Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].CO.C(Cl)Cl.CO>CN(C=O)C>[CH3:22][N:23]([CH:25]=[N:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CN(C)C=Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
100 mg (0.37 mmol) of 7-amino-3-β-D-ribofuranosyl-(3H)-1,2,3-triazolo[4,5-d]pyrimidine are left to stir overnight, at room temperature, in 2 ml of dry DMF and 0.25 ml (1.85 mmol) of N,N-dimethylformamide dimethyl acetal. 4 ml of methanol is then added to this reaction mixture. After having been stirred for a further 2 hours, the mixture is evaporated to dryness, and the residue is coevaporated with toluene and then chromatographed on silica gel. (Column: 3×20 cm, eluent CH2Cl2 /MeOH 98:2-90:10). 0.06 g (52%) of a colorless, glassy solidified substance is obtained in the main zone. TLC (silica gel, CH2Cl2 /MeOH=9:1): Rf =0.25 UV λmax (ε)=235, 325.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].[CH:14]([CH:16]=O)=[O:15].Cl>C(O)(=O)C>[CH3:4][C:2]([C:5]1[C:6]2[O:13][C:14](=[O:15])[CH2:16][C:7]=2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: O=CC=O
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(c(C(C)(C)C)c1)OC(=O)C2
Temperature: 120 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
In 1600 ml of acetic acid were dissolved 400 g of 2-(1,1-dimethylethyl)-4-methoxyphenol, 360 g of 40% glyoxal solution and 20 ml of 36% hydrochloric acid and the solution was heated at 120° C. with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure and allowed to stand overnight. The resultant solid residue was washed with diethyl ether to give 105 g of 7-(1,1-dimethyethyl)-5-methoxy-2(3H)-benzofuranone as a light red solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([O:12]CC)=[O:11]>C(O)C>[F:16][C:4]([F:3])([F:15])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1scnc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1scnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
An aqueous sodium hydroxide solution (2 ml) was added to a solution of ethyl 4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (301 mg) in ethanol (3 ml), followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and water was added thereto, followed by washing with diethylether. A 1M hydrochloric acid (2 ml) was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid (261 mg) as a light brown solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[N:16]=[C:15]2[NH:17][CH:18]=[CH:19][C:14]2=[CH:13][CH:12]=1)[CH2:9][CH3:10])(C)(C)C.Cl>O1CCOCC1>[NH:17]1[C:15]2=[N:16][C:11]([CH:8]([NH2:7])[CH2:9][CH3:10])=[CH:12][CH:13]=[C:14]2[CH:19]=[CH:18]1
Reactant: CCC(NC(=O)OC(C)(C)C)c1ccc2cc[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(N)c1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.8 %

Procedure:
To a solution of [1-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-propyl]-carbamic acid tert-butyl ester (230 mg, 0.84 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (500 uL, 2.00 mmol). The reaction was stirred at room temperature for 1 h. Solvents were removed and the resulting brown oil was suspended in Toluene (3 mL×2). Removal of solvents to dryness affords 197 mg of the title compound 1-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-propylamine as a HCl salt, m/z 176.40 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
A mixture of 2-ethylanthraquinone (25 Kg, 105.9 mol), NBS (19.1 Kg, 107.3 mol) and benzoyl peroxide (70%, 200 g, 0.58 mol) in CCl4 (˜150L) is stirred at reflux for 1.5 hours. On cooling, the precipitate is collected by filtration and washed on the filter with ethanol, hot water and finally ethanol again. After drying, this may be used without further purification (i.e. recrystallisation from benzene/methanol (1:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH2:20]([N:24]1[C:28](=[CH2:29])[C:27]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:26][C:25]1=[O:35])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][C:27]3([O:26][C:25](=[O:35])[N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[C:28]3=[CH2:29])[CH2:30][CH2:31]2)=[CH:4][CH:3]=1
Reactant: C=C1N(CCCC)C(=O)OC12CCNCC2
Reactant: Clc1ccc(C(=CCCBr)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)CC2
Reaction time: 5 h
Yield: 79 %

Procedure:
10.7 g of 4,4-bis(4-chlorophenyl)-3-butenyl bromide are added to the solution of 4.5 g of 3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of acetone containing 4.20 g of anhydrous potassium carbonate and 0.5 g of potassium iodide. The heterogeneous reaction mixture is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, water is added to the residue and extracted with benzene. The benzene phase is washed with water until halide-free, filtered through a silica gel bed and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 79.0% yield, m.p.: 110°-111° C.
Reaction SMILES: C(O)(=O)C.[CH:5]1([O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[N+:20]([O-:22])=[O:21])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[BH4-].[Na+]>CS(C)=O>[CH:5]1([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])/C=C/c1ccc(OC2CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To an acetic acid (3.3 mL) and dimethyl sulfoxide (55 mL) solution of 1-cyclohexyloxy-4-((E)-2-nitro-vinyl)-benzene (3.3 g, 13.1 mmol) described in Manufacturing Example 79-1-2 was added sodium borohydride (793 mg, 21 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (1.45 g, 44%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([O:23][CH3:24])(=[O:22])[C:20]#[CH:21].CN1CCOCC1>CC#N>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18]/[CH:21]=[CH:20]/[C:19]([O:23][CH3:24])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccc(O)c1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)/C=C/Oc1cccc(CCCO[Si](C)(C)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
To a solution of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenol (1.78 g) in MeCN (10 mL) were added methyl propiolate (0.667 mL) and NMM (0.0441 mL) at ambient temperature and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=97:3) to afford methyl (2E)-3-[3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenoxy]-acrylate (1.80 g) as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:8][CH2:9][CH:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC(CN)CC(=O)OCc1ccccc1
Yield: 88 %

Procedure:
A solution of (38) (1.77 g, 4.78 mmol) in 4M HCl in dioxane (20 mL) was stirred at ambient temperature for 30 min. Removal of the solvent in vacuo afforded the title compound (39) as a white crystalline solid (1.4 g, 88%). 1H—NMR (CDCl3, 400 MHz): δ 0.85 (d, 6H), 1.17 (m, 1H), 1.30 (m, 1H), 1.58 (m, 1H), 2.32 (m, 1H), 2.57 (m, 2H), 3.03 (m, 2H), 5.09 (s, 2H), 7.30 (m, 5H), 8.39 (br.s, 3H). MS (ESI) m/z 250.25 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: CN(C)CCN
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)NCCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ccncc3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 4-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (117 mg, 60.9% yield) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1c(C)nc(-c2ccc(NC(=O)CCl)cn2)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 52 (0.100 g, 0.434 mmol) in THF (5 mL), was added triethylamine (0.065 g, 0.65 mmol) and chloroacetylchloride (0.073 g, 0.65 mmol), and the reaction mixture was stirred at room temperature for a period of 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][C:12]([Cl:18])=[CH:13][CH:14]=2)[N:9]=1.C(N(CC)CC)C.CO>C(Cl)Cl>[Cl:18][C:12]1[N:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([NH:7][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[N:9]2)=[CH:14][CH:13]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc2ccc(Cl)nc2n1
Temperature: 4 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Methacryloyl chloride (9 g) dissolved in methylene chloride (30 cc) is added in the course of 20 minutes to a solution of 2-amino-7-chloro-1,8-naphthyridine (9 g) and triethylamine (19 g) in methylene chloride (300 cc). After 30 minutes' heating under reflux, the solution obtained is washed with 0.5 N hydrochloric acid (150 cc) and distilled water (2×150 cc) and then concentrated to dryness under reduced pressure (4 kPa). The solid obtained (13.5 g) is dissolved in boiling methanol (350 cc). After 3 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with methanol (2×30 cc) and dried in the air. The isolated product (9 g; m.p. 195° C.) is then added in the course of 5 minutes to concentrated sulphuric acid (d=1.83; 19 cc). The reaction mixture is heated for 10 minutes to 60° C., stirred for 1 hour at 25° C. and then poured into distilled water (200 cc). The precipitate formed is separated by filtration, washed with distilled water (5×20 cc) and recrystallized in acetonitrile (70 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)methacrylamide (5.4 g), m.p. 182° C., is thereby obtained.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1OCC)(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]>>[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1[NH2:1])(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]
Reactant: N
Reactant: CCOc1c(NC/C=C/CP(=O)(OCC)OCC)c(=O)c1=O
Product: CCOP(=O)(C/C=C/CNc1c(N)c(=O)c1=O)OCC
Reaction time: 72 h
Yield: 68 %

Procedure:
Ethanolic ammonia (235 mL) was combined with [(E)-4-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester (7.15 g, 21.6 mmol) and the solution was left stirring for 3 days and then evaporated. Recrystallization from methanol in ethyl acetate removed a yellow impurity, but flash chromatography (7.5 cm diameter, elution with 5% methanol in dichloromethane) was required to eliminate a more polar contaminant. Recrystallization of this material with methanol in ethyl acetate (final volume=200 mL) afforded [(E)-4-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester as a flocculant white solid (4.43 g, 68%, mp 145°-147° C.); IR (KBr, cm-1): 3280, 3100, 1800, 1640; MS (+FAB): 303 (MH+, 100), 135 (62); 1H NMR (DMSO, 400 MHz): δ 7.5 (br s, 3NH), 5.74-5.68 (m, 1H), 5.57-5.48 (m, 1H), 4.09 (br s, 2H), 4.02-3.91 (m, 4H), 2.64 (d of d, J=21.5 and 7 Hz, 2H), 1.19 (t,J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)nc1
Product: Nc1ccc(Oc2ccnc(Cl)c2)nc1
Yield: 34.8 %

Procedure:
Using a procedure analogous to Example A1, 5-amino-2-hydroxypyridine (10.15 g, 92 mmol) and 2,4-dichloropyridine (13.64 g, 92 mmol) were combined to provide 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (7.09 g, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (m, 1H), 7.61 (m, 1H), 7.26 (m, 1H), 7.0 (s, 1H), 6.97-6.94 (m, 2H), 5.4 (brs, 214); MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(=NOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
15.1 g of trityl chloride were added over 20 minutes to a cooled mixture of 11.45 g of the product of Step A, 23 ml of dry dimethylformamide, 45 ml of dry methylene chloride and 7 ml of triethylamine and 50 ml of hydrochloric acid were added thereto with stirring. The mixture was decanted and the aqueous phase was extracted with methylene chloride. The organic extracts were washed with water, reextracted, dried and vacuum filtered. The filtrate was evaporated to dryness to obtain 30.1 g of raw anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetate.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:32][CH2:31][C:29]1[N:28]=[N:27][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CN)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a slurry of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (120 mg, 0.15 mmol) In DCM (1.5 mL) at 0° C. was added TFA: DCM (1:1, 4.5 mL) followed by triethylsilane (72 μL, 0.45 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE: Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (11.3 mg, 14%). LCMS: m/z=528.9 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 7.30 (s, 2H), 6.75 (s, 1H), 5.27 (dd, J=8.6, 5.6 Hz, 1H), 4.82 (qd, J=14.9, 5.0 Hz, 2H), 4.23 (q, J=5.1 Hz, 1H), 4.09 (s, 2H), 1.37 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C1(CNCC2CCCCC2)CCCCC1.[C:27]([NH:35][C:36]1[CH:48]=[C:47]([CH:49]=[CH2:50])[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C(=O)C>[C:27]([NH:35][C:36]1[CH:48]=[C:47](/[CH:49]=[CH:50]/[C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)NC(=O)C3)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 35 %

Procedure:
0.20 g of 6-bromo-2-oxoindoline, 0.40 mL of N,N-dicyclohexylmethylamine and 18 mg of trans-di(μ-acetato)bis-o-(di-o-tolylphosphino)benzyl dipalladium(II) were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.46 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 7 hours. After the reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoate as green solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]#[C:10][Si](C)(C)C)[CH:5]=[N:6][CH:7]=1.CC([O-])(C)C.[K+].O>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:8][CH:9]=[CH:10][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cncc(NC#C[Si](C)(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of the compound of step 1 (5.12 g, 25.1 mmol) in NMP (125 ml) was added dropwise at room temperature to potassium tert-butylate (5.91 g, 52.6 mmol) in NMP (125 ml). The reaction mixture was stirred for 4 h at room temperature, then water was added and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 2.5 g of the title compound.