Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(CO)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br

Procedure:
To a solution of 2-bromo-5-hydroxymethyltoluene (87.4 g) in methylene chloride (350 ml) were added, under ice-cooling with stirring, trietylamine (72.7 ml) and 4-dimethylaminopyridine (DMAP)(500 mg), and then thereto was added t-butyldimethylsilyl chloride (65.5 g). The mixture was stirred at 0° C. for 15 minutes, and stirred at room temperature for 3 hours. The reaction mixture is filtrated, and the filtrate was concentrated under reduced pressure. To the residure was added water (100 ml), and the mixture was extracted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 85%). 1H NMR (200 MHz, CDCl3): δ 3.31 (s, 4H), 3.73-3.85 (m, 3H), 4.06-4.16 (m, 4H), 7.03-7.11 (m, 3H), 7.20-7.34 (m, 1H), 7.50-7.62 (m, 3H), 7.67-7.74 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH2:23][CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH2:23][CH3:24]
Reactant: CCCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.3 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 5.62 mg (0.0458 mMol) propyl chloroformate, 11.2 mg (81%) of the title compound were recovered.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Triethylamine (0.480 mL, 3.44 mmol) was added to (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol (0.70 g, 2.30 mmol) in DCM (10 mL) cooled in ice, and then methanesulfonyl chloride (0.213 mL, 2.76 mmol) was added. After 1 hour, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated to yield (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (0.87 g, 2.27 mmol, 98.9% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 1H), 7.29-7.24 (m, 1H), 7.16 (t, 1H), 5.51-5.47 (m, 1H), 3.94-3.89 (m, 1H), 3.81-3.76 (m, 1H), 2.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, 6H).
Reaction SMILES: C(N[C:9](=[O:37])[CH:10]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C@@H:22]([O:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O:42]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.O.[OH-].[Li+].Cl>C(#N)C.O>[CH:31]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]([OH:42])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-benzyl-2-cyclohexyl-2-[5,6-difluoro-2-((S)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide (2.16 g, 4 mmol, 1.0 equiv) in acetonitrile (25 ml) were added di-tert.-butyl-dicarbonate (1.123 g, 5 mmol, 1.2 equiv., [CAS RN 24424-99-5]) and N,N-dimethylaminopyridine ((0.051 g, 0.1 equiv., [CAS RN 1122-58-3]). The mixture was stirred 48 h at room temperature. A solution of lithium hydroxide monohydrate (0.54 g, 3.0 equiv., [CAS RN 1310-66-3]) in water (4 ml) was added, and the mixture vigorously stirred overnight at room temperature, and 2 h at 70° C. The mixture was allowed to cool to room temperature and poured into 1M aqueous hydrochloric acid (25 ml). The product was extracted with ethyl acetate (3×50 ml) and the combined organic phases washed with brine and dried over magnesium sulfate. The brown residue was purified by column chromatography on silica gel (75 g, 1:0 to 98:2 EtOAc/AcOH eluant) to afford the product as an off-white mixture of diastereomers. MS (ISN): 413.1 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9](O)(=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)CCCCCC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCC(=O)Nc1cncc(Br)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
The mixture of 5-bromopyridin-3-amine (2.0 g, 11.6 mmol) and heptanedioic acid (2.22 g, 13.9 mmol) was heated and stirred at 130° C. for 8 h. After the reaction was completed, the solution was cooled to 50° C. and added to NaOH solution. The mixture was filtered. The filtration was extracted with EtOAc (50 mL×3) and concentrated HCl was added until pH=1. The solid was collected to give the product as a yellow solid 2.42 g (yield 66.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:16][O:17][N:18]([CH3:25])[C:19](N(OC)C)=[O:20].Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([N:18]([O:17][CH3:16])[CH3:25])=[O:20])=[C:4]([O:8][CH3:9])[C:3]=1[F:10]
Reactant: CON(C)C(=O)N(C)OC
Reactant: COc1cccc(Cl)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)N(C)OC)ccc(Cl)c1F
Temperature: -70 °C
Yield: 38.4 %

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 10 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After 1.5 hours at −70° 1 g (6.9 mmol) N,N′-dimethoxy-N,N′-dimethyl urea in 6 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 7.5 ml of a 2 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%) to yield 0.59 g 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid. 1H-NMR (CDCl3); δ=3.35 (br, 3H), 3.49 (br, 3H), 3.98 (s, 3H), 6.99 (dd, 1H), 7.13 (dd, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.[CH2:12]([C:19]1[NH:24][C:23](=[O:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=2)=[CH:21][N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([C:19]1[NH:24][C:23](=[O:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([I:11])[S:10][C:3]=34)=[C:28]([F:33])[CH:27]=2)=[CH:21][N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(I)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (0.030 g, 0.10 mmol; prepared according to the procedure described by Ragan, J. A. Org. Proc. Res. Dev. 2003, 7, 676) and 2-benzyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one (0.025 g, 0.084 mmol) in DMF (1 mL) was added Cs2CO3 (0.033 g, 0.10 mmol). The reaction mixture was stirred at 130° C. for 18 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude dark yellow solid. Purification of the crude product was achieved by flash column chromatography (25:1 dichloromethane/methanol) and then by trituration with dichloromethane. The resulting solid was filtered, washed with dichloromethane, collected and dried under vacuum to yield the desired product (0.008 g, 17%) as a pale yellow solid. LRMS (ESI pos) m/e 556 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Yield: 226.5 %

Procedure:
To 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added triphosgene (3.55 g, 12 mmol). This mixture was heated to reflux under a nitrogen atmosphere for 3 hours. It was cooled to ambient temperature, and diethyl ether (50 mL) was added. The mixture was filtered to yield 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (5.25 g, 91%) as a solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:29]=[O:30])=[CH:23]2.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:24]([CH:29]=[O:30])=[CH:23]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
p-Toluenesulfonyl chloride (2.445 g, 12.82 mmol), N,N-dimethyl-4-aminopyridine (0.196 g, 1.603 mmol) and triethylamine (2.253 ml, 16.03 mmol) were added to a solution of 5-fluoro-1H-indole-2-carbaldehyde (0.523 g, 3.21 mmol) in dichloromethane (10 ml) and stirred at room temperature for 20 hours. After reaction, the mixture was poured into saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to give 823 mg (81% yield) of the title compound as a white crystal:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:66]=[N+:67]=[N-:68].[Li+].C(Br)(Br)(Br)Br>CN(C=O)C.CO>[CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:30])[CH3:31])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36][N:66]=[N+:67]=[N-:68])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCN=[N+]=[N-])[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Utilizing the conditions of Hetz et. al., J. C. S. Perkin 1 1980, 306, to a solution of compound 39 (1 eq) in DMF is added triphenylphosphine (1 eq) and lithium azide (5 eq) at room temperature. Carbon tetrabromide (1 eq) is added and the reaction mixture is stirred until judged complete by tlc. MeOH is added to quench the reaction mixture and the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography to yield the title compound, 40.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.Br[C:30]1[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=2)=[O:37])=[C:33]([CH3:35])[N:34]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:30]2[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:9]1=[NH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 5 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with 2-bromo-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 5% yield: mp 140-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.41 (t, J=5.8 Hz, 1H), 7.39-7.23 (m, 7H), 7.12-7.08 (m, 1H), 6.68 (m, 1H), 4.43 (s, 2H), 4.30 (d, J=5.8 Hz, 2H) 3.94 (m, 2H), 3.35-3.27 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 158.3, 153.5, 151.1, 150.4, 148.0, 147.9, 138.2, 137.2, 129.0, 128.2, 127.8, 124.4, 117.7, 116.5, 48.4, 44.4, 43.9, 42.1, 17.6; MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:48]/[O:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:12]([NH:14][C@@H:15]2[C:46](=[O:47])[N:17]3[C:18]([C:30]([O:32]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:31])=[C:19]([S:22][CH2:23][C:24]4[S:28][N:27]=[N:26][C:25]=4[CH3:29])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:48]/[OH:49])/[C:12]([NH:14][C@@H:15]2[C:46](=[O:47])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([S:22][CH2:23][C:24]4[S:28][N:27]=[N:26][C:25]=4[CH3:29])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Cc1nnsc1CSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cc1nnsc1CSC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
Under N2 atmosphere, a solution of aluminum chloride (1.88 g, 14.05 m mol) in anisole (4.5 ml) was added slowly to a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(4-methyl-1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylate (2.60 g, 2.81 m mol) in anisole (4.5 ml) and nitromethane (18 ml) at −30˜20° C. After the mixture was stirred for 1 hour at the same temperature, the reaction was quenched with 1N hydrochloric acid (18 ml), and poured into water/ethyl acetate. The aqueous layer was separated, and the organic layer was reextracted with water. The combined aqueous layer was concentrated in vacuo, chromatographed on a HP-20 column (eluent: water-methanol). After concentration, the resulting precipitate was collected by filtration, and dried in vacuo to afford 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(4-methyl-1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylic acid (150.8 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])(=O)=O.O>CS(C)=O>[C:1]([C@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])#[N:2]
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](C#N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 50 °C
Yield: 45 %

Procedure:
Potassium cyanide (280 mg, 4.30 mmol) was added to a solution of (5)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (prepared as described for CT11558) (770 mg, 2.15 mmol) in dimethylsulfoxide (10 ml). After heating at 50° C. for 24 hours, the mixture was poured into water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (40 ml), saturated aqueous sodium chloride solution (40 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-cyanohexyl)-3,7-dimethylxanthine (CT16575) (280 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22](OCC)=[O:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:30]>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22]([NH2:30])=[O:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Reactant: N
Product: NC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of ethyl 5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-1H-1,2,4-triazole-3-carboxylate (867 mg) in 0.88 ammonia (25 ml) was stirred at room temperature for 18 h. The mixture was evaporated and the residual solid was washed with boiling methanol to leave the title compound as a white solid (255 mg) m.p. 212°-4° dec.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C(N1CC(OC2C=CC=C(C(F)(F)F)C=2)C1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:46]=1[N:52]=[C:53]=[S:54]>C(Cl)Cl>[CH3:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([CH3:44])[C:46]=1[NH:52][C:53]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[S:54]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: Cc1cccc(C)c1N=C=S
Agent: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=S)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of 30.0 g (0.078 mole) of 1-benzhydryl -3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 12.7 g (0.078 mole) of 2,6-dimethylphenylisothiocyanate in 25 ml of methylene chloride. The product began to precipitate during the addition and an addition 50 ml of methylene chloride was added to facilitate stirring. After stirring overnight at ambient temperature, the product was collected by filtration (13.5 g, m.p. 196°-199° C.). A 6.0 g sample was recrystallized from isopropanol to give 5.3 g of product, m.p. 197°-199° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.Br[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ncccn2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.10 g), 2-bromopyrimidine (0.076 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (0.016 g), 1,4-dioxane (2.0 mL) and 2.0M aqueous cesium carbonate solution (0.38 mL) was heated by microwave irradiation at 90 to 130° C. for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in tetrahydrofuran (5.0 mL) and 1.0M aqueous lithium hydroxide solution (0.38 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 0.1M aqueous hydrochloric acid solution and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.021 g).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[Cl:6][CH2:7][N+:8]12[CH2:15][CH2:14][N:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2.[F:16][B-:17]([F:20])([F:19])[F:18].[Na+].[F:22]F>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:6][CH2:7][N+:8]12[CH2:15][CH2:14][N+:11]([F:22])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: ClC[N+]12CCN(CC1)CC2
Reactant: FF
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[N+]12CC[N+](CCl)(CC1)CC2
Yield: 89 %

Procedure:
Treatment to a vigorously-stirred cold (-35° C.) solution of the slightly impure 1-chloromethyl-4-aza-1-azoniabicyclo [2.2.2]octane tetrafluoroborate (1.01 g, 7.28 mmol) and sodium tetrafluoroborate (0.80 g, 7.28 mmol) in dry acetonitrile (200 cm3) with neat fluorine at 10-20 mmHg (1.3-2.7 kPa) pressure until its uptake appeared to cease provided 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (2.20 g, 6.51 mmol, 89%), almost pure according to elemental analysis (C, 24.4: H, 4.6: N, 7.9%. Calc. C, 23.7; H, 3.95; N, 7.9%) and n.m.r. analysis [δF (solution in D2O; ext. CF3CO2H ref.) 125.5 (br. s; FN+), -72.0 (s; BF4-) p.p.m. (a trace of F- impurity caused an absorption at -50.7 p.p.m.); δH (same soln.) 4.53 (m; 3×CH2), 4.97 (m; 3×CH2), 5.50 (s; CH2Cl) p.p.m. (residual H in D2O, 4.70 p.p.m.)](isolated by filtering the product to remove NaF then evaporating the filtrate to remove CH3CN). This bis(tetrafluoroborate) melted with decomposition at 170° C. (turning brown at about 160° C.) after recrystallisation from an acetonitrile-diethyl ether mixture; rapidly liberated iodine from potassium iodine (moist starch-iodide paper); and converted phenol in warm acetonitrile to a mixture of ortho- and parafluorophenol.