H), 7.68 (q, 2H), 7.14 (t, 2H), 6.40 (d, 1H), 5.61 (d, 1H), 4.36 (m, 1H), 2.0–2.2 (m, 2H), 1.4–2.0 (m, 6H); 19F NMR (CDCl3) δ −112.5; MS m/z 530 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Cl:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.[Si](C#N)(C)(C)C.[N:27]1([C:32](N2C=CN=C2)=[O:33])C=CN=[CH:28]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:14]([C:13]4[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:12]=4[Cl:11])[CH2:28][NH:27][C:32]3=[O:33])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cccc(Cl)c2Cl)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,3-dichloro-benzaldehyde (0.700 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.5 mL, 3.6 mmol), di-(imidazol-1-yl)methanone (0.308, 1.9 mmol) as described in method 2. Yield: 0.014 g (1%); MS m/z 347.2 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 3.08-3.11 (m, H); 3.96-4.01 (m, H); 5.83-5.86 (m, H); 7.09 (s, H); 7.24-7.30 (m, 3H); 7.44 (s, H); 7.52-7.56 (m, 2H); 8.08 (s, H); 12.23 (bs, H), HPLC (λ=214 nm, [B]: rt 9.28 min (94.1%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([N:13]([C:16]([C:18]2[C:23]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=3)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=2)=[O:17])[CH2:14][CH3:15])=[N:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:14]([N:13]([C:10]1[CH:11]=[CH:12][NH:8][N:9]=1)[C:16]([C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)(=[O:27])=[O:26])=[CH:22][C:21]([Cl:39])=[CH:20][N:19]=1)=[O:17])[CH3:15]
Reactant: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccn(C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylic acid tert-butyl ester from step 2 was dissolved in a mixture of DCM and TFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated, purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-(1H-pyrazol-3-yl)-amide: 1H NMR (400 MHz, CDCl3) δ 8.11 (d, 1H), 8.0 (d, 1H), 7.94 (m, 1H), 7.88 (br, 1H), 7.6 (d, 1H), 7.37 (br, 1H), 5.8 (s, 1H), 3.8 (m, 2H), 1.1 (m, 3H); MS m/z: 508 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([Cu])#[N:10].[OH-].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Br)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A stirred solution of 2,5-dibromopyridine (39.465 g, 0.17 mol) in anhydrous NMP (100 mL) was treated with CuCN (14.42 g, 0.17 mol) for 20 hours at 110° C. under nitrogen. The reaction mixture was cooled to 40° C. and treated with aqueous sodium hydroxide (2M; 200 mL) and then with ethyl acetate (200 mL). The mixture was stirred for 1 hour and then filtered through Celite to remove the resulting precipitate. The retained solid was washed with aqueous sodium hydroxide (2M; 600 mL) and then with ethyl acetate (600 mL). The organic layers were combined and washed with aqueous ammonium hydroxide (5M; 800 mL), dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The involatile residue was purified by chromatography on silica gel [elution gradient 1% to 7% of ethyl acetate in hexanes] to give the title compound (8.538 g, 28%), as a colorless amorphous solid.
Reaction SMILES: [FH:1].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[CH:18]1(O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[F:1][CH:18]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH:18]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: F
Reactant: OC1CCCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=CCCCCCC1
Product: FC1CCCCCCC1
Reaction time: 19 h

Procedure:
Procedure for the fluorination of alcohols (examples 74-84): To a suspension of the disubstituted aminodifluorosulfinium salt (1.5 mmol), triethylamine trihydrofluoride (326 μL, 2.0 mmol) and triethylamine (139 μL, 1.0 mmol) in dichloromethane (3.0 mL), at room temperature and under nitrogen, is added cyclooctanol (132 μl, 1.0 mmol). The reaction mixture is stirred for 19 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using dichloromethane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide fluorocyclooctane of admixed with cyclooctene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[Cl:24][CH2:25][C:26](OCC)(OCC)OCC>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[Cl:24][CH2:25][C:26]1[NH:8][C:7]2[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:19])[F:20])[CH:10]=3)[N:4]=[C:3]([C:22]#[N:23])[C:2]=2[N:1]=1
Reactant: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Reactant: CCOC(CCl)(OCC)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Yield: 41.9 %

Procedure:
3,4-Diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (1 g, 3.1 mmol) was dissolved in acetonitrile (20 ml) and ytterbium triflate (38 mg, 0.062 mmol) and 2-chloro-1,1,1-triethoxyethane (1.83 g, 9.3 mmol) were added. The mixture was heated to reflux overnight. Mixture was evaporated under reduced pressure, partitioned between ethyl acetate (100 ml) and water (100 ml), and organics were dried then evaporated under reduced pressure to afford a dark brown oil. Triturated with DCM (50 ml) to afford 495 mg of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a light brown solid. 1H NMR (DMSO) δ 8.47-8.33 (m, 3H), 7.41 (d, 1H), 5.05 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). MS m/z 381.1 (M+1).
Reaction SMILES: ClCC1C=CC(CC[Si](OC)(OC)[O:12]C)=CC=1.[SiH4].C(=S)([S-])N.[Na+].[C:24]([O-:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].[C:30]1([CH3:36])C=CC=C[CH:31]=1>O.CC(C)=O>[CH3:26][C:25]([C:24]([O:29][CH2:36][CH:30]1[O:12][CH2:31]1)=[O:28])=[CH2:27]
Reactant: Cc1ccccc1
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCc1ccc(CCl)cc1)(OC)OC
Agent: NC(=S)[S-]
Agent: [Na+]
Agent: [SiH4]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCC1CO1

Procedure:
First, a magnetic structure 2 having a coating layer 16 on the surface thereof is prepared. Magnetite particles are heated under a dry N2 atmosphere and are then dispersed in anhydrous toluene. To this magnetite particle/toluene dispersion liquid, 2-(4-chloromethylphenyl)ethyltrimethoxysilane as a silane-coupling agent is added for introducing a chloromethyl group to the magnetite particles. This reaction can be confirmed by detecting Cl atoms by XPS. The magnetite particles to which chloromethyl group is introduced are dispersed in water. Sodium dithiocarbamate is added thereto for the reaction with the chloromethyl group. Thus, an initiating point for UV graft polymerization is introduced to the surfaces of the magnetite particles. This reaction can be confirmed by detecting N atoms and S atoms by XPS. Then, the magnetite particles and acetone are weighed into a reaction vessel and the magnetite particles are dispersed in the acetone by sonication. Then, glycydil methacrylate is weighed into the reaction vessel, and the reaction vessel is purged with nitrogen. Then, UV graft polymerization is performed with UV light of a wavelength of 312 to 577 nm irradiated by a UV lamp at room temperature for 2 hr to form polyglycidyl methacrylate on the surfaces of the magnetite particles. This reaction can be confirmed by an increase in the particle diameters measured by a dynamic light scattering method.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20]CC)=[O:19])[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:24])=[O:25])[C:18]([OH:20])=[O:19])[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (740 mg, 1.82 mmol) in tetrahyrofuran/methanol/water (4:1:1, 18.2 mL) was added lithium hydroxide monohydrate (152 mg, 3.63 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1N in water) and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid as a solid. 674.9 mg.
Reaction SMILES: [Cl:1][C:2]([Cl:8])([Cl:7])[C:3](=N)OC.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[F:24]>C(O)(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[N:23]=[C:3]2[C:2]([Cl:8])([Cl:7])[Cl:1])=[CH:12][C:11]=1[F:24]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Solvent: CC(=O)O
Product: Fc1cc(-n2c(C(Cl)(Cl)Cl)nc3cccnc32)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 2,2,2-trichloroethanimidoate (0.743 mL, 6.00 mmol) was added to a solution of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) (951 mg, 4.00 mmol) in acetic acid (4 mL), and the reaction mixture was stirred at room temperature for 5 hours. After concentration in vacuo, the residue was purified via chromatography on silica gel (Gradient: 5% to 100% ethyl acetate in heptane) to afford the product as a white solid. Yield: 1.04 g, 2.85 mmol, 71%. LCMS m/z 366.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (dd, J=8.1, 1.5 Hz, 1H), 7.64 (ddd, J=8.5, 7.8, 0.3 Hz, 1H), 7.42 (dd, J=8.1, 4.7 Hz, 1H), 7.39 (ddd, J=8.8, 2.4, 0.2 Hz, 1H), 7.32 (ddd, J=8.5, 2.4, 1.3 Hz, 1H).
Reaction SMILES: [C:1](CP(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:27][CH2:28][C:29]#[CH:30])[C:22]=1[O:23][CH2:24][C:25]#[CH:26])[CH:18]=O.[CH3:31]N(C)C=O>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18](=[CH2:31])[C:1]#[N:2])[CH:20]=[C:21]([O:27][CH2:28][C:29]#[CH:30])[C:22]=1[O:23][CH2:24][C:25]#[CH:26]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C#CCOc1cc(C(=C)C#N)cc(Cl)c1OCC#C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diethyl cyanomethylphosphonate (1.42 g) was dissolved in dimethylformamide (50 ml), and sodium hydride (0.32 g; 60% dispersion in mineral oil) was added thereto at 0° C. under cooling. After the foaming ceased, 3-chloro-4,5-dipropargyloxybenzaldehyde (2.00 g) was added to the reaction mixture, which was stirred at room temperature overnight, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(3-chloro-4,5-dipropargyloxyphenyl)acrylonitrile (1.85 g). m.p., 110°-111° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C.C(OCC)(=O)C.O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)CCO
Product: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)nc1
Temperature: 25 °C

Procedure:
A solution of 1.0 g (6.4 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 1.77 g (12.8 mmol) of 2-chloro-5-cyanopyridine and 2.71 g (25.6 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated at reflux for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate, the layers were separated, and the aqueous layer extracted with ethyl acetate. The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give (7S,8aS)-7-hydroxymethyl-2-(5-cyanopyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine.
Reaction SMILES: I[C:2]1[C:3]([NH2:14])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:29](=O)([O-])[O-:30].[Cs+].[Cs+]>CO.[Cu]I>[CH3:29][O:30][C:2]1[C:3]([NH2:14])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(N2CCOCC2)ncc1I
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cnc(N2CCOCC2)cc1N
Temperature: 130 °C
Yield: 49.6 %

Procedure:
A stirred suspension of 81.4 g (267 mmol) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine, 4.06 g (21.3 mmol) copper(I) iodide, 5.77 g (32.0 mmol) 1,10-phenanthroline and 174 g (533 mmol) cesium carbonate in 600 ml methanol was heated at 130° C. for 30 min in a microwave oven. The resulting mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (1/7 methanol/dichloromethane) to afford 27.7 g (50%) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine as a dark brown crystalline solid. ES-MS m/e (%): 210 (M+H+, 100).