Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][OH:32])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[C:35]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:37]=[CH:38][CH:39]=1.O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][O:32][S:40]([C:35]1[C:34]([CH3:44])=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:42])=[O:41])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(CC(CO)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Reaction time: 6.5 h
Yield: 88.3 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-hydroxymethylethylcarbamic acid benzyl ester (2.07 g, 4.63 mmol) in pyridine (46 ml), toluenesulfonyl chloride (6.79 g, 35.6 mmol) was added under cooling with ice. After stirring for 6.5 hours, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1), giving the titled compound (2.46 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:3]1.C[Si]([NH-])(C)C.[Na+].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C(Cl)(Cl)Cl.C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)[CH2:10][CH2:11]2)=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN1CCCC(CN2CCNCC2)C1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCCC(CN2CCN(C(=S)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[(1-methylpiperidin-3-yl)methyl]piperazine (400 mg) in chloroform (10 ml) was added a 2M solution of sodium(trimethylsilyl)amide in THF (2.2 ml). The resulting solution was stirred at room temperature for 10 minutes. 3,4-Dichlorophenylisothiocyanate (0.44 ml) was added and mixture stirred at room temperature for 1 hour. The reaction was quench with water (1 ml) then concentrated in vacuo before being separated between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (1.0 g). The resulting powder was purified by column chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 10% methanolic ammonia in dichloromethane to give the title compound (726 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:27])[NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19]1)[C@H:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:7][C@@H:8]([C@H:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:10])[C:16]([NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:27]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[(1S,2R)-2-tert-butoxy-1-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (0.17 g, 0.45 mmol) was dissolved in DCM (1 mL) and to this was added TFA (0.2 mL). The reaction was allowed to stir at RT for 24 h. The solvent was removed under reduced pressure and the residue triturated with Et2O to give (2S,3R)-2-amino-3-tert-butoxy-N-(1-pyrimidin-2-yl-cyclopropyl)-butyramide trifluoro-acetic acid (0.16 g, 0.45 mmol) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18](Br)([CH3:20])[CH3:19]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)Br
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(N)ncnc21
Yield: 72 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 0.0077 mol) and K2CO3 (4.2 g, 0.031 mol) in DMF (50 mL) was brought to 80° C. under an argon atmosphere. Isopropylbromide (1.0 g, 0.0084 mol) was added with a syringe. Reaction was refluxed under argon atmosphere for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 mL) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using silica gel column chromatography [MeOH—CH2Cl2, 5:95] yielding BA12 (1.68 g, 72% yield). ESI-MS (M+H)+ m/z calcd 304.0, found 304.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10](=[O:21])[C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC(O)C.[Al](OC(C)C)(OC(C)C)OC(C)C>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([OH:21])[C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCC2
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(R)-t-butyl 1-(2,3-dihydrobenzofuran-6-yl)-1-oxopropan-2-ylcarbamate (306d, 2.21 g, 7.59 mmol) was dissolved in propan-2-ol (6.35 mL, 83.4 mmol) and toluene (10 mL). Al(OiPr)3 (0.310 g, 1.52 mmol) was added, and the reaction vessel was capped and flushed with argon. The mixture was stirred at 50° C. overnight. Then another portion of Al(OiPr)3 (330 mg) was added, and stirring was continued for 5 h. The mixture was cooled to r.t., and partitioned between aq. HCl (1N, 25 ml) and ethyl acetate (80 ml). The organic layer was separated and dried. The solvent was removed in vacuo and purified by flash chromatography on silica gel with n-heptane/ethyl acetate (6:4) to give 1.58 g (71%) of subtitle compound.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O>[N:38]1([CH2:37][CH2:36][O:27][C:25]2[CH:24]=[CH:23][C:20]3[N:21]4[CH:22]=[C:15]([C:12]5[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=5)[N:16]=[C:17]4[S:18][C:19]=3[CH:26]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1)([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC#N>[CH3:39][C:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([S:47][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:45][CH:46]=1)([CH3:32])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2inlet was added 5-(chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (7.87g, 20.09mmoles, 1eq) and dry CH3CN (100ml, 0.27M). Solid cesium carbonate (16.4g, 50.22mmoles, 2.5eq) was added all at once followed by the quick addition of ethyl 2-methyl-2-(4-sulfanylphenoxy)propanoate (5.79g, 24.11mmoles, 1.2eq) in dry CH3CN (10ml). The reaction was allowed to stir at room temperature for 2hours at which point the solvent was removed under reduced pressure. The resulting residue was partitioned between EtOAc and 1N NaOH. After the phases were separated the organic fraction washed with H2O, brine and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield the titled compound in >100% yield. Sometimes because of the difficult separation between the thiophenol and the product, the crude product was carried forward without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[C:15]3[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][N:3]=1.O1CCOCC1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N1C=CC=CC=1>ClS(O)(=O)=O>[N:34]1([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[C:15]4[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:6]=2)(=[O:10])=[O:9])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Agent: O=S(=O)(O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)N1CCCCC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cold (5° C.) solution of the 0.456 M solution of 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl chloride (2 mL, 0.912 mmol) in chlorosulfonic acid from above was added anhydrous dioxane (1 mL) and piperidine (1.8 mL, 18.24 mmol). After 30 minutes of stirring, pyridine (1 mL, 12.3 mmol) was added and the reaction mixture stirred for an additional hour at room temperature. The reaction mixture was concentrated in vacuo, the residue dissolved in CH2Cl2 and the pH adjusted to 14 using 6 N NaOH (aq). The solution was extracted with CH2Cl2 (×4) and the combined organic layers dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified twice by silica gel chromatography (0-5% MeOH in EtOAC) to give the title compound as a pale yellow solid (269 mg, 66% yield). MS(ES)+ m/e 446.3 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][C:30]2=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].O>C1COCC1>[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29]/[C:30]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C1\CCCc2ccc([N+](=O)[O-])cc21
Temperature: -78 °C
Yield: 83 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide, (1.0 M in hexanes) (5 mL, 28 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 28 mmol) in THF (30 mL). The reaction was maintained at −78° C. for 16 minutes and then 7-nitro-1-tetralone 6.1 (available from Astratech) (3 g, 16 mmol) was added in one portion, and the resulting mixture was stirred at −78° C. and allowed to warm to room temperature for 20 hours. The resulting mixture was poured into water (30 mL) and then extracted with EtOAc (300 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 6.2 in 83% yield.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:13]=2)=[O:10])=[C:7]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OO.C([O-])(O)=[O:34].[Na+].C(Cl)Cl>FC(F)(F)C(O)C(F)(F)F>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:20])(=[O:21])[NH2:19])[CH:13]=2)=[O:10])=[C:7]([S:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:34])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)c(Sc2ccccc2)c1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)c(S(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-tert-butyl-2-(phenylthio)-N-(3-sulfamoylphenyl)benzamide (15.4 mg, 0.035 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.3 mL) was added H2O2 (30% wt in water, 0.01 mL, 0.07 mmol). The reaction was stirred at room temperature for 40 min, and saturated NaHCO3(aq) and CH2Cl2 (1 mL each) were added. The organic layer was filtered through a pad of Na2SO4 and concentrated. The product was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 4-tert-butyl-2-(phenylsulfinyl)-N-(3-sulfamoylphenyl)benzamide. LC/MS: m/z 457.4 (M+H)+ at 1.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[N:24]=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC>[N:24]1[CH:23]=[CH:28][CH:27]=[C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[N:25]=1
Reactant: Oc1cccnn1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2cccnn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 3-hydroxypyridazine, using dry DME as the reaction solvent: MS (ESI) m/z 391 (M+1).
Reaction SMILES: N[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].C1CCN2C(=NCCC2)CC1>O>[NH:13]1[C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]([NH2:5])=[N:14][S:10]1(=[O:12])=[O:11]
Reactant: N#Cc1cccnc1N
Reactant: NS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NC1=NS(=O)(=O)Nc2ncccc21
Temperature: 160 °C

Procedure:
A stirred mixture of 2-aminonicotinonitrile (238 mg, 2.0 mmol), sulfamide (192 mg, 2.0 mmol), and 1 mL of DBU was heated at 160° C. under nitrogen overnight. After it was cooled down to room temperature, the reaction mixture was diluted with water, and extracted three times with EtOAc. The aqueous layer was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (t, J=5.6 Hz, 1H), 7.95 (brs, 2H), 8.22 (d, J=5.2 Hz, 1H), 8.39-8.37 (m, 1H), 12.58 (brs, 1H). MS 199 (MH+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 was dissolved in N,N-dimethylformamide (3 ml). 1-Methylpiperazine (36 mg, 0.36 mmol), EDC (90 mg, 0.47 mmol) and HOBT (75 mg, 0.55 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (78 mg, Yield 64%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=2)[O:45][CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([O:45][CH2:46][CH2:47][CH2:48][N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)[CH:54]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOS(C)(=O)=O)c2)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCN3CCOCC3)c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
A solution of Intermediate 76a (214 mg, 0.27 mmol) and DIPEA (95 μL, 0.54 mmol) in THF (5 mL) was treated with morpholine (47 μL, 0.54 mmol). The mixture was stirred at 50° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the product was purified by MDAP purification (Method 7) to give the title compound (72 mg, 34%). LCMS (Method 5): Rt 3.60 min, m/z 782.6 [MH+].+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.94 (4H, m), 1.99-2.17 (2H, m), 2.24-2.32 (3H, bs), 2.36-2.42 (2H, t, J=6.9), 3.11-3.17 (4H, m), 3.48-3.52 (4H, m), 4.09-4-15 (2H, t, J=6.52 Hz), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.03-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>CC(C)=O.O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
294 g (2.51 mol) of L-valine was dissolved into 786 g of ion-exchange water, 358 g (2.42 mol) of an aqueous solution of 27% sodium hydroxide and 363 g of acetone. With stirring the solution, 533 g (2.43 mol) of lauroyl chloride and 358 g (2.47 mol) of an aqueous solution of 27% sodium hydroxide were simultaneously added dropwise thereto so that pH=12±0.2 and the temperature is kept at 19 to 20° C. After completion of the addition, the solution was stirred at 20° C. for 60 minutes. Then, it was heated up to 40° C., and 171 g of 75% sulfuric acid was added thereto in order to adjust pH=1.5. The layers of the oily substance and water phase that separated at 60° C. were split, and 1950 g of warm water of 60° C. was added to the oily substance. After the mixture was cooled down to 20° C., the precipitated solid substance was filtered out and washed with water. Then, the substance was vacuum-dried at 50° C. to obtain 710 g of N-lauroyl-L-valine (2.37 mol, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:18]([F:20])[F:19])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(Cl)ccc1-c1cc(OC(F)F)[nH]n1
Reaction time: 6 h
Yield: 14.7 %

Procedure:
64 g of the 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole obtained in step 1.1 were initially charged in 600 ml of dioxane. A solution of 24 g of sodium hydroxide in 70 ml of water was added, and the mixture was heated at reflux. With stirring, 238.7 g (2.76 mol, 9.2 eq.) of gaseous chlorodifluoromethane were added, and during the addition the pH was monitored constantly and, when it approached the neutral range (pH<9), increased by addition of additional NaOH solution to about pH 12. After 6 h, the mixture was allowed to cool, 1800 ml of water were added and the mixture was extracted twice with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. This gave 58.7 g of crude 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole. 32.3 g of this mixture were distilled under reduced pressure, giving 11.6 g of the title compound as an oil of a purity of 86%. Yield: 22.9%