Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]=[CH:32][N:33]([C@@H:36]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]3[O:38][C:39](=[O:41])[CH3:40])[C:34]=2[NH2:35])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]=[CH:32][N:33]([C@@H:36]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]3[O:38][C:39](=[O:41])[CH3:40])[C:34]=2[NH:35][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[S:13])=[O:29])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(c3ccccc3)c3ccccc3)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(N=C=S)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(c3ccccc3)c3ccccc3)c2NC(=S)NC(=O)OCc2ccccc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 46 h
Yield: 98 %

Procedure:
Four portions of benzyloxycarbonyl isothiocyanate (Caution: stench, handle in a well ventilated hood only, crude, 2.0 g each, total 41 mmol) were added to a solution of 5-amino-1-(2,3,5-tris-O-acetyl-β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid diphenylmethyl ester (1.1 g, 2 mmol) in CH2Cl2 (10 mL) at 0 h, 6 h, 22 h and 30 h. The reaction mixture was stirred at room temperature under an argon atmosphere for a total of 46 h after the addition of the first portion of benzyloxycarbonyl isothiocyanate, then chromatographed on silica gel (100 g, column packed in CH2Cl2, 100-mL fractions), with CH2Cl2 (100 mL), followed by 25% EtOAc in CH2Cl2 as the eluant. Fractions 6 to 11 were combined, concentrated, and pumped under reduced pressure to give 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5-[[[[(phenylmethoxy)carbonyl]amino]thioxomethyl]amino]-1H-imidazole-4-carboxylic acid diphenylmethyl ester as a pale yellow foam: 1.46 g (98% yield); IR (CHCl3) 3405, 3250, 3200, 1750, 1738, 1600, and 1505 cm-1 ; HRMS [(+) FAB] m/z found 767.2060 [calcd for C37H36N4NaO11S, 767.1999 (M+Na+)], 745.2297 [calcd for C37H37N4O11S, 745.2180 (M+H+)]; NMR (CDCl3)δ2.04 (s, 3), 2.10 (s, 3), 2.13 (s, 3), 4.33 (m, 2), 4.39 (m, 1), 5.10 (s, 2), 5.35 (m, 1), 5.52 (m, 1), 5.87 (m, 1), 7.10 (s, 1), 7.32 (m, 15), 7.87 (s, 1), 8.16 (s, 1), 10.95 (s, 1); UV max (95% C2H5OH) 215 nm (sh, ε35000), 266 (13850).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[C@H:14](OS(C)(=O)=O)[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:10]1)=[O:7])(C)(C)C>N1C=CC=CC=1>[O:7]=[C:6]1[NH:8][C@@H:9]2[CH2:10][N:11]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:12][CH2:13][C@@H:14]2[O:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Solvent: c1ccncc1
Product: O=C1N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]2O1

Procedure:
A solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)piperidine-1-carboxylate in pyridine (0.16 M) was heated to 120° C. in the microwave for 10 minutes. The solution was then concentrated to almost dryness and the forming solid was filtered to give the desired product. The filtrate was further purified via silica gel column chromatography eluting with ethyl acetate (100%) to yield (3aR,7aS)-benzyl 2-oxohexahydrooxazolo[4,5-c]pyridine-5(6H)-carboxylate in 75% combined yield. LCMS (m/z): 277.1 (MH+), Rt=2.327 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([OH:25])=[N:23][N:24]=1.[CH3:26][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([O:25][CH3:26])=[N:23][N:24]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(O)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1nnc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)s1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-((5-hydroxy-1,3,4-thiadiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (100 mg, 0.26 mmol) from step 2 in dichloromethane (8 mL) and methanol (2 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 0.65 mL, 1.3 mmol). The reaction mixture was stirred with gradual warming to ambient temperature over 1 h and concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (69 mg, 0.17 mmol, 66%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A mixture of 2-chloro-6-fluorobenzyl chloride (52.9 g, 0.296 mol) and 2-amino-3hydroxypyridine (29.6 g, 0,269 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (46.7 g, 62%), m.p. 123°-130° C.
Reaction SMILES: [CH:1]1([N:7]([CH3:24])[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[N:12]=[CH:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C.CO>[NH2:21][C:17]1[CH:16]=[C:15]([C:13]2[N:12]=[CH:11][N:10]([C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:24])=[O:9])[CH:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C(=O)n1cnc(-c2cccc([N+](=O)[O-])c2)c1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)n1cnc(-c2cccc(N)c2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.7 %

Procedure:
10% Palladium on carbon (0.122 g, 0.115 mmol) was added to a stirred solution of N-cyclohexyl-N-methyl-4-(3-nitrophenyl)-1H-imidazole-1-carboxamide (0.755 g, 2.299 mmol) in a mixture of ethyl acetate (46 mL) and methanol (46 mL) under an atmosphere of argon at room temperature. The mixture was then allowed to stir at room temperature under an atmosphere of hydrogen for 50 minutes. The mixture was filtered through celite and the pad was washed with methanol. The combined filtrate was evaporated to give a clear oil/foam (691 mg, 100%) that was used in the next step without further purification.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH2:25][C:26]4[N:27]=[N:28][N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=4)[C:17](=[O:50])[CH:16]([NH:51][C:52]([NH:54][C:55]4[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=4)=[O:53])[C:15]3=[O:62])=[N:9]2)C=CC=CC=1.Cl.O>CO>[NH:30]1[C:26]([CH2:25][N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([CH2:13][C:10]3[NH:9][N:8]=[N:12][N:11]=3)[C:15](=[O:62])[CH:16]([NH:51][C:52]([NH:54][C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)=[O:53])[C:17]2=[O:50])=[N:27][N:28]=[N:29]1
Reactant: Cc1cccc(NC(=O)NC2C(=O)N(Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c3ccccc3N(Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)NC2C(=O)N(Cc3nnn[nH]3)c3ccccc3N(Cc3nnn[nH]3)C2=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
To a solution of Compound 8k (353 mg, 0.363 mmol) in methanol (20 ml) is added 10% HCl (5 ml) and the mixture is stirred for 15 hr at room temperature. After the addition of water (150 ml), the mixture is extracted with ethyl acetate. The organic layer is washed with water and extracted with 10% aqueous sodium carbonate. The aqueous layer is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and distilled under reduced pressure to remove the solvent. Crystallization from methanol/benzene gives Compound 81 (118 mg, 66.7%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:4]1[C:18](Cl)=[O:19])[CH3:2].Cl.[CH3:22][N:23](C)O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:22][NH:23][C:18]([C:4]1[N:3]([CH2:1][CH3:2])[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=1)=[O:19]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)Cl
Reactant: CN(C)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Reaction time: 4 h
Yield: 93.6 %

Procedure:
This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride (70 mL) and stirred at room temperature for 2 hours to give 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) after a usual workup. 1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35 mL) and added to a prepared solution of N,O, dimethyl-hydroxylamine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine (13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes. The reaction was complete after 4 hours. Solvent was removed in vacuo and the residue was taken back in a mixture of saturated aqueous NH4Cl: H2O (1:1, 150 mL) solution and extracted with ether. Combined ether extracts were washed with brine dried (MgSO4) and filtered. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave the title compound as a light yellow oil (2.48 g g, 82% yield), 1H NMR (400 MHZ, CDCl3) □ 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), MS m/e (M+H)+ 313.1.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white solid. UPLC-MS (condition 1) tR=1.61 min, m/z=459.0 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.53 (s, 3H) 2.88 (d, J=11.49 Hz, 1H) 3.15-3.27 (m, 2H) 3.38 (td, J=9.96, 7.21 Hz, 1H) 4.15-4.22 (m, 1H) 4.84 (d, J=3.42 Hz, 1H) 7.34 (d, J=8.07 Hz, 3H) 7.68 (dd, J=7.95, 2.32 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.99 (d, J=2.45 Hz, 1H) 8.48 (d, J=2.20 Hz, 1H) 8.75 (d, J=2.45 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CS(C)=O.C1COCC1.[Cl-].[NH4+]>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:23][CH:22]=[CH2:21])[C:8]#[N:9]
Reactant: CC(C#N)c1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=CCC(C)(C#N)c1ccccc1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of 2-phenylpropionitrile (4.04 g, 30.79 mmol) in 40 mL of DMSO was added 34 mL (34 mmol) of a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) in THF over a 5 minute period. After 10 minutes, allyl bromide (6 mL, 69.33 mmol) was added dropwise (exothermic). The mixture was cooled with an ice-water bath. The mixture stirred for 20 minutes, becoming a solid mass. An additional 20 mL of DMSO was added. After 10 minutes, the mixture was diluted with 200 mL of ammonium chloride and extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with six 75 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5.25 g (99.5% yield) of 2-methyl-2-phenylpent-4-enenitrile as yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].C(NC(C)C)(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([S:40][CH:41]([CH3:43])[CH3:42])[CH:31]=2)=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C@@H:2]([NH:1][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([S:40][CH:41]([CH3:42])[CH3:43])[CH:31]=2)=[CH:28][CH:29]=1)[CH3:12]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(-c2ccc(OCCBr)cc2)cc1SC(C)C
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1SC(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 4-[(1R,2S)-2-amino-1-hydroxypropyl]-phenol (75.4 mg) in N,N-dimethylformamide (1 ml) were added diisopropylamine (72.9 μl) and methyl 4′-(2-bromoethoxy)-3-(isopropylthio)-4-biphenylcarboxylate (142 mg) in N,N-dimethylformamide (0.4 ml) at room temperature and stirred at 100° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution, water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give methyl 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-amino]ethoxy]-3-(isopropylthio)-4-biphenylcarboxylate (113 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5].[Cl:13]N1C(=O)CCC1=O>CC#N>[Cl:13][C:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc([N+](=O)[O-])c1N
Solvent: CC#N
Product: COc1cc(Cl)cc([N+](=O)[O-])c1N
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 21, Step A (26.6 mmol, 4.5 g) in MeCN (30 mL) at 60° C. was added N-chlorosuccinimide (29 mmol, 3.9 g). The solution was brought to reflux for 2 h and allowed to stand at ambient temperature for 16 h. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3. The organic phase was washed with brine, dried with Na2SO4, and concentrated in vacuo to afford the product as a brown solid. LC-MS (ESI, Method B): 2.14 min, m/z 203.11 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([CH3:33])(=[O:32])=[O:31]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:33][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:31])=[O:32]
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1COc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 40 °C
Yield: 3.3 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.245 mmol) was dissolved in DMF (1.5 mL). K2CO3 (42 mg, 0.30 mmol), tetrabutylammonium iodide (14 mg, 0.038 mmol), and 1-bromomethyl-2-methylsulfonyl-benzene (which is available from Combi-Blocks; 62 mg, 0.25 mmol) were added. The reaction mixture was heated at 40° C. for 13 h. The reaction mixture was cooled to room temperature and partitioned between H2O (5 mL) and EtOAc (5 mL). The organic layer was dried (Na2SO4), filtered, evaporated, and purified twice by chromatography (40-60% EtOAc/hexanes) to give 3-[4-(2-methanesulfonyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (3 mg, 3%) as a white powder. HRMS Calcd. for C18H17N2O5S (M+H)+, 373.0853. Found: 373.0854.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:34](Cl)(Cl)=[S:35].C1C=CC(C2C(=O)C3(OC(=O)C4C3=CC=CC=4)OC=2)=CC=1>O.C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][N:9]([CH2:10][C:11]([OH:13])=[O:12])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1)=[C:34]=[S:35]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CC(CN(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C1OC2(OC=C(c3ccccc3)C2=O)c2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CN(CC(=O)O)CC(Cc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O

Procedure:
The precursor 5 (0.33 mmol) was taken up in H2O (10 ml) and stirred rapidly in a 10 ml round bottom flask fitted with an addition funnel. The pH was adjusted to 8.5 with solid NaHCO3 and thiophosgene (42 mg, 0.365 mmol) in CHCl3 (10 ml) was added dropwise. Stirring was continued until the solution tested negative for amine by the fluorescamine method. The aqueous layer was taken to dryness. Purification was done by column chromatography on a 1×30 cm Florisil™ column eluted with acetonitrile:water (30:8). The product eluted from the column cleanly as determined by TLC and was stored in a dessicator in a freezer and re-purified immediately prior to use.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+]>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Temperature: 0 °C

Procedure:
6-Chloro-3-nitropyridine (54.5 grams), 4-chlorothiophenol (50.0 grams), and lithium hydroxide (12.5 grams) were mixed in about 500 ml. of DMF and stirred overnight (about 18 hours) at room temperature. The reaction mixture was poured into ice-water, filtered, and the separated product washed three times with water and air dried, yield, 100 grams.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Product: CCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-butyl chloroformate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-])=O.[OH-].[Na+]>CC(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2scnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1ccc2scnc2c1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A mixture of 3.46 g of 5-nitrobenzothiazole and 15.7 g of stannous chloride dihydrate in 55 mL of 2-propanol is heated to reflux for 3 hours. The cooled reaction mixture is poured into 150 mL of ice/water and neutralized to pH 7 using solid sodium hydroxide. The mixture is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered through a short pad of silica gel, and rotary evaporated to provide 2.45 g of 5-aminobenzothiazole as a yellow-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([NH2:15])[CH:5]=1.[CH:17](O)=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][C:13]#[N:14])[CH:17]=[N:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: O=CO
Reactant: COC(=O)c1ccc(NCCC#N)c(N)c1
Product: COC(=O)c1ccc2c(c1)ncn2CCC#N
Temperature: 50 °C
Yield: 95 %

Procedure:
To 3-amino-4-(2-cyano-ethylamino)-benzoic acid methyl ester (4.0 g) was added formic acid (25 ml) and the mixture heated to 50° C. for 3 h. It was then concentrated and the residue recrystallised from EtOAc to afford 4.0 g (95%) of 1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 230 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.95 (t, 2H), 4.0 (s, 3H), 4.55 (t, 2H), 7.4 (d, 1H), 8.1 (m, 1H), 8.15 (s, 1H), 8.55 (s, 1H)