Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1CCNCC1
Product: O=S(=O)(Cl)N1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 4 g of sulfuryl chloride in acetronitrile was treated dropwise with 861 mg of piperidine at ambient temperature under an atmosphere of nitrogen. After complete addition, the mixture was refluxed for 18 h, cooled to room temperature and concentrated in vacuo to yield the title product as a red oil. TLC: Rf=0.86, CH2Cl2. (1 H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [CH3:1][O-].[Na+].C(OCC)=O.[CH:9]1([C:12]([CH3:14])=[O:13])[CH2:11][CH2:10]1.Cl.[CH3:16][NH:17][CH3:18]>C1COCC1.CO>[CH:9]1([C:12](=[O:13])[CH:14]=[CH:16][N:17]([CH3:1])[CH3:18])[CH2:11][CH2:10]1
Reactant: CNC
Reactant: CC(=O)C1CC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C=CC(=O)C1CC1
Reaction time: 4 h

Procedure:
To a suspension of 5.94 g (0.11 mol) of sodium methoxide in 200 mL of dry THF was added 8.89 mL (0.11 mol) of ethyl formate, followed by methyl cyclopropyl ketone (9.91 mL, 0.10 mol, [765-43-5]). The reaction mixture rapidly turned yellow and was stirred at 25° for 4 hours. The reaction mixture was then concentrated and the residue was dissolved in 100 mL of methanol. To this was added a solution of 8.97 g (0.11 mol) of dimethylamine hydrochloride in 50 mL of methanol. The mixture was stirred for 1 hour at 25° , then the reaction mixture was concentrated. The residue was suspended in 100 mL of dry benzene and then concentrated. The residue was then triturated with 100 mL of dry benzene, filtered, and the filter cake was washed with additional dry benzene. The benzene solution was dried and concentrated to yield a yellow oil that crystallized upon cooling (11.97 g, 86%). mp 55°. NMR (CDCl3): 7.58 (d, 1 H); 5.21 (d, 1 H); 3.20-2.60 (br d, 6 H); 1.80 (m, 1 H); 1.00 (m, 2 H); 0.77 (m, 2 H). Mass spec 140 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[N:19][CH:20]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]([O:13][CH2:12][C@@H:9]2[CH2:22][CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:18]=[N:19][CH:20]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1

Procedure:
A 332 mg (1.2 mmol) sample of 1-BOC-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 240 mg (1.38 mmol) of 5-bromo-3-hydroxypyridine, prepared as in Example 65b above, were reacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THF according to the procedure of Example 14a, to give 355 mg of the title compound. MS (DCI/NH3) m/e 357/359 (M+H)+, 374/376 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J-1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6 Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H), 2.10-1.80 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([Li])CCCCC.[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[Se:16][CH:17]=[CH:18][CH:19]=1.CI.N>C1COCC1.CC(OC)(C)C.[Cl-].[NH4+]>[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[Se:16][C:17]([CH3:1])=[CH:18][CH:19]=1
Reactant: [Li]CCCCCC
Reactant: CCCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CI
Product: CCCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
3.5 ml (20.6 mmol) of TMP are initially introduced at −20° C. in THF, and 7.7 ml (19.3 mmol, 2.5 M in hexane) of n-HexLi are metered in. After 25 min at this temperature, a solution of 5.5 g (16.0 mmol) of 2-(3-fluoro-4′-propylbiphenyl-4-yl)selenophene in 50 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −70° C., and 13.6 g (95.8 mmol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. The solution is diluted with MTBE, and sat. ammonium chloride soln. and conc. ammonia soln. are added successively. The mixture is stirred vigorously for a few minutes, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by chromatography. The further purification is carried out by recrystallisation from n-heptane. 2-(3-Fluoro-4′-propylbiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 97° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=1)=[CH:12]2)=[O:6])[CH3:3].[C:42](=[O:45])([O-])[O-:43].[K+].[K+].O1[CH2:52][CH2:51]CC1>>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[N:25][C:42]([O:43][CH2:51][CH2:52][S:29]([CH3:32])(=[O:31])=[O:30])=[O:45])=[CH:27][CH:28]=1)=[CH:12]2)=[O:6])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Product: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(N)=NC(=O)OCCS(C)(=O)=O)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
300 mg (0.5 mmol) of 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, 170 mg (0.6 mmol) of 2-(methylsulphonyl)-ethyl-4-nitrophenylcarbonate and 210 mg (1.5 mmol) of potassium carbonate are stirred in 30 ml tetrahydrofuran for 5 hours at ambient temperature. Then the reaction mixture is filtered and the mother liquor is concentrated by evaporation. The residue is taken up in methylene chloride and washed with sodium hydrogen carbonate solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on aluminium oxide and eluted with methylene chloride/ethanol (99:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask fitted with a condensor and addition funnel, N-methylpiperazine (10.0 grams, 0.1 mol) was stirred while 2-fluoronitrobenzene (14.1 grams, 0.1 mol) was added dropwise under nitrogen. Caution—a vigorous exotherm occurred when approximately 20% of the 2-fluoronitrobenzene had been added. Following completion of the addition (˜30 min.) the reaction was stirred another 60 min. at room temperature, diluted with methylene chloride (100 mL) and washed with saturated aqueous Na2CO3 and saturated aqueous sodium chloride. After drying with MgSO4, the solvent was removed in vacuo to give 2-(4-methylpiperazin-1-yl)-1-nitrobenzene as an orange oil, 20.4 grams. Mass spectrum: 221 (M+), 174 (M-HNO2) 1H-NMR (CDCl3, 300 MHz) δ 7.8-7.0 (4H, m), 3.05 (4H, m), 2.55 (4H, t), 2.3 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C1(C)C=CC=CC=1.[CH2:31]([N:38]=[C:39]=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([NH:38][C:39]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: S=C=NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (2 ml) and ethanol (2 ml) to prepare a solution. Benzyl isothiocyanate (48 μl) was then added to the solution, and the mixture was stirred at 80° C. for 6 hr. The reaction solution was concentrated, and ether and hexane were added to the residue. The resultant crystal was collected by filtration to give the title compound (46 mg, yield 65%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[O:18]=[C:19]1[CH2:24][O:23][C:22]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:21]=2[NH:20]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCCCC)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:29]([C:27]3[CH:26]=[CH:25][C:22]4[O:23][CH2:24][C:19](=[O:18])[NH:20][C:21]=4[CH:28]=3)=[O:30])[C@@H:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 117 °C
Yield: 63.6 %

Procedure:
In a 250 mL 3-necked flask, ethyl [(3S)-7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 27a, 4.2 g, 14.0 mmol) and 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (2.73 g, 14.1 mmol) were suspended in butyl acetate (40 mL). DIPEA (7.31 mL, 42.0 mmol) was added followed by T3P (50% in BuOAc) (17.8 g, 28.0 mmol). The reaction was heated in an alumina block for 7 h at 117° C. (internal reaction temp. the heating block was set to 135° C.). The reaction was allowed to cool to r.t over night. The crude reaction was diluted with EtOAc (150 mL) and washed with sat. aq. NaHCO3 (100+30 mL), 1 M citric acid aq. (50 mL), 1 M HCl (50 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford crude product as a red and foamy oil. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 30% to 75% of EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelengths 254/280 nm. The title compound (4.23 g, 63.6%) was obtained as a foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10]1(O)C=CC=C[CH:11]=1.[OH-].[Na+].Br[CH2:20][C:21]([O:23]CC)=[O:22].[Br-].[Na+].C>C(O)C.C(Cl)(Cl)(Cl)Cl>[C:21]([O:23][O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[C:7]([CH2:10][CH3:11])[C:2]=1[Cl:1])(=[O:22])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: Oc1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Cl)cc(OOC(C)=O)c1Cl
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a three-necked, 1000 ml flask provided with a mechanical stirrer and a reflux condenser was added 130.4 grams (0.8 mole) 2,5-dichlorophenol (prepared as described in step 1) dissolved in 300 ml absolute, i.e., anhydrous, ethanol. To the phenol solution was added, at ambient temperature, 32.4 grams (0.81 mole) sodium hydroxide dissolved in 300 ml absolute ethanol. The resulting mixture was stirred for 30 minutes and then 133.6 grams (0.8 mole) ethyl bromoacetate was added over a period of 15 minutes. The resulting mixture was stirred for about 30 hours at ambient, i.e., about 23° C., temperature. (A white precipitate, believed to be sodium bromide, was apparent after stirring for about 1 hour.) After completion of stirring the mixture was filtered and the filtrate was concentrated on a rotary evaporator at 55° C., 140 mm Hg and a suspended solids containing liquid was obtained. Both the liquid and the solids were taken-up in 200 ml carbon tetrachloride and transferred to a separatory funnel. The mixture was washed twice with 50 ml portions of 1 N sodium hydroxide solution and once with 50 ml of water. After washing, the organic phase was separated, dried over magnesium sulphate, filtered and the filtrate concentrated on a rotary evaporator at 55° C., 140 mm Hg, a reddish-yellow liquid being obtained. The liquid was taken up in 150 ml of carbon tetrachloride, treated with 2 grams activated charcoal, filtered and the filtrate was concentrated on a rotary evaporator at 55° C., 140 mm Hg. 190 grams of a light yellow liquid corresponding to a 92 percent yield of ethyl-2,5-dichlorophenoxy acetate was thus obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.Cl[S:8]([OH:11])(=O)=[O:9].[O:12]([CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH3:26]>>[S:8]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:14][CH:15]=1)(=[O:11])(=[O:9])[NH2:26]
Reactant: c1ccc(OCCn2ccnc2)cc1
Reactant: O=S(=O)(O)Cl
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: NS(=O)(=O)c1ccc(OCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
Phosphorus pentachloride (2.08 g) was added cautiously to chlorosulphonic acid (2.91 g) and the resulting solution was cooled to 0° C. 1-(2-Phenoxyethyl)imidazole (1.88 g) was added in portions, allowing the effervescence to subside after each addition. The mixture was heated on a steam bath for 10 minutes, cooled, and poured onto a mixture of crushed ice and excess concentrated ammonia solution. The resulting gummy solid was filtered off, washed with water, sucked as dry as possible at the filter pump and chromatographed on silica gel. Elution with a mixture of chloroform and methanol (4:1) gave a gum which crystallised on trituration with a few mls. of ethanol. The solid was crystallised from ethanol to give 1-[2-(4-sulphamoylphenoxy)ethyl]imidazole (0.5 g), m.p. 147.5°-148.5° C. Found: C, 49.57; H, 4.93; N, 15.36. C11H13N3O3S requires: C, 49.42; H, 4.90; N, 15.72%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=c1ccc(Br)c[nH]1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1ccc(NN=C(c2ccccc2)c2ccccc2)c[nH]1
Yield: 28.5 %

Procedure:
5-Bromo-2(1H)-pyridone (2.0 g, 11.5 mmol) in 25 mL dry toluene was treated with benzophenone hydrazone (2.50 g, 12.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg, 0.345 mmol), and sodium tert-butoxide (2.2 g, 23 mmol). The mixture was degassed with argon for 15 minutes. Added Pd(II)(OAc)2 (80 mg, 0.345 mmol) and stirred at 90° C. for 16 hours. Extracted using EtOAc/H2O (3×150 mL EtOAc, 1×150 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 0-12% MeOH/DCM) to afford 5-(2-(diphenylmethylene)hydrazinyl)pyridin-2(1H)-one (950 mg, 3.28 mmol, 29%). 1H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.49 (s, 1H), 7.61-7.25 (m, 12H), 6.31 (d, 1H); LC-MS (ESI) m/z 290 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[N:21][CH:22]=1.N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([CH3:39])=[CH:34][C:33]=1[S:40](Cl)(=[O:42])=[O:41].Cl>C1COCC1.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([NH:15][S:40]([C:33]2[CH:34]=[C:35]([CH3:39])[C:36]([Cl:38])=[CH:37][C:32]=2[Cl:31])(=[O:42])=[O:41])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[N:21][CH:22]=1
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(=O)NCc2ccco2)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(=O)NCc3ccco3)c2)c(Cl)cc1Cl
Reaction time: 21 h
Yield: 89.6 %

Procedure:
To a 0.2M solution of N-(2-furanylmethyl) 5-amino-2-(3-chloro-5-pyridyloxy)benzamide (2.6 g, 7.6 mmol, prepared in Example 35.3) in a 1:1 THF/CH2Cl2 solution was added pyridine (0.67 mL, 8.3 mmol) followed by 2,4-dichloro-5-methylbenzenesulfonyl chloride (2.16 g, 8.3 mmol). The resulting mixture was stirred for 21 hr. A 1M aqueous solution of HCl (100 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (100 mL). The organic layers were combined and washed once with a brine solution (200 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was purified by chromatography (10-40% EtOAc in hexane) to yield 3.86 g (90%) of product as an off white solid.
Reaction SMILES: Cl.Cl.[NH2:3][OH:4].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9]2.Cl[C:16](Cl)(Cl)[CH:17]([OH:19])O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O>[CH2:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][C:17](=[O:19])[CH:16]=[N:3][OH:4])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)CCC2
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Yield: 60 %

Procedure:
This compound is prepared according to the process described in Organic Syntheses, 1925, V, 71-74. A solution of 16.5 ml of concentrated HCl in 120 ml of water and a solution of 41.5 g of hydroxylamine hydrochloride in 70 ml of water are added to a mixture of 25 g of 5-aminoindane, 35 g of chloral hydrate and 22 g of Na2SO4 in 600 ml of water, and the mixture is then refluxed for 30 minutes. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is taken up in a pentane/iso ether mixture and the precipitate formed is spin-filtered off. 23 g of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:6]1[C:10]2[N:11]=[CH:12][S:13][C:9]=2[C:8]([C:14]#N)=[C:7]1[CH3:16])[CH3:5].[OH-:17].[Na+].Cl.O1CCCC1.C[OH:26]>O>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[C:10]2[N:11]=[CH:12][S:13][C:9]=2[C:8]([C:14]([OH:26])=[O:17])=[C:7]1[CH3:16])[CH3:5]
Reactant: [OH-]
Reactant: CO
Reactant: COCC(C)n1c(C)c(C#N)c2scnc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)n1c(C)c(C(=O)O)c2scnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a solution of 4-(1-methoxypropan-2-yl)-5-methyl-4H-pyrrolo[2,3-d]thiazole-6-carbonitrile (1.0 g, 4.25 mmol) in tetrahydrofuran/methanol=1:1 (30 mL) was added sodium hydroxide (680 mg, 17 mmol) resolved in 15 mL water. The resulting reaction system was heated to 80° C. and allowed to stir for 24 hours at 80° C. The pH was adjusted to around 7 by progressively adding 4N hydrogen chloride below 0° C., solvent and water was removed in reduced pressure to give the title compound (500 mg, 46%) as an yellow solid. LCMS (M+H+) m/z: calc'd. 254.07. found 254.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1.[NH2:14][OH:15]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]([NH:14][OH:15])=[NH:9])=[CH:6][N:7]=1
Reactant: NO
Reactant: CNC(=O)c1nc(C#N)cnc1N
Solvent: CCO
Solvent: O
Product: CNC(=O)c1nc(C(=N)NO)cnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
3-Amino-6-cyano-N-methylpyrazine-2-carboxamide (839 mg, 4.7 mmol) was suspended in ethanol (25 mL) followed by addition of 50% aqueous hydroxylamine (2 mL, 31.3 mmol) and the mixture was stirred at room temperature for one hour. The suspension obtained was diluted with water (2 5mL) and the insoluble solid collected by filtration and washed with water. The solid was dried in vacuo to give 3-amino-6-[(hydroxyamino)(imino)methyl]-N-methylpyrazine-2-carboxamide (664 mg, 67% yield) as a white solid: MS (EI) for C7H10N6O2: 211 (MH+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([Se]C2C=CC=CC=2)[CH2:8][N:7]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:5].N1C=CC=CC=1.OO>ClCCl>[CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:5]
Reactant: CCOC(=O)[C@H]1C[C@H]([Se]c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: OO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1C=CCN1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 7.35 g (0.016 mol) (2R,4S)-4-phenylselanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 80 ml dichloromethane were added at 0-5° C. 1.93 ml (0.024 mol) pyridine and 4.6 ml 30% hydrogen peroxide and stirring was continued for 1.5 hours. The mixture was extracted with 5% aqueous HCl, saturated aqueous sodium carbonate, and water. Chromatography on silicagel with ethylacetate/hexane 1:5 yielded 2.99 g (77%) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as colorless oil. MS m/e (%): 186 (11), 168 (48), 140 (32), 112 (100), 68 (85), 57 (58). [α]D=+242° (c=1% in chloroform).
Reaction SMILES: [ClH:1].O.[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1>[Fe].C(O)C>[ClH:1].[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncnc(N)c2c1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
A mixture of iron (113.9 g), conc. hydrochloric acid (57 ml) and water (2.3 liters) was stirred at 95° C. for 20 minutes. To the mixture was added during 10 minutes 4-amino-6-nitroquinazoline (114.1 g). The reaction mixture was stirred at 95° C. for an hour and a half and then filtered. The filter cake was washed with hot water. The combined filtrate and washings were concentrated under reduced pressure to give a residue, to which was added a small volume of ethanol to give precipitates. The precipitates were separated by filtration and dried to give 4,6-diaminoquinazoline hydrochloride (94.8 g). The same compound (4.3 g) was recovered from the mother liquor in the same manner as mentioned above.