Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(#N)C>[CH2:17]([O:24][C:25](=[O:33])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCCNC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCCCCNc1nc(Cl)ncc1Br)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 860 mg (3.8 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.2 ml (8.5 mmol) of triethylamine in 6 ml of acetonitrile is mixed at 0° C. with 1.0 g (3.7 mmol) of (5-amino-pentyl)-carbamic acid-benzyl ester. The reaction mixture is slowly heated to room temperature while being stirred by removal of the ice bath. After 60 hours, it is mixed with water and then extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is formed is purified by chromatography (hexane/ethyl acetate 1:1). 1.2 g (2.8 mmol, corresponding to 77% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:37]([N:39]([CH2:55][CH3:56])[C:40]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([S:51](Cl)(=[O:53])=[O:52])=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)=[O:41])[CH3:38].O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:51]([C:47]3[CH:46]=[C:45]4[C:50](=[CH:49][CH:48]=3)[N:42]([C:40]([N:39]([CH2:55][CH3:56])[CH2:37][CH3:38])=[O:41])[CH2:43][CH2:44]4)(=[O:52])=[O:53])[C:18]2=[O:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC2(c3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCN(C(=O)OC(C)(C)C)CC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Reaction time: 0.5 h
Yield: 126.8 %

Procedure:
A solution of 1 g of 3-[[2-(1-tert-butoxycarbonylpiperid-4-yl)ethyl]amino]-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one in 5 ml of DMF is cooled to +4° C. under an argon atmosphere and 0.087 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 30 minutes at +4° C., 0.627 g of 1-(diethyl-aminocarbonyl)indoline-5-sulfonyl chloride is added and the mixture is stirred for 3 hours at RT. 50 ml of water are added to the reaction mixture, extraction is carried out with AcOEt, the organic phase is washed with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (88/12; v/v) as the eluent to give 1.97 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=139° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 67.3 %

Procedure:
A mechanical stirrer was used for this reaction. A solution of diisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL) was cooled to −78° C. and then treated with a 2.5 M solution of n-butyllithium in hexanes (83.4 mL, 0.21 mol). The yellow-orange reaction mixture was stirred at −78° C. for 35 min and then slowly treated with a solution of 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL). The reaction mixture turned dark in color. The reaction mixture was then stirred at −78° C. for 50 min, at which time, a solution of iodomethylcyclopentane (50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was added slowly. The reaction mixture was then stirred at −78° C. for 50 min, and then allowed to warm to 25° C., where it was stirred for 36 h. The reaction mixture was quenched with water (100 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (1.5 L). The organic phase was washed with a saturated aqueous sodium chloride solution (1×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (41.79 g, 68%) as a yellow viscous oil: EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([NH:12][NH2:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NNc1ncccc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 65 °C
Yield: 54.8 %

Procedure:
To a 1000 mL flask, anhydrous ethanol (300 mL), sodium ethoxide (16.97 g, 0.249 mol) and 3-chloro-2-hydrazinylpyridine (30.47 g, 98%, 0.21 mol) were added. The reaction mixture was heated to reflux for 5 minutes. Diethyl maleate (36.0 g, 0.31 mol) was added dropwise and heated to reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (45.36 g, 0.42 mol) and then diluted with 300 mL water. The reaction mixture was cooled down to room temperature, solid is separated to be filtered, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate (31.03 g) as an orange solid in 52% yield. HPLC area normalization method content is 94% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][C:23]=1[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:17][C:18]4[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:21]=[CH:22][C:23]=4[CH3:24])=[O:16])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (5.3 g, 22.49 mmol) obtained in Step 3 of Preparation Example 4 was dissolved in DMF (60 mL). t-Butyl 3-amino-4-methylphenylcarbamate (6 g, 26.99 mmol) obtained in Step 2 of Preparation Example 9, EDCI (6.5 g, 33.74 mmol), HOBT (6.1 g, 44.98 mmol) and TEA (4.7 mL, 33.74 mmol) were sequentially added to the reaction mixture, which was stirred at room temperature for 24 hours. After the reaction was completed water (120 mL) was added thereto, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13](=[O:16])(O)[O-:14].[K+].[C:18](=O)=O.Cl>OCC(CO)O>[CH3:18][O:14][C:13]([C:3]1[C:4]([OH:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:16]
Reactant: O=C([O-])O
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: O=C=O
Agent: Cl
Agent: [K+]
Solvent: OCC(O)CO
Product: COC(=O)c1c(O)cc2ccccc2c1O

Procedure:
A mixture of 1,3-dihydroxynaphthalene (480 mg, 3.00 mmol) and potassium bicarbonate (750 mg, 7.5 mmol) in glycerol (1 mL) was heated under 1 atmosphere of CO2 to 115° C. for 5 hours then poured into 0.5M HCl (20 mL) and extracted with diethyl ether (3×5 mL). The combined ether layers were washed with brine (1×5 mL), dried (MgSO4) and filtered. This solution was then treated with a solution of diazomethane in diethyl ether until bubbling ceased. The ether was removed under reduced pressure and purified on silica gel eluting with 20% ethyl acetate/hexanes to provide (75 mg, 11%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].[CH3:20][C:21]1([CH3:29])[O:25][C@H:24]([C@H:26]([OH:28])[CH3:27])[CH2:23][O:22]1>O1CCCC1.CC1CCCO1>[Cl:8][C:6]1[CH:7]=[C:2]([O:28][C@@H:26]([C@@H:24]2[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]2)[CH3:27])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:5]=1
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Reactant: Fc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2ccc(F)cc2)n1)[C@@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The sub-title product of step (ii) (85.7 g) and 60% sodium hydride (14.2 g) were suspended in tetrahydrofuran (1000 mL) and cooled in ice/water for 30 minutes. A solution of (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (Intermediate A) in 2-methyltetrahydrofuran (53% w/v) (104 mL) was added dropwise over 20 minutes and the reaction was stirred at 0° C. to room temperature for 20 hours. The reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous was re-extracted with ethyl acetate (2×500 mL) and the combined organics were dried and evaporated in vacuo. The crude material was purified by flash silica chromatography with gradient elution 0-30% ethyl acetate in isohexane using Isolera LS. Pure fractions were evaporated to dryness to afford to afford the sub-title product (94 g) as a yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 11H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+-cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1](NCCCCCCCCCCC(O)=O)([O:3]C(C)(C)C)=[O:2].[CH3:22]N(C)C=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29]C=1>CN(C)C1C=CN=CC=1>[NH2:27][C@H:32]([C:1]([OH:3])=[O:2])[CH2:31][CH:30]([CH3:29])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Reactant: c1ccncc1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
N-BOC-11-aminoundecanoic acid (Bachem, 0.60 g, 2.0 mmoles) was activated with disuccinimidylcarbonate (0.56 g, 2.2 mmoles) and 4-dimethylamino-pyridine (0.02 g, 0.2 rnmoles) in 10 mL of dimethylformamide/pyridine (2/1, v/v) and reacted with the resin product from Part C for 60 minutes at room temperature. The resulting resin was separated by filtration, the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C. The hydrogen fluoride was removed by evaporation, and the product was extracted into 30% acetic acid/water and then lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 84.8 mg of 98% pure (by HPLC) L-leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate. HRMS: (M+H) calcd 530.3918, found 530.3919. Amino acid analyses: calcd serine 1.00, lysine 1.00, leucine 1.00; found: serine 1.05, lysine 1.00, leucine 1.05.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2c(F)cccc2N1CCCCl
Yield: 59.9 %

Procedure:
8-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF45) (0.290 g, 1.74 mmol), Cs2CO3 (0.848 g, 2.6 mmol) and 3-chloro-1-iodopropane (0.390 g, 1.91 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF51(2082)) (0.254 g, 60%). 1H NMR (CDCl3) d 7.01-6.95 (m, 1H), 6.88-6.82 (m, 2H), 4.66 (s, 2H), 4.13-4.08 (m, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.19-2-12 (m, 2H); 13 C NMR (CDCl3) d 164.2, 152.1 (d, J=246.8 Hz), 133.9 (d, J=15.0 Hz), 130.6 (d, J=3.1 Hz), 122.6 (d, J=8.1 Hz), 111.8 (d, J=18.4 Hz), 110.1 (d, J=3.4 Hz), 67.8, 42.4, 39.5, 30.1.
Reaction SMILES: C(OC([C@@H:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16]Cl)[CH:13](N)[S:14][C@H:9]12)=O)(C)(C)C.[I-:36].[Na+].[CH:38]([NH:40][C:41]1[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[N:44]=[CH:43][CH:42]=1)=[O:39].[OH2:51]>CN(C)C=O.C(OCC)(=O)C>[I-:36].[C:12]([O:51][C:34]([NH:10][C@@H:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:12]([CH2:16][N+:44]3[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41]([NH:40][CH:38]=[O:39])=[CH:42][CH:43]=3)[CH2:13][S:14][C@H:9]12)=[O:35])([CH3:16])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)C(N)S[C@H]12
Reactant: O
Reactant: O=CNc1ccnn1CCOC=O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Reaction time: 24 h

Procedure:
To a mixture of benzhydryl 7β-tert-butoxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylate (20 g) and sodium iodide (5.82 g) in N,N-dimethylformamide (20 ml) was added 5-formamido-1-(2-formyloxyethyl)pyrazole (21.34 g) at room temperature. After being stirred for 24 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, aqueous sodium chloride solution, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate iodide (29.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH:33]([C:36]1C=CC=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1)(C)[CH3:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:38]=[CH:37][CH:36]=[CH:33][CH:34]=4)[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(Br)c3O2)cc1
Reactant: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccccc4)c3O2)cc1
Yield: 78 %

Procedure:
Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: COCCOC[O:7][CH:8]([C:10]1[S:14][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:9].S(=O)(=O)(O)O>CO.O>[OH:7][CH:8]([C:10]1[S:14][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:20])=[O:21])[CH3:9]
Reactant: COCCOCOC(C)c1sc(S(N)(=O)=O)cc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CC(O)c1sc(S(N)(=O)=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
The 5-[1-(methoxyethoxymethoxy)ethyl]-4-methylsulfonylthiophene-2-sulfonamide (5.94 g, 0.0159 mol) was dissolved in 50/50 methanol/water (30 ml) with warming and concentrated sulfuric acid (15 ml) was added. The solution was cooled to ambient temperature and stirred for 1 hour. The methanol was removed in vacuo and the aqueous acid was diluted with water (50 ml). The product was extracted into ethyl acetate. The extract was washed with saturated NaHCO3 solution, water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A colorless oil was obtained which solidified to a white solid. Several recrystallizations from water gave pure product (1.04 g, 23%), m.p. 121-127° C. NMR supported the structure and HPLC confirmed the purity.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14]([O:16]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:6]=2[CH:5]=1)[CH3:2].[CH3:33][NH:34][CH3:35].O>C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14](=[O:16])[N:34]([CH3:35])[CH3:33])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc2c(c1)C(CC(=O)Oc1ccc([N+](=O)[O-])cc1)=Cc1ccccc1N2C
Reactant: CNC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCSc1ccc2c(c1)C(CC(=O)N(C)C)=Cc1ccccc1N2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 11.35 g of 2-ethylthio-5-methyl-11-(p-nitrophenoxycarbonyl)methyl [5H] dibenzo (b,f) azepine in 45 ml of chloroform was stirred until dissolution occured and a solution of 12 ml of dimethylamine in 45 ml of chloroform was added dropwise thereto in 10 minutes. The mixture was stirred for 1 hour at room temperature and then was poured into 250 ml of ice and water. The organic phase was recovered by decanting and was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 9 g of 2-ethylthio-5-methyl-11-dimethylcarbamoylmethyl [5H] dibenzo (b,f) azepine which was used as is for the next step. The product occured as a yellow oil soluble in chloroform, ethanol and ethyl acetate and insoluble in water.