Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22]Cl>C(Cl)Cl>[ClH:22].[CH2:1]([O:8][C:9](=[O:12])[CH2:10][NH:21][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: NCCc1ccccc1
Reactant: ClCl
Solvent: ClCCl
Product: Cl
Product: O=C(CNCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of benzyl-2-bromoacetate (3.3 ml, 20.0 mmol) in CH2 Cl2 (30 ml) was added drop-wise to a solution of phenethylamine (12.6 ml, 100 mmol) in CH2Cl2 (30 ml) stirring at 0° C. After warming to room temperature the reaction was stirred for 24 hours, then filtered and the solvent evaporated in vacuo. The resulting residue was dissolved in ethyl acetate, and washed with brine and dried over sodium sulfate. The ethyl acetate was evaporated in vacuo. The crude material was purified using silica gel flash column chromatography eluting sequentially with hexane and ethyl acetate-hexane (9:1, v/v). The fraction containing the product had traces of benzyl-2-bromoacetate as an impurity. This portion was redissolved in CHCl3 and washed with 1N HCl. The chloroform layer was dried and the HCl salt was precipitated with petroleum ether. Yield 2.3 g colorless solid. 1H NMR (CDCl3) δ 1.95 (br s, 1H), 2.73-2.9 (m, 3H), 3.44 (s, 2H), 5.12 (s, 2H), 7.13-7.36 (m, 10H). 13C NMR (CDCl3) 6 36.17, 50.46, 50.63, 66.32, 26.06, 128.18, 128.3, 128.4, 128.50, 135.4, 139.4, 171.88.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:43]([S:48](Cl)(=[O:50])=[O:49])=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[C:42]([CH3:41])=[CH:47][CH:46]=[CH:45][N:44]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1cccnc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (161 mg), 15-crown-5 (110 mg), crude 3-methylpyridine-2-sulfonyl chloride (153 mg) in tetrahydrofuran (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 72 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→11:9) to give the title compound as a colorless oil (yield 113 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:26]([O:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 66.1 g. (0.25 mol.) of (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid and 250 ml. each of pyridine and acetic anhydride was stirred at 25° C. under N2 for 20 hours and stripped of solvent at 40° C. to give an orange-brown oil. To a suspension of this material in 500 ml. of H2O and 100 ml. of tetrahydrofuran was added 166 g. (2.0 mol.) of NaHCO3. The suspension was stirred at 25° C. for 4.0 hours, washed with ether, acidified with 2N-aqueous HCl and extracted with ether. The ether solutions were washed with saturated brine, dried over sodium sulfate and stripped of solvent to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as an orangeish resin. Crystallization from diethyl ether petroleum ether (b.p. 30°-60° C.) gave (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as a granular white solid.
Reaction SMILES: [Br:1]Br.[N+]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-])=O.[N+](C1C=CC=CC=1)([O-])=O>O>[Br:1][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Temperature: 200 °C

Procedure:
A 1 liter double mantle flask equipped with propeller or anchor stirrer, bromine inlet with metering pump, and reflux condenser attached to a waste gas adsorption unit, is charged with 1265 parts by weight of 1-nitroanthraquinone and 60 parts by weight of nitrobenzene. The mixture is heated to 240° C. and, at this temperature and with efficient stirring, elementary bromine is pumped in by means of the metering pump. The rate of addition is so chosen that gentle bromine reflux is always maintained in the reflux condenser. After about 200 to 220 ml of bromine have been added over 10 hours, no more bromine is taken up by the reaction mixture and the presence of 1-nitroanthraquinone can no longer be detected in a thin-layer chromatogram. The mixture is then cooled to 200° C. and the melt is discharged through the bottom outlet into 2 liters of vigorously stirred water. The resultant suspension is then refluxed and nitrobenzene is separated in a water separator. After about 1 hour the suspension is cooled to about 80° C., filtered, and the filter cake is washed with hot water and dried in vacuo at 120° C., affording 1400 parts by weight of 1-bromoanthraquinone in 96-97% purity. The yield, based on 1-nitroanthraquinone, is 97.5 %.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1O[C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:37]([CH2:36][CH2:35][N:33]([CH2:32][CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:34])[C:14](=[O:16])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1
Reactant: COc1ccc(CCN(C)CCN)cc1OC
Reactant: COc1ccccc1Cc1nc2ccccc2c(=O)o1
Solvent: Cc1ccccc1C
Product: COc1ccccc1Cc1nc2ccccc2c(=O)n1CCN(C)CCc1ccc(OC)c(OC)c1
Yield: 21.9 %

Procedure:
268 mg (1 mmol) of 2-(2-methoxyphenylmethyl)-4H-3,1-benzoxazine-4-one and 238 mg (1 mmol) of 2-[[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamino]]ethyl-amine were heated in xylene (10 ml) under reflux for 10 hours . After the xylene was distilled off, the residue obtained was purified by silica gel column chromatography (eluent; 2% ethanol/chloroform) to obtain 107 mg (52%) of 2-(2-methoxyphenylmethyl)-3-[2-{N-(3,4-dimethoxyphenylethyl)-N-methylamino}ethyl]-4(3H)-quinazolinone as an oily substance. Subsequently, the thus obtained quinazolinone was dissolved in ethanol (2 ml) and to the resulting soluion there was added a 7% hydrogen chloride-ethanol solution (1 ml). Further, ether was added to the reaction mixture thus obtained, and the precipitated colorless crystals were collected by filtration to obtain 99 mg of the hydrochloride which is the desired compound.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)N.C=O.[C:15](O)(=O)C>C(#N)C.CCOCC>[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[N:2]([CH3:1])[CH3:15]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Nc1cccc(Br)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)c1cccc(Br)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
According to the procedure of Borch and Hassid, J. Org. Chem. 37:1673 (1972), sodium cyanoborohydride (4.75 g, 75.0 mmol) was added to a stirred solution of 3-bromoaniline (4.30 g, 25.0 mmol) and 37% aqueous formaldehyde (20 mL, 0.25 moles) in acetonitrile (200 mL). Glacial acetic acid (2.5 mL) was added drop-wise (10 min) to the stirred suspension, without cooling. The temperature gradually increased to 40° C. After stirring for 2 h, the mixture was treated with a second 2.5 mL portion of acetic acid. Stirring was continued for another hour. The mixture was then poured into ether (400 mL) and extracted with 1 M aqueous KOH (3×100 mL). The ether layer was washed once with saturated aqueous NaCl, dried (K2CO3) and evaporated. This left a biphasic mixture, which was separated by careful pipetting. The larger fraction was vacuum distilled to give 4.13 g (82.6% yield) of colorless oil, bp 79-80° C. at 0.4 mm Hg.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphory-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and D-alanine benzylester p-toluene sulfonic acid salt (1.3 g, 3.5 m mole) were dissolved in DMF (5 ml), and WSC (0.64 ml) was added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order. The mixture was dried with anhydrous sodium sulfate and the thus obtained solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-alanine benzylester material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.Cl.[H][H].Cl.[CH2:22](O)C>CO.C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH3:22])[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CO
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1C

Procedure:
3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.31 g) obtained from Referential Example 87 was dissolved in methanol (50 mL). To the resultant solution, 10% palladium-carbon (0.504 g), 35% aqueous formalin (1.85 mL), and 1M HCl in ethanol (15.4 mL) were added at room temperature, and the mixture was stirred in a hydrogen atmosphere for 19 hours. 10% Palladium-carbon (0.95 g), 35% aqueous formalin (1.8 mL), and 1M HCl-ethanol (15 mL) were added thereto, followed by stirring in a hydrogen atmosphere for 23 hours. After the system was purged with nitrogen, the resultant mixture was neutralized through addition of the aqueous sodium hydroxide, and insoluble matter was removed by filtration. The filtrate was brought to dryness under reduced pressure. The residue was purified through silica gel column chromatography (chloroform−7N ammonia/methanol), to thereby give the title compound as an oily product (2.28 g, 65%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.[F:35][C:36]1[CH:44]=[C:43]2[C:39]([C:40]([CH2:45][C:46]([NH2:49])([CH3:48])[CH3:47])=[CH:41][NH:42]2)=[CH:38][CH:37]=1>>[ClH:20].[F:35][C:36]1[CH:44]=[C:43]2[C:39]([C:40]([CH2:45][C:46]([NH:49][CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:47])[CH3:48])=[CH:41][NH:42]2)=[CH:38][CH:37]=1
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2cc(F)ccc12
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Product: CC(C)COc1ccccc1OCCNC(C)(C)Cc1c[nH]c2cc(F)ccc12
Product: Cl

Procedure:
Proceeding as an Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2- (6-fluoro-1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(6-fluoro-1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(2-methyl-prop-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[CH2:10][O:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[O:14])=[CH:4][CH:3]=1.[O:24]=[C:25](Cl)OC(Cl)(Cl)Cl.[O:32]1CCOC[CH2:33]1>>[N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13](=[O:14])[CH2:12][O:11][CH2:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]=[C:33]=[O:32])=[CH:3][CH:4]=2)=[O:23])=[CH:21][CH:20]=1)=[C:25]=[O:24]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC(=O)COCC(=O)Oc2ccc(N)cc2)cc1
Reactant: C1COCCO1
Product: O=C=Nc1ccc(OC(=O)COCC(=O)Oc2ccc(N=C=O)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (4-amino-phenoxycarbonylmethoxy)-acetic acid 4-amino-phenyl ester (27) (2 grams, 6.32 mmoles) in dry 1,4-dioxane (32 ml) under nitrogen atmosphere was cooled to 10° C. and added a solution of diphosgene (4 grams, 13.47 mmoles) in 1,4-dioxane (8 ml) in one lot and heated to a temperature of 100° C. for 2 hours. The condenser was then arranged for distillation and solvent removed by distillation at atmospheric pressure until the volume of the reaction mixture was reduced to approximately one third. Fresh dry dioxane (10 ml) was added and distilled off the solvents under vacuum. The residue was re-evaporated two times from dry dioxane (2×10 ml) to give crude 28 (4-Isocyanato-phenoxycarbonylmethoxy)-acetic acid 4-isocyanato-phenyl ester, which was recrystallized from toluene as a white powder with a melting point of 150.5-152.4° C., IR: 2316.1 cm−1, 2274.3 cm−1. The pure product 28 was also characterized using 1H NMR spectroscopy in CDCl3: δ 4.56 (s, 2H, CH2), 7.10 (s, 4H, Ar).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.[Br:16]Br>C(O)(=O)C.C(Cl)Cl>[Br:16][C:6]1[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[NH:8][N:7]=1
Reactant: BrBr
Reactant: O=Cc1cc(C(F)(F)F)cc2cn[nH]c12
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)cc2c(Br)n[nH]c12
Reaction time: 1 h

Procedure:
To a mixture of 5-(trifluoromethyl)-1H-indazole-7-carbaldehyde (270 mg, 1.26 mmol) in acetic acid (5 mL) was added bromine (97 μL, 1.89 mmol) slowly over 5 min. After 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 340 mg (92%) as a yellow powder. 1H-NMR (CDCl3, 300 MHz) δ 10.18 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H). Mass spec.: 294.81 (MH)+.
Reaction SMILES: [N:1](C(OCC)=O)=[N:2]C(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)=[C:16]([C@H:33](O)[CH3:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:55]1C=CN=C1>ClCCl.[Zn](N=[N+]=[N-])N=[N+]=[N-]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)=[C:16]([C@@H:33]([N:55]=[N+:1]=[N-:2])[CH3:34])[CH:15]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: C[C@@H](O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1c[nH]cn1
Agent: [N-]=[N+]=N[Zn]N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](N=[N+]=[N-])c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
A solution of diethyl azodicarboxylate (49.6 mL, 0.315 mol) was added dropwise to a stirred mixture of tert-butyl 4-{4-chloro-2-[(1R)-1-hydroxyethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (3-5) (26.7 g, 78.9 mmol), Zn(N3)2.2Py (prepared according to the method described by Viaud, M-C; Rollin, P. in Synthesis, 1990: 130-131) (48.5 g, 0.158 mol), triphenylphosphine (82.7 g, 0.315 mol) and imidazole (21.5 g, 0.315 mol) in dichloromethane at approximately 0° C. After the addition, the resulting mixture was allowed to warm to ambient temperature and stirred vigorously for 3 d. The reaction mixture was filtered through a short column of silica gel eluted with the appropriate volume of dichloromethane to remove excess salts and polar byproducts. The filtrate was concentrated in vacuo and the crude residue was purified by flash chromatography on silica gel (12.5% ethyl acetate/hexanes as eluent) to furnish 3-6 (23.9 g) as a viscous pale yellow oil.
Reaction SMILES: C1([C@H]2O[C@@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]CO2)C=CC=CC=1.Cl.[O:25]1CCOC[CH2:26]1.C([O-])(O)=[O:32].[Na+]>CO>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([O:13][CH:11]([CH2:10][OH:32])[CH2:26][OH:25])(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: C1COCCO1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCO[C@@H](c3ccccc3)O2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
In 50 ml of methanol were dissolved 5.00 g of cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane, and 5 ml of a 4N HCl-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 2 hours. To the reaction mixture were added 3.5 g of, NaHCO3 powder, and the mixture was stirred for 10 minutes. Then, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The thus obtained oil was subjected to column chromatography using silica gel and eluted with ethyl acetate to obtain 3.70 g (yield: 100%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([O:24][C@H:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]4[CH2:50][CH2:51]4)[CH:38]=3)[CH2:34][C:33]3[C:32]([Cl:52])=[CH:31][N+:30]([O-:53])=[CH:29][C:28]=3[Cl:27])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (0.234 g, 0.606 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.212 g, 0.505 mmol), EDC (0.290 g, 1.514 mmol) and DMAP (0.031 g, 0.252 mmol) in DCM (15 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 1N NaHCO3 and brine. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.200 g, 0.254 mmol, 50% yield). MS/ESI+ 787.8 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[CH:4][N:3]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-4-methylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 13.00 (1H, br s, NH), 8.38 (1H, s, A-ring CH ortho to 2×Cl), 8.13 (1H, d, J 11 Hz, A-ring CH ortho to SO2NH), 7.53 & 7.05 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 7.43 & 7.14 (2×1H, 2×s, pyridyl CH's), 7.34 (1H, d, J 11 Hz, A-ring CH ortho to Cl), 2.90-2.81 (4H, m, CH2NCH2), 2.21 (3H, s, CH3), 1.62-1.48 (4H, m, CH2CH2CH2CH2CH2), 1.39-1.27 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.43 minutes. LC/MS rt=7.43 minutes, 572/574 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5]NN=1.COC(=O)C1C=CC(OCC2CC2)=C(Cl)C=1.[CH3:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28]C)=O.[H-].[Na+].C(#N)CC>C1(C)C=CC=CC=1.O>[CH3:5][CH:6]([C:26](=[O:28])[C:25]1[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=1[CH3:23])[C:2]#[N:1]
Reactant: COC(=O)c1ccccc1C
Reactant: Nc1cc[nH]n1
Agent: COC(=O)c1ccc(OCC2CC2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)C(C)C#N
Temperature: 80 °C
Yield: 88 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1). The mixture of methyl 2-methylbenzoate (3.0 mL, 20.0 mmol, 1.0 eq) and NaH (1.6 g, 40.0 mmol, 2.0 eq) in dry toluene (20 mL) was heated at 80° C. and then propionitrile (6.7 mL, 94.4 mmol. 4.7 eq) was added dropwise; the reaction was heated for 18 hours. The crude product was dissolved in water and extracted with DCM, and it was used in the following step without further purification (3.04 g, yield: 88%).