Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C@@H:2]([C@H:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[O:14]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@@H](Cl)[C@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1O[C@@H]1c1ccccc1

Procedure:
To a mixture of (2S,3R)-methyl-2-chloro-3-hydroxy phenylpropionate (CV, EXAMPLE 4, 31.6 g, 0.15 mol) in DMF (730 ml) is added water (13.5 ml) followed by potassium carbonate (62 g, 0.45 mol) at 25° with stirring. The mixture is allowed to stir at 25° for 72 hr and then poured into a mixture of ethyl acetate (3 l) and water (500 ml). The organic phase is separated and the aqueous phase is back washed with ethyl acetate (400 ml×2). The combined organic phases are washed with water (400 ml×3). The aqueous phases are extracted with ethyl acetate (100 ml). The combined organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to about 800 ml, the organic mixture is again washed with water (250 ml×4). The organic phase is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give the title compound, [α]25D=+15.0° (c=1.52, chloroform); NMR (300 MHz, CDCl3) 7.45-7.33, 4.30, 3.88 and 3.58 δ; CMR (300 MHz, CDCl3) 167.0, 132.7, 128.5, 128.0, 126.5, 57.5, 55.8 and 52.0 δ; MS (m/z) 178 (M+), 161, 131, 107, 105, 91, 79, 77 and 51.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20]OCC1C=CC=CC=1)[CH:2]=[CH2:3].B(Cl)(Cl)[Cl:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20][Cl:30])[CH:2]=[CH2:3]
Reactant: ClB(Cl)Cl
Reactant: C=CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(CCl)nc(C(C)C)c1Sc1cccc(Cl)c1
Temperature: -40 °C
Yield: 13 %

Procedure:
In 5 ml of methylene chloride was dissolved 470 mg (1.13 mmol) of 1-allyl-2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1H-imidazole (17g), with cooling to -40° C., 0.7 ml (1.36 mmol) of methylene chloride solution of boron trichloride (1.94 molar) was added with stirring, and the mixture was stirred for 30 minutes. To this reaction mixture, a saturated aqueous solution of sodium bicarbonate was added for neutralization, methylene chloride layer was washed with water arid dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate: methylene chloride=1:4). From the first fraction, 50 mg (yield 13%) of 1-allyl-2-chloromethyl-5-(3-chlorophenylthio)-4-isopropylimidazole (28a) was obtained as oil, and then, 155 mg (yield 43%) of Compound I-17 was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CS(C)=O.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:31])[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)Cc3ccccn3)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of sodium hydride (0.21 g, 8.8 mmoL) in 10 mL of DMSO was stirred under N2 as 4-[4-(2-pyridine-2-yl-acetyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.50 g, 8.83 mmol) in 15 mL of DMSO was added dropwise. After 30 min, a solution of ethyl bromoacetate (1.47 g, 8.83 mmol) in 8.0 mL of toluene was added dropwise. The reaction was stirred at rt for 2 h and then quenched with saturated NH4Cl solution, and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl solution and dried over Na2SO4. The crude product was purified by Combiflash chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give the product (4.0 g, 94%): Mp 118-120° C.; MS m/z 483 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.C(OC([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][NH:46][CH2:45][CH:42]3[CH2:43][CH2:44][NH:39][CH2:40][CH2:41]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCC3CCNCC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:43].[Na+].C(=O)C>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCN(CC)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To the product of Example 378 (31 mg, 0.05 mmol) and sodium triacetoxyborohydride (414 mg, 2.0 mmol) in dichloromethane/methanol (5 mL, 9:1) was added acetaldehyde (112 μL, 2.0 mmol). The mixture was stirred at room temperature for 16 hours and evaporated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (25 mg, 77%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.35 Hz, 3 H) 1.09 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.55 (m, 2 H) 3.24 (m, 3 H) 3.38 (q, J=6.99 Hz, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 6.87 (d, J=8.82 Hz, 1 H) 7.26 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.88 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=1.84 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); (ESI+) m/z 656, 658 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]([Cl:15])[C:6]=1[NH:16][C:17]([O:19]C)=O)(OC)=[O:2].C([O-])(=O)C.[NH4+:25]>>[Cl:15][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:5]2[C:6]=1[NH:16][C:17](=[O:19])[NH:25][C:1]2=[O:2]
Reactant: COC(=O)Nc1c(Cl)cc(OC)c(OC)c1C(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COc1cc(Cl)c2[nH]c(=O)[nH]c(=O)c2c1OC
Temperature: 128 °C
Yield: 48.7 %

Procedure:
A mixture of 1.21 g (4.0 mmol) of methyl 2-carbomethoxy-6-chloro-3,4-dimethoxybenzenecarbamate and 3.17 g (20 mmol) of ammonium acetate was prepared and heated to 128° C. A solution was obtained and after one hour a white solid precipitated. The reaction mixture was cooled to room temperature, 25 mL of water was added, and the reaction mixture was cooled to 5° C. The product was filtered and washed with 2×5 mL of distilled water and 1×10 mL of methanol. Drying under vacuum gave 500 mg (49%) of white product, mp 286°-289° C. NMR (TFA) δ 4.02 (s, 3H, OCH3), 4.12 (s, 3H, OCH3), 7.60 (s, 1H, ArH), 9.68 (br s, 1H, NH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[C:13]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:14]([CH:17]=[N:18][NH:19][C:20](=[S:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][S:16][C@H:11]12)=[O:8].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[C:13]([C:28]([O:30][CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])=[C:14]([C:17]3[S:27][C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:18]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NNC(=S)c3ccccc3)CS[C@H]12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3nnc(-c4ccccc4)s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 1 g of benzhydryl 7-thienylacetamido-3-thiobenzoylhydrazonomethyl-3-cephem-4-carboxylate in 10 ml of dioxane is added 0.28 g of DDQ, followed by stirring at room temperature for 30 minutes. The reaction mixture is filtered and the filtrate cake is washed with a small amount of dioxane. The combined filtrate is evaporated to dryness in vacuo and the residue recrystallized from ethyl acetate to give 0.6 g of benzhydryl 7-thienylacetamido-3-(5-phenyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([CH3:13])=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].C(N(C(C)C)C(C)C)C.[Cl-].[C:24]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([CH3:13])=[CH:8][C:3]=1[N:4]([C:27](=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH2:32][CH3:33])=[O:30])[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1cc(NC(C)C)c(C)cc1I
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)N(c1cc(C)c(I)cc1C)C(C)C
Temperature: 25 °C

Procedure:
2.0 g (6.9 mmol) of 2,5-dimethyl-4-iodo-N-isopropyl-aniline and 2.4 ml of (13.8 mmol) of N-ethyl-diisopropylamine are dissolved in 30 ml of tetrahydrofuran and, after the addition of 1.5 ml (10.5 mmol) of ethyl succinate chloride, refluxed for 2 hours. After cooling to ambient temperature the mixture is diluted with ethyl acetate and washed successively with 1 molar hydrochloric acid and 1 molar sodium hydroxide solution. The organic phase is dried over sodium sulphate and evaporated down.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14]2)([O-:3])=[O:2].OC1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2.[OH-].[K+].[N+:46](C1C=C([N+]([O-])=O)C=CC=1Cl)([O-:48])=[O:47]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:46]([O-:48])=[O:47])[CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1

Procedure:
2,4-Dinitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavane (0.226 g) was used in 5 ml of dry DMSO under nitrogen. Also KI (0.249 g) and KOH (0.112g) and 2,4-dinitrochlorobenzene (0.210 mg) were added in similar manner. Product was purified by column chromatography (CH2Cl2:n-heptane/75:25 as the eluant). 1H-NMR (400 MHz; d6-DMSO): δ 8.88 (d, 1H, J=2.8 Hz), 8.45 (dd, 1H, J=9.4 Hz, J=2.9 Hz), 7.48-7.30 (m, 5H), 7.14 (d, 1H, J=9.3 Hz), 7.10 (d, 1H, J=2.8 Hz), 7.05 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 6.98 (d, 1H, J=8.7 Hz), 5.16 (dd, 1H, J=10.2 Hz, J=2.1 Hz), 3.08-2.93 (m, 1H), 2.83-2.71 (m, 1H), 2.25-2.13 (m, 1H), 2.08-1.94 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=2)[CH:3]=1.[Mg].[C:18](=[S:20])=[S:19]>>[CH2:13]([S:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([SH:20])=[S:19])[CH:11]=[CH:10]2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCSc1ccc2cc(Br)ccc2c1
Reactant: S=C=S
Agent: [Mg]
Product: CCCCSc1ccc2cc(C(=S)S)ccc2c1

Procedure:
Compound 12 (3.71 g, 0.013 mol), magnesium turnings (0.94 g, 0.039 mol), carbon disulphide (1.09 g, 0.014 mol). A purple solid was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:41]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@@H:42]([C:55](O)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:41]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@@H:42]([C:55]([NH:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
The obtained wet crystals of D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (15 mL), Fmoc-D-Lys(Boc)-OH (444 mg, 948 μmol) and HOBt (12.8 mg, 94.7 μmol) were added at room temperature, and EDC HCl (200 mg, 1.04 mmol) was further added under ice-cooling. The mixture was warmed to room temperature and stirred overnight. Chloroform (20 mL), Fmoc-D-Lys(Boc)-OH (89 mg, 190 μmol) and EDC.HCl (40 mg, 210 μmol) were added, and the mixture was further stirred for 1 hr and concentrated under reduced pressure. The residue was precipitated with methanol (15 mL) to give Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.35 g, 85% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[Br:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[CH2:33][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Yield: 70 %

Procedure:
In an analogous manner to general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.20 g, 0.75 mmol) was treated with cesium carbonate (0.24 g, 0.75 mmol) and 1,3-bis(bromomethyl)benzene) (0.80 g, 3.00 mmol) to provide 0.23 g (70%) of 1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide. MS (ES) m/z 446.7; HPLC purity 98.5% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)[CH:27]=3)[CH2:24][C:23](=[O:39])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (115 mg).
Reaction SMILES: [Cl:1][CH:2]=[C:3](Cl)Cl.[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:13][O:12][C:6]1[CH:11]=[CH:10][C:9]([CH:3]([C:9]2[CH:10]=[CH:11][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH2:2][Cl:1])=[CH:8][CH:7]=1
Reactant: COc1ccccc1
Reactant: ClC=C(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C(CCl)c2ccc(OC)cc2)cc1
Temperature: 15 °C

Procedure:
To a 500-milliliter jacketed flask equipped with a mechanical stirrer, thermometer, and dropping funnel, and cooled to approximately 2° C. with circulating trichloroethylene thermostated cooling liquid, was charged 43.2 grams (0.40 mole) of anisole and 30.6 grams (0.20 mole) of commercial chloroacetal. To the cooled and stirred solution was added a solution of 80.0 grams (0.82 mole) of concentrated sulfuric acid dissolved in 50 milliliters of glacial acetic acid over a 1.17-hour period (1 hour and 10 minutes) at a rate sufficient to maintain the temperature at less than 15° C. When the addition was complete, the solution was stirred an additional 10 minutes, allowed to warm to 15° C. and poured into 1 liter of an ice/water mixture. The mixture was extracted with three 150-milliliter portions of diethyl ether, washed successively with three 100-milliliter portions of saturated aqueous sodium carbonate and three 100-milliliter portions of cold water, and dried over anhydrous sodium sulfate. Evaporation of the ether in vacuo yielded 55.0 grams (almost quantitative) of crude 1,1-bis(4-methoxyphenyl)-2-chloroethane as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:36][S:37]([O:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:53])[NH2:52])[CH:47]=2)[CH:42]=1)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].[NH:6]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([O:18][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:52])[NH2:53])[CH:47]=3)[CH:42]=2)=[O:17])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)Nc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C=CC(=O)Oc2ccc3cc(C(=N)N)ccc3c2)cc1
Yield: 42.6 %

Procedure:
To a solution of 3.0 g of 4-guanidinocinnamic acid methanesulfonate in 30 ml of anhydrous pyridine, was added 2.4 g of DCC. To the mixture, while being cooled in ice and stirred, was added 2.8 g of 6-amidino-2-naphthol methanesulfonate. After having been stirred for 24 hours, the reaction mixture was filtered to remove insolubles and the filtrate was mixed with ethyl ether to separate an only substance which was left standing at room temperature to crystallize. Upon recrystallization from a methanol-ethyl ether mixture, there was obtained 2.4 g of 6-amidino-2-naphthyl 4-guanidinocinnamate dimethanesulfonate.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:9][NH2:10])=[O:8])[CH2:2][CH2:3][CH3:4].[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CCCCc1ccccc1C(=O)NN
Reactant: O=CC=Cc1ccc([N+](=O)[O-])o1
Solvent: ClCCl
Product: CCCCc1ccccc1C(=O)NN=CC=Cc1ccc([N+](=O)[O-])o1
Temperature: 25 °C

Procedure:
A solution of 1.7 g of the butyl benzhydrazide mentioned under (4) above in 20 ml of dichloromethane is mixed with a solution of 3.5 g of 3-(5-nitro-2-furyl)acrylaldehyde in 20 ml of dichloromethane, and the mixture is stirred at room temperature. The yellow-brown product (precipitated after a reaction time of 3 hours) is sucked off, the filtrate is concentrated, and the resulting solid material is likewise isolated. The two precipitates are recrystallized together from 200 ml of ethanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>N1C=CC=CC=1>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]3[CH:17]=[CH:16][N:15]4[N:18]=[CH:19][C:20]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:28]=6)=[CH:25][CH:26]=5)=[C:14]4[N:13]=3)[C:5]2=[O:40])(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C[C@H](C(C)C)N(c3ccn4ncc(-c5ccc(-c6ncn(COCC[Si](C)(C)C)n6)cc5)c4n3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, Step 6; 0.160 g, 0.284 mmol) in pyridine was added 4-methylbenzene-1-sulfonyl chloride (0.136 g, 0.711 mmol) and the reaction stirred overnight at ambient temperature. The reaction was next concentrated in vacuo and the reaction chromatographed using EtOAc as eluent to yield (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl 4-methylbenzenesulfonate (0.14 g, 68.7%).