Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:28]([NH:32][S:33]([C:36]1[C:37]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:43][C:44]=1[F:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3 mL, 37.2 mmol) followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 50 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 40 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([O:27]C(C)(C)C)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl>C(#N)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: Cl
Solvent: CC#N
Product: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To the solution of tert-butyl 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinate (250 mg, 0566 mmol) in 10 ml of acetonitrile was added 6 M of hydrochloric acid (1 ml, 6 mmol). The reaction solution was stirred at room temperature for 1 hour and then at 60° C. for 2 hours. The crude reaction solution was concentrated and re-dissolved with 10 ml of acetonitrile. The resulting solution was evaporated in vacuo to give light brown oily product 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (215 mg, 0.56 mmol). ES/MS m/z 386.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][C:29](O)=[O:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)Cc1cnoc1-c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)Cc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.20 g), 5-phenyl-4-isoxazolylacetic acid (0.84 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-5-phenyl-4-isoxazolylacetamide (1.58 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:5][C:4]=1[N+:20]([O-])=O.C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[C:6]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([NH2:20])[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)COC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)COC(C)=O)cc1N
Temperature: 40 °C
Yield: 99.1 %

Procedure:
Acetic acid 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (625 mg, 2.00 mmol) was dissolved in 10 mL MeOH. Ethyl acetate (10 mL), ammonium formate (1.26 g, 20.0 mmol), and Pd/C (56 mg) were added and the mixture was heated to 40° C. overnight. The mixture was then filtered through celite and partitioned between sat'd NaHCO3 and EtOAc. The EtOAc extract was washed with brine. The washes were extracted once more with EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated to provide 500 mg of acetic acid 2-(3,5-diamino-4-methoxy-phenyl)-2-methyl-propyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:27][O:26][C:24]([CH:23]([OH:28])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:29])=[CH:17][CH:18]=1)=[O:25]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)C(O)Cc1ccc(OCC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 68.9 %

Procedure:
A mixture of 1.16 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 1.71 g of methyl 3-[4-(2-oxopropoxy)phenyl]lactate (prepared as described in Preparation 6) and 40 ml of benzene was heated under reflux for 3.5 hours, whilst the water being formed during the reaction was continuously removed. After completion of the reaction, the benzene used in the reaction was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of absolute methanol. 2.04 g of sodium cyanoborohydride were added, whilst ice-cooling, to the solution, and the resulting mixture was allowed to react overnight at room temperature. At the end of this time, methanol was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate and with an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.9 g of the title compound having an Rf=0.30 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([NH2:37])=[C:24]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[C:31]([F:36])[CH:30]=5)[CH:25]=3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)C.C(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]2[C:34]([CH:35]=[C:26]([C:24]3[C:23]([NH2:37])=[N:22][CH:21]=[C:20]([C:18]4[CH:17]=[N:16][N:15]([CH:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)[CH:19]=4)[CH:25]=3)[N:27]=[CH:28]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5ccc(F)cc5cn4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(F)cc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
For the deprotection, 1N HCl in diethyl ether (1.0 mL) was added to a solution of 4-{4-[6-amino-5-(7-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (entire quantity isolated in the previous step) in DCM (1.0 mL) in a sealed test tube. The reaction stirred at rt for 1 h. The mixture was concentrated in vacuo to give the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.37 (4H, br.s), 3.54-3.68 (3H, m), 4.20 (1H, d, J=5.6 Hz), 4.64 (1H, br.s), 7.58-7.72 (1H, m), 7.81 (1H, br.s), 7.98 (1H, br.s), 8.06 (1H, br.s), 8.27 (2H, br.s), 8.69-8.90 (2H, m), 9.48 (1H, br.s). HPLC: tR=1.74 min. (ZQ2, polar—5 min.). MS (ES+): m/z=389.18 (95) [MH+].
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C@@H:4]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:3]12.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:5]1[CH2:6][CH2:7][O:2][C@@H:3]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][C@@H:4]12)=[O:27]
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared according to the procedure of Example 2, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]-benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O.[OH-].[Li+]>CS(C)=O>[CH:7]([N:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]([NH:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[N:6]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1nc(N)c(C#N)n1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])n1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) in dimethylsulphoxide (590 ml) and stir in the presence of lithium hydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C. Pour the reaction mixture onto ice-water, stir for one hour, filter and wash the filter pad well with water to leave a yellow crystalline solid to give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile (73.7 g, 93% yield): 1HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm (tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25 ppm (s, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:37][CH:38]([F:41])[CH2:39]O>C(#N)C>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][O:5][CH2:39][CH:38]([F:41])[F:37])=[O:26])[CH2:30][CH2:29]1
Reactant: OCC(F)F
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOCC(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (218 mg, 0.5 mmol) obtained in Example 1201a), potassium carbonate (69 mg, 0.5 mmol, 1.0 eq.) and 2,2-difluoroethanol (0.5 ml) were suspended in acetonitrile (3 ml) and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was concentrated, and chloroform (10 ml) and water (10 ml) were added to the residue. After partitioning, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate) to give the title compound as a white powder (50 mg, 24%).
Reaction SMILES: [N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([OH:12])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([O:12][S:35]([CH3:34])(=[O:37])=[O:36])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 94.8 %

Procedure:
A solution of p-methoxybenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (310 mg., 0.82 mMol) and Et3N (1.72 μl, 1.23 mMol) in anhydrous CH2Cl2 (4 ml.) is cooled in an ice bath under N2. A solution of MeSO2Cl (83 μl, 1.07 mMol) in anhydrous CH2Cl2 (1 ml.) is added dropwise with stirring over 6 min. The resulting solution is stirred 15 more min. in the cold, then diluted with ice cold CH2Cl2 (5 ml.) and washed with ice cold H2O (5 ml.), 5% HCl (5 ml.), and 5% NaHCO3 (5 ml.). The CH2Cl2 solution is dried over MgSO4, filtered, and evaporated in vacuo to provide p-methoxybenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (355 mg.) as a pale yellow gum: ir (CHCl3) 4.78, 5.63, 5.78, 6.64, 7.43, 7.99, 8.48, and 11.08μ; nmr (CDCl3) δ2.03 (s, 3, CH3), 2.68 (s, 3, SO2CH3), 3.00 (d, l, J=14Hz, SCH), 3.80 (s, 3, OCH3), 3.82 (d, l, J=14Hz, SCH), 4.47 (d, l, J=1.3Hz, H7), 4.65 (s, l, H4), 4.97 (d, l, J=1.3 Hz, H6), 5.00 and 5.28 (ABq, 2, J=10.5 Hz, CH2Ar), and 6.87 and 7.33 (two d's, 4, J=9Hz, ArH).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:26][C:25]([CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:26][C:25]([CH2:27][CH2:28][NH:29][C:10]([C:2]3[CH:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1cc2ncccn2n1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc2ncccn2n1
Yield: 53.3 %

Procedure:
The title compound was prepared using the method of Example 20 but starting from pyrazolo[1,5-a]pyrimidinecarboxylic acid (82 mg; 0.5 mmol) and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (146 mg; 0.5 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% DCM/MeOH) to obtain 107 mg of the title compound. The product was further purified by trituration in toluene to give 55 mg of pure product (27%). 1H-NMR (400 MHz; d1-CDCl3): δ 3.06 (t, 2H), 3.83 (m, 2H), 6.233 (d, 1H), 6.61 (d, 1H), 6.93 (dd, 1H), 7.35-7.41 (m, 2H), 7.44 (dd, 1H), 7.70 (d, 1H), 8.55 (dd, 1H), 8.57-8.60 (m, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.C[NH:17][C:18](=[NH:20])S.OS(O)(=O)=O>>[NH2:20][C:18]1[O:14][C:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:5][C:4](=[O:3])[N:17]=1
Reactant: CNC(=N)S
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: Nc1nc(=O)cc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared from ethyl(4-chloro)benzoylacetate (5.0 g, 22 mmol) (obtained in preparation 2) and methylthiopseudourea.H2SO4 (3.31 g, 12 mmol) by following the procedure described in preparation 4, (0.573 g, 11.6%). MS m/z: 223 (M+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[K+]>O.CO>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1sc2ncccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc2ncccc2c1Br

Procedure:
A solution of ethyl 3-bromothieno[2,3-b]pyridine-2-carboxylate (14a) (50 mg, 0.17 mmol) and potassium hydroxide (96 mg, 1.7 mmol) in water (2 mL) and methanol (2 mL) was stirred at 80° C. for 1 hour. Water (10 mL) was added to the reaction mixture which was washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 4 with a hydrochloric acid aqueous solution 1N and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired acid (14b) as a white solid without further purification (30 mg, 0.12 mmol, 68%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C@H:10]([CH2:25][CH2:26][CH3:27])[C@H:11]([CH3:24])[C:12](N1C2C=CC=CC=2OC1=O)=[O:13]>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C@@H:11]([CH3:24])[C@H:10]([OH:9])[CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[C@@H](O)[C@H](C)C(=O)n1c(=O)oc2ccccc21
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@H](C)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
Benzylamine (0.6 mL, 5.5 mmol) is added dropwise to a solution of N-[(2S*,3R*)-3-hydroxy-2-methylhexanoyl]-2-benzoxazolinone (1.31 g, 5.0 mmol) in 10 mL of tetrahydrofuran. A mildly exothermic reaction ensues. After 15 min, the solvent is evaporated. The residue is redissolved in 50 mL of CH2Cl2 and washed successively with equal volumes of 1 N HCl, 1 N NaOH, water, and brine. After drying over MgSO4, the solution is evaporated to yield 1.12 g (95% yield) of the product as a white solid which was recrystallized from ethyl acetate/hexanes as white needles, mp 114-115° C. 1H-NMR (d6-DMSO, 400 MHz) δ 8.27 (t, J=6, 1H), 7.30 (m, 2H), 7.22 (m, 3H), 4.49 (d, J=6, 1H), 4.27 (dd, J=6, 15, 1H), 4.20 (dd, J=6,15, 1H), 3.44 (m, 1H), 2.20 (q, J=7, 1H), 1.43 (m, 1H), 1.22 (m, 3H), 1.04 (d, J=7, 3H), 0.79 (t, J=7, 3H). 13C-NMR (d6-DMSO, 100 MHz): 175.2, 140.2, 128.6, 127.6, 127.1, 71.8, 46.9, 42.2, 37.6, 19.0, 14.7, 14.5.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([Cl:23])[CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[C:22]([N:21]=1)=[C:13]1[C:14]([C:4]3[C:3]([S:9](=[O:11])(=[O:10])[NH:12]1)=[CH:2][CH:7]=[C:6]([Cl:8])[CH:5]=3)=[CH:15][CH:16]=2
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3ccc(Cl)nc23)-c2cc(Cl)ccc21
Yield: 42.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(2-chloro-quinolin-8-yl)-benzenesulfonamide (Intermediate 287) (0.1 g, 0.27 mmol), t-butyl nitrite (0.05 ml, 0.41 mmol) and AcOH:THF (1 ml: 2 ml), gave the title compound (0.04 g, 45%) after purification by column chromatography with DCM/MeOH (90:10) as the eluent.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][F:22])[S:10]2)[C@H:6]1[O:23]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:22][CH2:21][CH2:20][NH:19][C:9]1[S:10][C@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:23])[C@H:7]2[N:8]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2SC(NCCF)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H]2SC(NCCF)=N[C@@H]2[C@@H](O)[C@@H]1O
Yield: 91.3 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(2-fluoroethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (29 g, 74 mmol) in methanol (200 mL) was treated with potassium carbonate (1 g, 7 mmol) overnight at room temperature. The solids were collected by filtration and washed with dichloromethane (3×50 mL) to afford compound 67 as a white solid (18 g, 92%). (ES, m/z) [M+H]+ 266.9; 1H NMR (300 MHz, D2O) δ 6.21-6.23 (d, J=6.3 Hz, 1H), 4.55-4.59 (m, 1H), 4.40-4.44 (m, 1H), 4.10-4.14 (t, J=5.7 Hz, 1H), 3.95-3.98 (t, J=5.4 Hz, 1H), 3.70-3.75 (m, 1H), 3.40-3.62 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]([C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[S:29])[CH:24]=[CH:25][CH:26]=1)#[N:20]>C(OCC)(=O)C.ClCCl>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: N#Cc1cccc(N=C=S)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C#N)c1
Yield: 84.4 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 3-cyanophenyl isothiocyanate (0.649 g, 4.0 mmol). Trituration in boiling ethyl acetate/dichloromethane (1:1) gave the product (1.358 g); m.p. 183-185° C.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH2:13]1[C:18](=O)[N:17](Br)[C:15](=[O:16])[CH2:14]1.COC(=O)C1C=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1C.N>C(Cl)(Cl)(Cl)Cl>[N+:30]([C:27]1[CH:28]=[C:13]2[C:14](=[CH:25][CH:26]=1)[C:15](=[O:16])[NH:17][CH2:18]2)([O-:32])=[O:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
AIBN (58.6 mg, 0.357 mmol), NBS (785 mg, 4.46 mmol), and 2-methyl-4-nitrobenzoic acid methyl ester (696 mg, 3.57 mmol) were suspended in CCl4 (35 mL) in a sealed tube. The above mixture was flushed with N2 for 5 min and heated at 80° C. for 22 h. After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain a crude light-brown solid. To above solid was added NH3 (7 N in MeOH, 5 mL), and the mixture was stirred at rt for 2 h and concentrated in vacuo to obtain a yellow solid. This crude solid was triturated with EtOAc (15 mL) and was then cooled at −20° C. The mixture was filtered to obtain the title compound as yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=4.51 (s, 2H), 7.13 (brs, 2H), 7.91 (d, 1H, J=8.4 Hz), 8.25 (dd, 1H, J=2.0 & 8.4 Hz), 8.48 (d, 1H, J=2.0 Hz), 9.04 (brs, 1H). MS (ES+): m/z 179.22 (100) [MH+]. HPLC: tR32 2.14 min (ZQ2000, polar—5 min).