Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CN(C=O)C>[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:3]=2)(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine and 1.43 g of 5-isopropyl pyridine-2-sulfonamide potassium salt were suspended in 20 ml of dry DMF. The mixture was stirred under argon at room temperature and became clear within a few h. After 16 h at room temperature, most of the solvent was removed by evaporation under reduced pressure. The residue was taken up in 20 ml water and the pH was adjusted to 4-5 by adding about 1 ml of acetic acid. A precipitate formed. The precipitate was filtered off, washed with water and dried. The yellow powder was further purified by column chromatography on silica gel eluting first with hexane:ethyl acetate 1:1 then with DCM:MeOH 10:1. 1.43 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a slightly yellow powder. LC-MS: tR=5.00 min, [M+1]+=512.19, [M−1]−=510.26.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)#[N:2].[NH4+].[OH-]>[Pd].CO>[C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(CC(=O)O)C=CCC=C1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Added 5% Pd/C catalyst (0.65 g, 0.31 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid (0.50 g, 3.1 mmol) and 28% NH4OH (42.5 μL, 38.3 μg, 0.31 mmol) in MeOH (15 mL). After shaking the reaction mixture under 50 psi H2 at room temperature for 1 hour, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure to afford 0.48 g (94%) of crude product.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:24]=[C:23]2[C:12]([CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH2:19][C@H:20](O)[CH3:21])[C:15]=32)=[CH:11][CH:10]=1)[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:16]1[C:15]2=[CH:23][C:24]3[C:13]([CH2:12][CH:11]=[CH:10][C:9]=3[O:8][CH2:6][CH3:7])=[C:14]2[CH:18]=[N:17]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccc2c(c1)-c1c(cnn1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 98.5 %

Procedure:
0.29 ml (3.79 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.49 g (1.9 mmol) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-1-yl)-propan-2-ol and 1.06 ml (7.6 mmol) of triethylamine in 30 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellowish solid obtained was dissolved in 25 ml of anhydrous dimethylformamide, treated with 0.25 g (3.8 mmol) of sodium azide and the reaction mixture was heated to 70° while stirring for 22 hours. After cooling, the solution was poured into 70 ml of semi-saturated sodium chloride solution and extracted twice with 70 mi of diethyl ether each time. The combined organic phases were washed once with 50 ml of water and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 0.53 g (99%) of (S)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2O)=[CH:19][CH:18]=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].O(Br)[Br:27].[P+5].[OH-].[Na+]>CN(C=O)C.O>[Br:27][C:21]1[C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: BrOBr
Reactant: O=[N+]([O-])c1ccc2c(O)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(Br)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A mixture of 3-(3,4-difluoro-benzenesulfonyl)-7-nitro-quinolin-4-ol (1.6 g, 4.37 mmol) and phosphorus(V) oxybromide (2.5 g, 8.72 mmol) in DMF (16 ml) was stirred at 65° C. for 1 hour. The reaction mixture was diluted with water (100 ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. After cooling the precipitate was filtered and washed with water. The obtained crude product was purified by crystallization from ethanol to obtain 1.25 g of the title compound in 67% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)COc1cccc(F)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(F)c1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a stirred mixture of 2-(3-fluorophenoxy)acetic acid (252 mg, 0.893 mmol) in DCM (5 mL) was added DIEA (173 mg, 1.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.893 mmol), and Bop-Cl (273 mg, 1.07 mmol). The mixture was stirred at 25° C. for 16 hours then quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the product (18 mg, Yield 5.6%). 1H NMR (400 MHz, METHANOL-d4) δ=7.26-7.29 (m, 1H), 7.13-7.02 (m, 4H), 6.76-6.69 (m, 3H), 4.55 (s, 2H), 4.06-4.00 (m, 1H), 3.71 (s, 1H), 3.47-3.31 (m, 2H), 2.91-2.90 (m, 2H), 2.86-2.77 (m, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 359.1 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.Cl[CH2:14][CH:15]=[CH2:16].Cl>CCOCC>[CH3:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:16][CH:15]=[CH2:14])=[CH:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: C=CCCl
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=CCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a Grignard reagent prepared from 12 g magnesium, 250 ml ether and 100 g 1-bromo-4-(1,1-dimethylethyl)benzene were added 50 g 3-chloro-1-propene dissolved in 150 ml ether. After the addition, the mixture was refluxed for one hour and kept stirring overnight at room temperature. The reaction mixture was then poured onto crushed ice and acidified with hydrochloric acid to dissolve any precipitated solid. The ether solution was separated, washed with water, and dried with anhydrous sodium sulfate, solvent removed and product distilled to provide 40 g of 1-(1,1-dimethylethyl)-4-(2-propenyl)benzene, listed in Table 1 as compound I-1. The product was characterized by a boiling point of 65°-66° C. at a pressure of 0.25 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>O1CCCC1>[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:11](=[O:13])[C:10]2[CH:14]=[C:6]([S:3]([N:2]([CH3:1])[CH3:17])(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=2[O:15][CH3:16])=[CH:38][CH:37]=1
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)NCc1ccc(OCCN(C)C)cc1
Yield: 91.4 %

Procedure:
To a cooled suspension of 3.20 g of 5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml of tetrahydrofuran were successively added dropwise 1.25 g of triethylamine and 1.34 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes and then a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was washed with isopropyl ether to give 4.10 g of colorless crystals, which were recrystallized from a mixture of ethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>C(O)(=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(F)cc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc(-n2ccc3c4c(N)nc(N)nc4ccc32)cc1

Procedure:
A solution of 15.94 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 800 ml. dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 10.66 g. 4-fluorobenzonitrile is followed by heating of the reaction mixture at 95° for 6 hours. Glacial acetic acid (40 ml.) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with excess aqueous potassium carbonate solution, collected, washed with water and dried. Two recrystallizations of the crude product from dimethylformamide, followed by washing with a small amount of dimethylformamide, with methanol and thorough drying, yield the title compound, m.p. 344° (dec.), NMR (dDMSO): δ 7.17 (doublet, J=9Hz, 5 or 6H), 7.42 (doublet, J=3Hz, 9H), 7.76-7.95 (four protons multiplet, 5 or 6H, 8H and two protons meta to the cyano group), 8.09 (two proton doublet, J= 8Hz, two protons ortho to the cyano group) p.p.m.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH:15]=[CH:14]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:19]1([S:25]([N:17]2[CH:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]=[CH:15][C:16]2=[O:18])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCOC1C=CC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
39.37 cm3 of a 1.4M solution of n-butyllithium in n-hexane is added to a solution of 10.1 g of 1,5-dihydro-5-n-hexyloxy-2H-pyrrol-2-one obtained at stage A in 170 cm3 of tetrahydrofuran cooled to -30° C. The temperature is maintained at -30° C. while agitating for 15 minutes, then is reduced to -35° C. and a solution of 9.73 g of benzenesulphonyl chloride in 70 cm3 of tetrahydrofuran is added, while maintaining the temperature at between -35° C. and -53° C. The temperature is allowed to return to the ambient, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1-2). 5.68 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1(N(CCCC)C2CCCCC2)CCCCC1.CC(C)CC=O.C1(N([CH:52]([CH2:58][CH2:59]CC)[CH:53]([O:56][CH3:57])[O:54][CH3:55])C2CCCCC2)CCCCC1>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:52]([CH:58]([CH3:59])[CH3:16])[CH:53]([O:56][CH3:57])[O:54][CH3:55])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C(OC)OC)N(C1CCCCC1)C1CCCCC1
Reactant: CCCCN(C1CCCCC1)C1CCCCC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(C)CC=O
Product: COC(OC)C(C(C)C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 66 %

Procedure:
The product was prepared by above general procedure and the same chemicals except employing dibenzylamine (1a′) (98 mg, 0.5 mmol), and 3-methylbutanal (2b′) (64 mg, 0.75 mmol). After 24 h, the crude product was purified by flash column chromatography (silica gel; ethyl acetate or diethyl ether/hexane=1:100) to afford the desired product 3b as a light yellowish oil (0.108 g, 66% yield); Rf=0.76 (hexane:ethyl acetate=3:1); 1H NMR (CDCl3, 400 MHz) δ 7.38-7.36 (m, 4H), 7.30-7.26 (m, 4H), 7.22-7.18 (m, 2H), 4.51-4.50 (d, J=4.28 Hz, 1H), 3.91-3.62 (m, 4H), 3.40 (s, 3H), 3.37 (s, 3H), 2.46-2.43 (m, 1H), 2.05-1.97 (m, 1H), 0.99-0.98 (t, J=6.82 Hz, 3H), 0.84-0.82 (t, J=6.68 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 140.7 (C×2), 129.2 (CH×4), 128.0 (CH×4), 126.6 (CH×2), 107.1, 62.5, 55.5 (CH2×2), 55.5, 54.8, 27.2, 20.9, 20.7 ppm; FTIR (neat): v=3015, 1215, 754, 700, 494 cm−1; HRMS (ESI, m/z): calcd for C21H30NO2+ [M+H]+ 328.2277, found: 328.2273.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:19][S:20]Cl.CSSC.ClCl>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(O)c2)c(Br)c1
Reactant: CSCl
Agent: ClCl
Solvent: ClCCl
Solvent: CSSC
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2Br)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-Bromo-4-nitrophenoxy)phenol (0.01 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of methyl sulfenyl chloride freshly prepared by reacting dimethyl disulfide (0.015 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml) with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-bromo-4-nitrophenoxy)-2-(methylthio)phenol as the residue.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClN1[C:18](=[O:19])[CH2:17][CH2:16]C1=O.C(O)C#C>C(N(CC)CC)C>[C:2]1([C:1]2[CH:16]=[C:17]([CH2:18][OH:19])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1cc(-c2ccccc2)no1
Yield: 76.8 %

Procedure:
10.0 mmol of Benzaldehyde oxime and 30 ml of dry dichloromethane were added into a 250 ml single-necked round-bottom flask. After the addition of 1.60 g (12.0 mmol) of N-chlorosuccinimide (NCS) under stirring, the mixture was slightly heated until NCS was completely dissolved. 0.56 g (10.0 mmol) of 2-propyn-1-ol was added dropwise, and then 20 ml solution of triethylamine in dichloromethane containing 10.1 g (10.0 mmol) of triethylamine was slowly added dropwise. After the addition was complete, the system was refluxed. After the completion of the reaction monitored by TLC, the mother liquor was washed with water, dried over anhydrous sodium sulfate and was separated on column (Vpetroleum ether:Vethyl acetate=5:1-2:1) to give 3-phenyl-5-hydroxymethyl-isoxazole in 76.8% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13])=[O:32]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[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: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 33.3 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (40.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 492; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, m), 7.88-7.84 (2H, m), 7.51-7.49 (1H, m), 7.37-7.28 (2H, m), 7.19-7.18 (1H, m), 4.18-4.15 (2H, m), 4.11-4.09 (2H, m), 3.03 (3H, s), 2.87 (3H, s), 1.29-1.23 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:13](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:13])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-bromo-2-methylbenzoic acid (0.538 g, 2.50 mmol) and HATU (1.289 g, 3.390 mmol) in DMF (8 mL) was added DIPEA (0.800 mL, 4.59 mmol). The mixture was stirred for 10 minutes before addition of NH4OH (0.50 mL) and then left stirring for 16 hours at room temperature. The mixture was poured in to water and cooled at 0° C. for 20 minutes before collecting the resulting precipitate via vacuum filtration to give the title compound (I69) (0.292 g, 55%); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=2.1 Hz, 1H), 7.45 (dd, J=8.2, 2.1 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 5.68 (bs, 2H), 2.44 (s, 3H). LCMS Method C: rt 4.89 min; m/z 214, 216 [M+H]+.
Reaction SMILES: O.NN.[N:4]1C=CC=CC=1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].O>O1CCCC1.C(OCC)(=O)C>[C:11](=[O:12])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:4]
Reactant: c1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained in Example 190, (1) (200 mg) was dissolved in tetrahydrofuran (2 ml), pyridine (58 μl) and benzyl chloroformate (68 μl) were added to the solution, and the resulting mixture was stirred at room temperature for 10 minutes. Distilled water and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol:28% aqueous ammonia=8:1:0.1) to obtain a benzyl carbamate compound (191 mg). (2) By using the compound obtained in (1) mentioned above (186 mg) as a starting material, a deprotected compound (156 mg) was obtained in the same manner as that of Example 4, (6). (3) By using the compound obtained in (2) mentioned above (60 mg) as a starting material, the compound shown in Table 5 (65 mg) was obtained in the same manner as that of Example 11.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])C>O>[N+:13]([C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH2:12][C:20](=[O:21])[C:19]([OH:25])=[O:18])([O-:15])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a cooled mixture prepared by adding 13.6 g. of sodium to 300 ml. of ethanol is added a solution of 100 g. of 4-chloro-2-nitrotoluene and 84 g. of diethyloxalate in 150 ml. of ethanol while maintaining the temperature below 20° C. The resulting mixture is refluxed for one hour, cooled, 400 ml. of water added and the resulting mixture refluxed for 90 minutes. The ethanol is then evaporated to a small volume and the resulting precipitate contains tan and black material and the black material is mechanically separated and discarded and the remainder (filtrate plus tan precipitate) used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:13][CH2:14][C:15]([O:17]CC)=O.Cl.[NH2:21][OH:22]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][CH2:14][C:15]([NH:21][OH:22])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: NO
Reactant: Fc1ccc(S)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CCSc1ccc(F)cc1)NO

Procedure:
10 g (0.078 mol) of p-fluorothiophenol are added to a solution of 4.5 g (0.083 mol) of sodium methylate in 25 ml of methanol, and a solution of 14.5 g (0.08 mol) of ethyl 3-bromopropionate in 20 ml of methanol is then added dropwise. The mixture is heated for 2 hours to the reflux temperature, the alcohol is evaporated in vacuo, the residue is taken up in ether, the ether solution is washed with water and dried, and the ether is evaporated. The residue is treated, for 24 hours at 20° C, with a solution of hydroxylamine in methanol prepared from 7.7 g (0.11 mol) of hydroxylamine hydrochloride and 12 g (0.22 mol) of sodium methylate in 150 ml of methanol. The methanol is evaporated in vacuo, 200 ml of water are added, the mixture is extracted with ether and the hydroxamic acid is precipitated with concentrated HCl. It is filtered off, washed with water and dried. 10 g (62%) are obtained. Melting point = 93° C.