Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24]I)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:27]#[N:28]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][C:27]#[N:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CCI
Agent: Cl
Product: N#CCCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 4-(4-chloro-benzenesulfonyl)-5,8-difluoro-3-(2-iodo-ethyl)-chroman (3.47 g, 6.94 mmol) in CH3CN (70 mL) was treated with n-Bu4NCN (2.2 g, 8.0 mmol). After 12 h, the reaction mixture was diluted with 1N HCl and extracted with Et2O (3×). The combined organic extracts were washed with 1N HCl (2×), saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to afford the title compound (2.6 g, 94%): 1H NMR (CDCl3 400 MHz) δ 7.74 (dd, J=8.8, 2.2 Hz, 2H), 7.55 (dd, J=8.8, 2.2 Hz, 2H), 7.07 (m, 1H), 6.46 (m, 1H), 4.99 (dd, J=12.4, 2.9 Hz, 1H), 4.34 (dd, J=12.4, 2.2 Hz, 1H), 4.32 (s, 1H), 2.99 (t, J=6.6 Hz, 1H), 2.47 (t, J=7.3 Hz, 2H), 1.76 (m, 1H), 1.65 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:9]([C:5]5[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=5[CH3:8])=[O:11])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)o1
Yield: 70.6 %

Procedure:
In the same manner as in Example 259 and using 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol), tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (520 μL, 6.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (390 mg, 69%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[N:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[N:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCCNCC3)ncc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ncc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-quinazoline
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11])(=[O:34])[CH3:33]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CN1C(=O)c2cccc(OC(C)=O)c2C1=O)C(C)=O
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
Ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (102.4 mg, 0.34 mmol) was dissolved in dichloromethane, and pyridine (55 μl, 0.682 mmol) and acetyl chloride (49 μl, 0.68 mmol) were then slowly added dropwise to the obtained solution at 0° C. The resulting mixture was then stirred at the same temperature for 10 minutes. After the reaction was completed, the reaction mixture was washed with water and then the aqueous layer was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and distilled under a reduced pressure. The desired product (64 mg, 54%) was obtained by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([S:3][CH2:1][CH3:2])=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CCS
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CCSC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 3 h
Yield: 50.6 %

Procedure:
0.7 g of ethyl mercaptan and 1.2 g of triethylamine were dissolved in 20 ml of N,N-dimethylacetamide. To the resulting solution, 3.5 g of 3-(2'-chloro 4'-trifluoromethylphenoxy)phenylacetyl chloride was dropwise added at 10° C. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, 50 ml of water was added to the liquid reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation-removal of the ether under reduced pressure, thereby to obtain a crude product. The so-obtained crude product was subjected to purification by the silica gel column chromatography (elution was performed by using a mixed solvent of toluene and n-hexane). As a result, there was obtained 1.9 g of S-ethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylthioacetate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[NH:35][C:36]([NH:38][NH2:39])=[S:37]>CO>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[C:27]=1[NH:35][C:36]([NH:38]/[N:39]=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:37]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1cccc(F)c1NC(=S)NN
Solvent: CO
Product: CC(C)c1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 73.2 %

Procedure:
To a solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (0.760 g, 2.28 mmol) in methanol (22.8 mL) in a 100 mL round-bottomed flask equipped with a magnetic stir bar and reflux condenser was added N-(2-fluoro-6-isopropylphenyl)hydrazinecarbothioamide (0.518 g, 2.28 mmol), and the reaction was heated to 65° C. and stirred for 6 hours. The temperature was lowered to 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature and the resulting solid was filtered, washed with methanol, and dried under vacuum (25 in Hg) at 55° C. to give the title compound (0.907 g, 1.67 mmol, 73% yield) as a white solid: mp 210-212° C.; 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.30-8.22 (m, 2H), 7.92 (s, 1H), 7.86-7.76 (m, 4H), 7.44-7.38 (m, 2H), 7.35 (dd, J=8.1, 5.6 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.04 (ddd, J=9.4, 8.2, 1.3 Hz, 1H), 3.22 (p, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H); ESIMS m/z 544 ([M+H]+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Si](C)(C)O)(C)(C)C.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: CC(C)(C)[Si](C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)cnc2ccccc12
Reaction time: 1.5 h

Procedure:
The mixture of [4-(tert-butyldimethylsilanyloxy)butyl](3-nitro-quinolin-4-yl)amine and tert-butyldimethylsilanol (110 g) from the previous step was dissolved in toluene (880 mL) and placed in a Parr hydrogenation vessel along with 5% platinum on carbon catalyst (3.0 g). The vessel was pressurized to 50 psi (3.4×105 Pa) hydrogen and shaken on the Parr apparatus for 1.5 hours, occasionally adding additional hydrogen to maintain a pressure of 50 psi (3.4×105 Pa). After 3 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide N4-[4-(tert-butyldimethylsilanyloxy)butyl]quinoline-3,4-diamine as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>ClCCl>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:32][CH:33]=4)[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)c1ccc(C(F)(F)F)cc1
Yield: 60.9 %

Procedure:
A mixture of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1.13 ml(0.014 mol) pyridine in 30 ml dichloromethane was stirred with 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride for 18 hours at room temperature. Then another 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride were added and stirring was continued at reflux temperature for 48 hours. After extraction with aqueous sodium hydroxide the organic solvents were distilled off and the residue was recrystallised from methanol to yield 0.28 g(60%) N-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-trifluoromethyl-benzamide as white crystals. MS m/e (%): 460 (M+H+, 100).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[C:18]([CH3:32])([CH3:31])[C:17]3=[O:33])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6].CO.O>O1CCCC1>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:19]2[CH2:20][N:16]([CH:15]3[CH:9]4[CH2:10][CH2:11][CH2:12][CH:13]3[CH2:14][CH:7]([C:5]([OH:6])=[O:4])[CH2:8]4)[C:17](=[O:33])[C:18]2([CH3:32])[CH3:31])=[N:24][CH:25]=1)#[N:30]
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(COc2ccc(C#N)cn2)C(C)(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)C(=O)N(C2C3CCCC2CC(C(=O)O)C3)CC1COc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
LiOH (0.2 g, 4.84 mmol) was added in one portion to a stirred solution of the product of Example 7E (0.532 g, 1.21 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL). The resulting solution was stirred overnight, followed by partitioning with diethyl ether and water. The organic layer was washed with water and the combined water layers were acidified with NaHSO4 solution and extracted with ethyl acetate. The combined ethyl acetate phases were dried (MgSO4), filtered, and evaporated. The acid product was used without further purification.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2Br)[C@H:9]([OH:23])[C@@H:8]1[OH:24])([OH:4])([OH:3])=[O:2].[CH2:25]([NH2:28])[CH2:26][NH2:27].[OH-].[Na+].C(=O)(O)[O-]>O>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2[NH:27][CH2:26][CH2:25][NH2:28])[C@H:9]([OH:23])[C@@H:8]1[OH:24])([OH:4])([OH:3])=[O:2]
Reactant: NCCN
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A reaction mixture consisting of 2.2 mmol 8-bromoadenosine-5'-monophosphate, prepared according to the method described in Arch. Biochem. Biophys. 163: 561-9(1974), 66 mmol ethylenediamine and 25 ml water was heated in an oil bath at 140° for 2 hr. The cooled mixture was adjusted to pH 11.5 with sodium hydroxide and passed into a 2.5×55 cm column of Dowex 1×8 (200-400 mesh, bicarbonate form). The column was washed with 300 ml water and then with a linear gradient generated with 3 liters water and 3 liters 0.5M ammonium bicarbonate. The absorbance of the effluent at 254 nm was monitored and a major peak of absorbing material eluted between 4.6 and 5.8 liters of the gradient.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.Cl.[NH2:23][C:24]1[S:25][C:26]([F:29])=[CH:27][N:28]=1.Cl[C:31](OC)=[O:32]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:31](=[O:32])[NH:23][C:24]3[S:25][C:26]([F:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CNc3ccc(Br)cc32)C1
Reactant: Nc1ncc(F)s1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(F)s1)c1ccc(Br)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that (S)-t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that 2-amino-5-fluorothiazole hydrochloride was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[Br-].[Na+]>C(O)C>[C:2]([NH:5][C:6]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)(NC(C)=O)C(=O)OCC

Procedure:
To a solution of sodium metal (2.9 g; 0.125 mol) in absolute ethanol (500 mL) was added diethyl acetamidomalonate (LX) (27.2 g, 0.125 mol) followed by 4-(trifluoromethyl)benzyl bromide (LXI) (29.9 g, 0.125 mol). The reaction mixture was stirred at reflux overnight, during which time substantial amount of sodium bromide precipitated. The reaction mixture was concentrated to ca. 30% of its initial volume under reduced pressure and poured into cold water (400 mL). The precipitate was filtered and washed with water (3×250 mL), hexanes (3×150 mL) and then air dried to yield diethyl 2-acetamido-2-(4-(trifluoromethyl)benzyl)malonate (LXII) as a white solid used directly for the next step.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1C)(=O)C.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]I)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:38]([O:41][CH2:42]C)(=[O:40])[CH3:39]>C1COCC1.O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:39]([C:5]2[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)[C:38]([O:41][CH3:42])=[O:40])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)Oc1ccc(Br)cc1C
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(CI)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)c1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution of 246.63 g of methyl-4-bromophenyl acetate and 342.54 g of 4-Iodomethyl benzoic acid tert-butyl ester in THF (1233 mL) was cooled to −8° C. A solution of lithium hexamethyl disilazide in THF (1185 mL, 1.0 M) was added dropwise ensuring that the temperature remaine below −2° C. After the addition was complete, the reaction was allowed to proceed for ˜45 min at the same temperature and then poured over a stirring mixture of ethyl acetate (2.46 L) and water (1.23 L). The organic phase was washed with saturated ammonium chloride and then with water. Dried over magnesium sulfate and concentrated under reduced pressure to obtain 450.5 g (100% yield) thick oil. HNMR: CDCl3, 1.41 (s, 9H), 2.88-2.90 (m, 1H), 3.24-3.28 (m, 1H), 3.45 (s, 3H), 3.63 (t, 1H). 6.96-6.99 (m, 4H), 7.25 (d, 2H), 7.68 (d, 2H)
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:19].[CH2:12]([N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: Cc1cc[n+](Cc2ccccc2)c2ccccc12
Product: [Br-]
Temperature: 25 °C
Yield: 57.9 %

Procedure:
To a solution of lepidine (14.3 g, 0.1 mol) in toluene (200 mL), benzyl bromide (34.2 g, 0.2 mol) was added dropwise at room temperature. After the addition, the mixture was heated to reflux for 5 hrs. The mixture was cooled to room temperature; the precipitate formed was collected by filtration, washed with toluene and dried under vacuum to give Compound 12 as yellow solid (18.2 g, 58%). It was used without any further purification. The structure of Compound 12 is given below:
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[CH3:13][CH:14]([CH3:18])[C:15]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)([OH:17])[CH3:16]
Reactant: CC(=O)C(C)C
Reactant: Ic1cnccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)C(C)(O)c1cnccn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
2-iodopyrazine (10 g, 48.55 mmol) in dry diethyl ether (100 ml) was cooled to −78° C. n-BuLi (2.5M in hexanes) (20.39 ml of 2.5 M, 50.98 mmol) was added dropwise over 10 minutes. A brown heterogeneous mixture was produced and it was stirred at −78° C. for 10 minutes, then warmed to −50° C. and stirred for an additional 60 minutes. The mixture was then re-cooled to −78° C. and 3-methylbutan-2-one (5.227 g, 6.493 ml, 60.69 mmol) was added. The mixture was stirred for 10 minutes. Further diethyl ether (10 ml) was added. The mixture was then allowed to warm to ambient. A saturated ammonium chloride aqueous solution (40 ml) and ethyl acetate (100 ml) were added and the mixture stirred for 5 minutes. The organic layer was separated and the aqueous extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude was purified on silica-gel, eluting with 40% ethyl acetate/petrol to afford the title compound as a pale yellow oil (4.74 g, 60%). 1H NMR (CDCl3) 0.75 (3H, d), 0.99-1.01 (3H, d), 1.58 (3H, s), 2.05-2.09 (1H, m), 4.10-4.40 (1H, m), 8.51-8.52 (2H, m), 8.73 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[O:13]=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:16][C:15]([Cl:18])([Cl:17])[CH:14]([OH:13])[CH:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Temperature: -5 °C
Reaction time: 3 h
Yield: 31.6 %

Procedure:
33.4 g (0.2 mol) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one were dissolved in 150 ml of methylene chloride and the solution was cooled to -5° C. 19 g (0.1 mol) of titanium tetrachloride, and then 29.5 g (0.2 mol) of chloral, were slowly added dropwise to this solution. The internal temperature was kept constant at -5° C. during the metering. Thereafter, the mixture was warmed slowly to the reflux and stirred for 3 hours. The reaction solution was poured onto ice and the white curdy precipitate which formed was filtered off. After boiling up in 250 ml of methanol and then drying, 19.9 g (32% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one of melting point 220°-222° C. were obtained.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].C(OP([C:21](Br)([F:23])[F:22])(=O)OCC)C>C(#N)C.O>[F:22][CH:21]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: CC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccccc1OC(F)F
Temperature: -20 °C
Yield: 91.7 %

Procedure:
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:28])([OH:27])[CH3:26])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([CH3:34])[CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:26])([OH:27])[CH3:28])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CN(C)CCO3)c21
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
To 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (0.13 g, 0.30 mmol) suspended in methanol (2 mL) was added formaldehyde (37% in water, 0.045 mL, 0.6 mmol). After 5 min, acetic acid (0.051 mL, 0.9 mmol) was added following by sodium triacetoxyborohydride (0.16 g, 0.75 mmol). After 1 h. the solvent was removed in vacuo and the residue suspended in 1N NaOH and extracted with ethyl acetate/tetrahydrofuran. The combined organic extracts were washed with brine and dried sodium sulfate. The filtrate was concentrated in vacuo to afford the desired compound as a solid (0.10 g, 77%) MS (ES+) m/z 442 [M+H]+.