Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)(=[O:17])=[O:16].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)=[C:8]([NH:14][S:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH:22]=2)(=[O:17])=[O:16])[CH:9]=1
Reactant: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in pyridine (4 ml) was added methanesulfonyl chloride (70 μl, 0.90 mmol). The reaction was stirred at room temperature for 2 hours and was concentrated, diluted with 1M HCl, and extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4% EtOAc in hexane) to yield the title compound (344 mg, 67%).
Reaction SMILES: O.[CH3:2][C:3](C1C=CC(O)=CC=1)([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[CH3:4].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:8]1([OH:11])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1.[C:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[OH:25])([CH3:4])=[CH2:2]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: C=C(C)c1ccccc1O

Procedure:
The mother liquor from the primary system contains water, acetone, impurities and residual BPA. This mother liquor is passed through preheaters into a flash chamber where the water, acetone and a portion of the phenol is flashed to a vapor. This vapor is fed to a distillation column for separating the water and acetone from the lower vapor pressure phenol. The bottoms stream from the flash chamber includes a concentration of impurities and residual BPA in a phenol carrier. From this stream, a small purge is taken to a catalytic decomposition zone where the phenol is distilled overhead and the BPA and impurities are cleaved at high temperature to form phenol and isopropenyl phenol. Phenol is recovered as raw material and recycled to the reaction zone. Uncleavable "heavies" and polymers are purged from the system as "tars." The balance of the flash pot bottoms stream is recycled to the reaction zone.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8](Cl)=[O:9])[CH3:2].[CH3:15][NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]2.C(N(CC)CC)C.CCCCCC>C1COCC1.C(OCC)(=O)C>[OH:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:17][N:16]([CH3:15])[C:8]([C:7]1[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C:3]=1[CH2:1][CH3:2])=[O:9])[CH:27]=[CH:26]2
Reactant: CNCc1ccc2cc(O)ccc2c1
Reactant: CCc1oc2ccccc2c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
2-Ethyl-benzofuran-3-carbonyl chloride, prepared in step 2 of Example 21, in 50 mL of anhydrous THF was added under nitrogen dropwise over 1 h to a suspension of 6-methylaminomethyl-naphthalen-2-ol (1.48 g, 7.9 mmol), prepared in the previous step, and triethylamine (1.1 mL, 7.9 mmol) in 150 mL anhydrous THF at room temperature. The reaction stirred at room temperature for 20 h (overnight). The solid present was removed by filtration and the filtrate concentrated under reduced pressure to give a brown foam. The foam was dissolved in ethyl acetate and extracted with 1N HCl. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a brown oil which solidified when treated with hexane. The crystals were triturated with hexane and dried under reduced pressure to give 2-ethyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.38 g, 84%) as tan solid, mp 80-90° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].O1CCCC1.[Br:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1>O>[Br:18][C:19]1[C:20]([NH:12][CH2:11][CH2:10][O:9][CH3:8])=[N:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COCCNc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 134 %

Procedure:
Triethylamine (53 μl) and 2-methoxyethylamine (23 mg) were added to a tetrahydrofuran (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (60 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=6:1 to 3:1), and a light yellow solid of 3-bromo-N-(2-methoxyethyl)-5-nitropyridin-2-amine (93.5 mg) was thus obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C1COCC1>[C:30]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(OC)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(OC)cc3n2)c1O
Temperature: -5 °C
Reaction time: 2 h

Procedure:
The esterification was carried out using the product from Example 11. In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.24 g (10.8 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 60 ml anhydrous THF. Triethylamine (1.2 ml) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (1.40 g, 13.4 mmol) was added dropwise and the mixture was stirred for 2 hr at 0° C. followed by 20 hours at ambient temperature. The salts were filtered off and the filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in ethanol to give a light yellow solid. 1H NMR (CDCl3) delta: 11.20 (s, 1H, phenol OH), 7.80 (m, 1H, Ar—H benzotriazole), 7.77 (s, 1H, Ar—H phenol), 7.17 (m, 1H, Ar—H benzotriazole), 7.14 (s, 1H, Ar—H phenol), 7.10 (m, 1H, Ar—H benzotriazole), to 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.38 (s, 2H, Ar—CH2), 3.92 (s, 3H, Ar—OCH3, phenol), 3.88 (s, 3H, Ar—OCH3, benzotriazole), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[NH:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]([OH:45])=O)=[CH:42][C:36]=3[N:35]=2)=[N:26]1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CS(C)=O>[CH2:46]([NH:53][C:43]([C:41]1[CH:40]=[CH:39][C:37]2[NH:38][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][N:26]=3)=[N:35][C:36]=2[CH:42]=1)=[O:45])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide is added, at a temperature in the region of 20° C., to a solution of 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide. After stirring at a temperature in the region of 20° C. for one hour, 15.7 ml of benzylamine are added, followed by addition of 12.4 ml of N,N-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide. After 20 hours, at a temperature in the region of 20° C., the reaction medium is concentrated under reduced pressure, at a temperature in the region of 40° C. The crude residue obtained is dissolved in DMSO and purified by preparative LC-MS. The fractions containing the desired product are combined and concentrated under reduced pressure at a temperature in the region of 40° C. 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-Carboxylic acid benzylamide are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[CH:5]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+]>CN(C)C=O>[CH3:15][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5]1
Reactant: Cn1cc(CCl)c(=O)c2ccccc21
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 16 h

Procedure:
3-Chloromethyl-1-methyl-4-quinolone hydrochloride (2.0 g.) was added portionwise during 1 minute to a stirred suspension of sodium methanesulphinate (5.0 g.) in anhydrous dimethylformamide (70 ml.) at room temperature. The mixture was stirred at this temperature for 16 hours, then evaporated to dryness. The residue was triturated with water (50 ml.), filtered, the filtrate basified with aqueous sodium hydroxide and then extracted with dichloromethane (2×50 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give the novel 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 201°-204° (from acetone).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][CH2:41][CH2:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH2:42][CH2:41][O:40][CH3:39])(=[O:44])=[O:45])=[CH:47][CH:48]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 122, 550 mg, 0.99 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (603 mg, 2.47 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.01 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.24 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (320 mg, 55%) as a white solid: LC/MS m/e calcd for C29H29FN2O6S2 [M+H]+ 585.69, observed 585.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58](O)=[O:59])=[CH:52]2)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=1[F:44])=[O:59])=[CH:52]2)(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
HATU (0.023 g, 0.062 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.013 g, 0.041 mmol), 5-(acetylamino)-1H-indole-2-carboxylic acid (0.009 g, 0.041 mmol) and DIPEA (0.011 mL, 0.062 mmol) in DMF (0.5 mL). The reaction mixture was stirred at RT overnight and was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.009 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.50 (s, 1H), 9.74 (s, 1H), 8.95 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.40-7.49 (m, 3H), 7.32-7.40 (m, 1H), 7.28 (s, 1H), 7.15-7.24 (m, 1H), 7.06 (s, 1H), 4.53 (s, 2H), 1.98 (s, 3H). MS: m/z 511 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12].ClC1C=CN=CN=1.CO[CH2:24][N:25]([CH2:30][Si](C)(C)C)[C:26]([CH3:29])([CH3:28])[CH3:27].FC(F)(F)C(O)=O>ClCCl>[C:26]([N:25]1[CH2:30][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Reactant: COC(=O)/C=C/c1ccc(F)cc1F
Agent: Clc1ccncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl (2E)-3-(2,4-difluorophenyl)acrylate from preparation 3 (10 g, 50.5 mmol) and N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (preparation 4) (10.3 g, 50.5 mmol) in dichloromethane (200 mL) at room temperature under dry nitrogen was added trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 17 hours. To the reaction mixture was then added a further portion of N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (from preparation 4) (3.9 g, 19.2 mmol) and trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 18 hours, then quenched by the addition of saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 40 g column) eluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour. The residue was then subjected to chiral HPLC (eluting with 95:5 hexane:isopropyl alcohol at 80 mL/min at ambient temperature on a Chirapak AD500*80 mm column) to afford the desired enantiomer of the title compound, which we designate here Enantiomer 1, and which was obtained as the faster running enantiomer (retention time 8 minutes) as a clear oil (6.1 g, 80%) with enantiomeric excess of >99% as determined by chiral HPLC with reference to a racemic standard. The undesired enantiomer was obtained as the slower eluting component (Enantiomer 2, retention time 8.7 min) 1H NMR (400 MHz, CDCl3) δH 1.10 (9H, s), 2.80 (1H, m), 3.00 (1H, m), 3.15 (3H, m), 3.60 (3H, s), 3.80 (1H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 298 (100%) [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][O:6][CH2:7][CH2:8]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:10]2[CH2:8][CH2:7][O:6][CH2:5][CH:4]2[C:3]([O:2][CH3:1])=[O:25])(=[O:13])=[O:12])=[CH:15][CH:16]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(COCCBr)C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonyl-amino)propionic acid methyl ester (0.15 g, 0.35 mmol) dissolved in DMF (2 mL) and cooled in an ice bath was added potassium carbonate (0.16 g, 1.15 mmol) and the reaction was stirred at room temperature for 1 hour. After removing the solvent, the residue was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 0.09 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester as an oil. Yield ˜73.8%. Electrospray Mass Spec 354.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:35])=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])C>CO>[OH:35][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([N:29]([CH3:31])[CH3:30])=[O:28]
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc([C@H](Nc2c(Nc3cccc(C(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 59 %

Procedure:
471 mg (2.6 mmol, 1.3 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 609 mg (2.0 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide dissolved under hot conditions in 40 ml of methanol. The reaction medium was heated at 50° C. for 17 hours. The methanol was evaporated off and the residue (green oil) was chromatographed on silica gel (column puriFlash IR-50SI-80G, Spot II) eluted with dichloromethane/methanol (97/3). The amorphous solid was taken up with diethyl ether to give a yellow powder which was recrystallized from n-propanol. 519 mg of 2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained. Yield=70%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][C:52]([F:55])([F:54])[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][C:52]([F:55])([F:54])[F:53])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3OC(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS (m/e): 457.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
A 250 mL roundbottom flask charged with 3,4-dichlorophenol (3.053 g, 18.7 mmol) in 50 mL CH2Cl2 was cooled to 0° C. in an ice bath. To the stirred solution was added concentrated H2SO4 (1.56 mL, 28.1 mmol). The solution became turbid. To this mixture was added concentrated HNO3 (1.2 mL, 18.7 mmol), dropwise and carefully to maintain a temperature below 5° C. The reaction was stirred for 30 min at 0° C., then cooled with an ice bath and quenched with 150 mL H2O. The layers were separated and the aqueous layer was extracted once with 35 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, concentrated under vacuum and purified using flash chromatography (10% EtOAc/hexanes as eluent) to yield the desired nitrophenol as a bright yellow solid (1.793 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)n1

Procedure:
Compound 628 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H26N6O4: 511.20; found: 511.04.