Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (370 mg, 0.827 mmol) (obtained as described in Reference Example 53(7)) in methylene chloride (19 ml) were added methanesulfonyl chloride (192 μl, 2.48 mmol) and triethylamine (348 μl, 2.48 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (422 mg, yield 97%) as a pale yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Br)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:34]#[N:35])[CH:31]=[N:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:35][C:34]([C:30]1[CH:31]=[N:32][CH:33]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=1)=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(=O)OC(C)(C)C
Reactant: N#Cc1cncc(OCc2ccccc2)c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C(N)c1cncc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Diisopropylamine (12.8 mL, 91 mmol) was added at 0° C. to a 3M solution of ethyl magnesium bromide in diethyl ether (15 mL, 45 mmol) and additional diethyl ether (40 mL). After one hour at 0° C. t-butyl acetate was added and stirring was continued for 30 minutes. 5-(benzyloxy)pyridine-3-carbonitrile (2.9 g, 13.8 mmol) in diethyl ether (40 mL) was added at 0° C. After 2.5 hours at 0° C. saturated aqueous ammonium chloride solution was added. Phases were separated and the aqueous phase was extracted with diethyl ether. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 45%) to yield 1.95 g tert-butyl 3-amino-3-[5-(benzyloxy)pyridin-3-yl]prop-2-enoate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1)(=[O:24])=[O:23]
Reactant: OCc1cc(-c2ncccn2)on1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(3-hydroxymethyl-isoxazol-5-yl)-pyrimidine (14 gm) and triethylamine (22 ml) in dichloromethane (400 ml), was added methanesulfonyl chloride (7.2 ml) at 0° C. The reaction mixture was stirred at 0° C. over a period of 0.5 h. The reaction was quenched by addition of water and layers were separated. Organic layer was evaporated under vacuum to provide title compound in 19.7 gm quantity (97.7%) as a yellow solid. This was used as such for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6](=O)[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8]N(C)C)[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:48][C:49]([NH2:51])=[NH:50])[CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:48][C:49]2[N:51]=[C:6]([CH:5]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:25])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][N:50]=2)[CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1
Reactant: CCOC(=O)C(C(=O)C(=CN(C)C)c1ccccc1)c1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C(c1ccccc1)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)ncc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl-5-dimethylamino-3-oxo-2,4-diphenyl-pent-4-enoate (102 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 28b). Obtained as a light-brown solid (5 mg, 3%). Mp 84-86° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:34])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[CH:23]=3)[CH2:19][C:18](=[O:34])[NH:17][C:9]=2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(C)C)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(C(C)C)cc3NC(=O)C2)c1

Procedure:
Prepared from (4-isopropyl-2-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example K88) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (94 mg).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:21][CH:22]=1.[I:28]I>O1CCCC1.CCCCCC>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27]2)=[C:21]([I:28])[CH:22]=1
Reactant: Clc1ccc(OCC2CC2)nn1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1cc(I)c(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 0.988 ml 2,2,6,6-tetramethylpiperidine in 10 ml tetrahydrofurane was added 3.534 ml of a 1.6M solution of n-butyl lithium in hexane at ambient temperature and the mixture was stirred at room temperature for 30 min. To this solution was added rapidly a precooled (−75° C.) solution of 0.300 g 3-chloro-6-cyclopropylmethoxy-pyridazine in 10 ml tetrahydrofuran at −75° C. After 5 minutes, a precooled solution of 0.701 g iodine in 10 ml THF was added rapidly. The reaction mixture was stirred at −75° C. for 30 minutes and then quenched with a saturated aqueous solution of ammonium chloride and diluted with ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.206 g of the title compound as light yellow solid. MS (EI): 310.9 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30](F)[C:29]=2[F:38])[CH:26]=1)[C:22]#[N:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C1COCC1>[Cl:18][C:19]1[CH:26]=[C:25]([O:27][C:28]2[C:29]([F:38])=[C:30]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil, 2.16 g, 54.1 mmol) was added to anhydrous THF (50 mL) and cooled to 0° C. under nitrogen. Di-tert-butyl malonate (4.65 g, 24.8 mmol) was added dropwise and the reaction mixture was stirred 15 min and allowed to warm to RT. The reaction was cooled to 0° C. and 3-chloro-5-[(2,3-difluoro-6-nitrophenyl)oxy]benzonitrile (7.0 g, 22.5 mmol) was added dropwise in a minimal amount of THF. The reaction was allowed to warm to RT and stirred for 3 h then 10% aqueous citric acid (50 ml) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and evaporated to afford the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.13 (dd, 1H), 7.84 (d, 1H), 7.65 (dd, 1H), 7.59-7.61 (m, 1H), 7.56-7.59 (m, 1H), 5.10 (s, 1H), 1.40 (s, 18H). MS: m/z 507.2 (M+1).
Reaction SMILES: O[C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].C(N(S(F)(F)[F:50])CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[F:50][C:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COCCCCC(F)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a 50 mL round bottom flask were added 0.0597 g (0.097 mmol, 1.0 equiv) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate and 5 mL of CH2Cl2. The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and 0.1860 g (ca. 10 equiv) of (diethylamino)sulfur trifluoride (DAST) was added. After 5 min, the dry ice-acetone bath was replaced by an ice-MeOH bath (−10° C.). After an additional hour, the reaction mixture was quenched with 10% Na2CO3 (10 mL), extracted three times with Et2O, and dried over Na2SO4. The crude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 15 min, flow rate 25 mL/min) to give 0.0478 g (80%) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-(1-fluoro-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate. LC-MS tR=2.59 min in 3 min chromatography, m/z 642 (M+Na+), 620 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.83 (br s, 1H), 7.36-7.19 (m, 5H), 5.42 (br s, 0.69H), 5.00 (br s, 0.31H), 4.39-4.36 (m, 1H), 4.14-4.03 (m, 3H), 3.72-3.46 (m, 2H), 3.28-3.24 (m, 5H), 2.94-2.86 (m, 4H), 2.62-2.40 (m, 2H), 2.11-0.81 (m, 25H), 0.03 and −0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.4, 157.8, 141.3, 141.0, 128.2, 128.1, 127.3, 126.9, 124.7, 124.6, 101.3, 99.5, 72.52, 72.46, 63.9, 63.8, 58.4, 58.3, 52.7, 52.6, 47.9, 47.6, 45.0, 44.82, 44.77, 44.6, 41.3, 41.1, 37.1, 36.9, 34.7, 34.6, 34.4, 34.3, 33.5, 33.4, 33.2, 29.6, 29.5, 26.4, 26.2, 26.13, 26.09, 25.1, 25.0, 24.6, 19.8, 17.7, −1.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl)C1CC1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (250 mg, 0.62 mmol) according to the general procedure M. Obtained as a yellow solid (215 mg).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][C:14]1[C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:17]([CH:23]=[O:24])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:13][C:14]2[C:22]3[CH:21]=[CH:20][S:19][C:18]=3[C:17]([CH:23]=[O:24])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Reactant: O=Cc1ccc(O)c2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1oc(C(C)(C)C)nc1COc1ccc(C=O)c2sccc12
Yield: 85.6 %

Procedure:
0.600 g of 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b], 3.197 mmol) was dissolved in 12 ml of acetone and treated successively with 0.570 g of 4-hydroxy-benzo[b]thiophene-7-carbaldehyde (3.197 mmol), 1.146 g of Cs2CO3 (3.517 mmol), and 0.0265 g of KI (0.16 mmol). The mixture was then refluxed under an atmosphere of Ar. After cooling, the reaction mixture was poured onto crashed ice, extracted twice with AcOEt, the organic layer washed with water, dried over magnesium sulfate, and the solvents removed i.V. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.901 g of the title compound as white crystals of mp. 119–200.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O-:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.N12CCCN=C1CCCCC2.[CH3:28][C:29]([CH3:37])([CH2:35][CH3:36])[C:30]([O:32][CH2:33]I)=[O:31]>C(Cl)Cl>[NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O:14][CH2:33][O:32][C:30](=[O:31])[C:29]([CH3:37])([CH3:28])[CH2:35][CH3:36])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12
Reactant: CCC(C)(C)C(=O)OCI
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)OCOC(=O)C1=C(COC)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1.46 g (6 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were suspended in 30 ml of methylene chloride, and 0.92 ml (6 mmol) of 1,8-diazabicyclo(5,4,0)-undec-7-ene (DBU) was added at 0° C. After 30 minutes, 1.66 g (6.5 mmol) of iodomethyl 2,2-dimethylbutyrate (compare preparation example 4) were added, while cooling with ice, and the mixture was subsequently stirred at room temperature for 2 hours. The precipitate which had separated out was filtered off with suction and the crude product was chromatographed (SiO2 ; toluene/ethyl acetate=1:1). 1.2 g (53%) of the title compound were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:12](=S)=[S:13].C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(#N)C.O>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[N:6]=[C:12]=[S:13])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(N)c1
Reactant: S=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N=C=S)c1
Temperature: 40 °C
Yield: 48.4 %

Procedure:
To 2-isopropyl-5-methylaniline (1.0 g, 6.7 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen was added carbon disulfide (3.0 mL, 50 mmol). The reaction was heated to 40° C. and cooled immediately. To this solution was added triethylamine (0.93 mL, 6.7 mmol). The reaction was heated to 50° C. for 90 minutes and cooled to room temperature overnight. The reaction mixture was transferred to a 100 mL round-bottomed flask and concentrated. The residue was taken up in acetonitrile (33.5 mL) and treated with N,N′-diisopropycarbodiimide (1.04 mL, 6.70 mmol). The reaction was stopped after a few h and concentrated. Purification by flash column chromatography using 2.5-5% ethyl acetate/hexanes as eluent provided a mixture of products. Re-purification by reversed phase column chromatography using 5-100% acetonitrile/water as eluent provided the title compound (65% in dichloromethane, 0.62 g, 31%), which was used without further purification: IR (thin film) 2963 (m), 2924 (m), 2869 (w), 2089 (vs), 1611 (w), 1501 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.6 Hz, 1H), 7.09-7.03 (m, 2H), 3.19 (h, J=6.8 Hz, 1H), 2.30 (s, 3H), 1.24 (d, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 141.50, 136.70, 134.59, 128.84, 128.58, 127.12, 126.05, 29.20, 22.83, 20.62.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CO>C(OCC)C>[Br-:16].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:4]=1)=[CH2:2]
Reactant: C=Cn1ccnc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Solvent: CO
Product: C=C[n+]1ccn(CCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-octyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The precipitate was filtered off and dried at room temperature to yield a yellow liquid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([S:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:21][C:22]=2[CH3:28])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(SC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 367 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 530.2 [M−H]−; Isomer 2 MS: 530.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH:6]=O)[CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[CH:16]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:17][NH2:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[CH:16]([O:19][Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17][NH:18][CH2:6][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5]1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Reactant: CC1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1(C)CCC1)c1c(Cl)cccc1Cl
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a mixture of 1-methylcyclobutanecarbaldehyde (38.3 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated and then purified by prep TLC eluted with 5% MeOH/DCM to provide 2-(2,6-dichlorophenyl)-N-((1-methylcyclobutyl)methyl)-2-((triethylsilyl)oxy)ethanamine (89 mg, 0.221 mmol, 56.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.18-7.22 (m, 2H), 6.98-7.10 (m, 1H), 5.57 (br. s., 1H), 3.30 (t, J=10.70 Hz, 1H), 2.74 (br. s., 1H), 2.60 (br. s., 1H), 2.51 (d, J=10.03 Hz, 1H), 1.68-1.89 (m, 4H), 1.60 (br. s., 2H), 1.47 (br. s., 1H), 1.03-1.14 (m, 3H), 0.76-0.84 (m, 9H), 0.41-0.54 (m, 6H); LCMS (ESI) m/z 402.4 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]4[CH:23]=[N:22][NH:21][C:18]4=[N:19][CH:20]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:24]N1C(=O)CCC1=O>ClC(Cl)C.ClCCl>[I:24][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:11]3[CH:10]=[C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:16]=2)[NH:21][N:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1cccc(-c2cnc3[nH]ncc3c2)c1)N1CCOCC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Morpholin-4-yl-[3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-methanone (2.30 g, 80% pure, ˜6 mmol) and of N-iodosuccinimide (2.50 g, 11.1 mmol) were dissolved in dichloroethane (180 mL). The mixture was stirred under reflux conditions for 5 h, then cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated aqueous solution of sodium thiosulfate (1×) and then with a saturated aqueous solution of sodium bromide(2×), dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with ether (80 mL) and dried to afford [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone as a beige powder (2.881 g, 88% yield over two steps). 1H-NMR (500 MHz, d6-DMSO) δ14.19 (s, 1H), 8.92 (d, 1H), 8.14 (d, 1H), 7.91 (m, 1H), 7.83 (m, 1H), 7.59 (ddd, 1H), 7.44 (dt, 1H), 3.75-3.35 (m, 8H).