Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH2:9][CH3:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(O)(=O)C>[Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[C:20]([CH3:21])[C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)[C:4]=1[CH2:9][CH3:10]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=C(C)c2ccc([N+](=O)[O-])cc2)cc[n+]1N
Reaction time: 48 h

Procedure:
A solution of 3.24 g (20 mmol) of 1,3-diamino-2-ethylimidazolium chloride and 16.5 g (100 mmol) of p-nitroacetophenone in 150 ml of glacial acetic acid is left to stand for 2 days, concentrated and the residue is crystallized from ethanol/ether. The crystals are placed on a column loaded with 50 g of silica gel. The material eluted with methylene chloride/methanol (7:3) is recrystallized from ethanol. There is obtained 1-amino-2-ethyl-3-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride of melting point 201°-203°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O.O>[F:13][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (see Example 41 for details), (5 g, 30.3 mmol) in sulfuric acid, cooled to −5° C. was added nitric acid, fuming (1.413 ml, 30.3 mmol) as a 1:1 mixture in water. The resulting mixture was stirred at −5° C. for 20 min. After 20 min the reaction was quenched via addition of ice, precipitating the product which was collected by filtration. The filter cake was dissolved in dichloromethane and a minimal amount of methanol, dried, filtered and concentrated onto silica gel then chromatographed using 0-10% ethyl acetate in dichloromethane to give the desired 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol, 93% yield). 1H NMR (DMSO-d6) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 1H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=4)=[N:23][C:22]=3[Cl:35])=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:35][C:22]1[N:23]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=2)[S:25][C:21]=1[CH2:20][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[NH:10][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2sc(NCc3cncc(F)c3)nc2Cl)c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cncc(CNc2nc(Cl)c(Cc3c[nH]c4ncc(Cl)cc34)s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (595, 0.030 g, 0.055 mmol) in tetrahydrofuran (6.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.034 g, 0.11 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0231, 1.5 mg, 6.7%). MS (ESI) [M+H+]+=408.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C@@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 186 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-84° C.; 400 MHz 1H NMR (DMSO) δ: 7.92-7.88 (m, 1H), 7.8-7.74 (m, 2H), 7.6-7.52 (m, 1H), 7.3-7.14 (m, 5H), 4.44 (brd, J=4.4 Hz, 1H), 3.9-3.8 (m, 1H), 3.07 (s, 2H), 2.82-2.7 (m, 3H), 2.64-2.56 (m, 1H), 2.46-2.28 (m, 4H), 2.04-1.94 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 436 [M+H]; enantiomeric excess determined from chiral HPLC: >99%; Chiral HPLC Rt=50.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13]N1C=CN=C1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Reactant: Cn1ccnc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-(3-chloro-4-fluorophenyl)acetic acid (18.46 g, 97.89 mmol) in acetic anhydride (463 mL) was added N-methylimidazole (3.9 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a colorless oil (14.5 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=6.9, 2.1 Hz, 1H), 7.14-7.00 (m, 2H), 3.66 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][N:10]([CH:13]([O:26][CH2:27][CH3:28])[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:15])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl.CCOC(C)=O>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][N:10]([CH:13]([O:26][CH2:27][CH3:28])[C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[O:15])[N:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:38])[CH3:37]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2cccc(N)c2)n1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2cccc(NC(C)=O)c2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred, cooled (0° C.) solution of (RS)-2-[3-(3-amino-phenyl)-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (117 mg, example 5.2) in dichloromethane (5 ml) under an argon atmosphere were added triethylamine (0.06 ml) and acetyl chloride (0.02 ml). Stirring at 0° C. was continued for 3 hrs. The mixture was diluted with EtOAc, washed with 1.0 N HCl and brine, dried (MgSO4), filtered and concentrated. The crude product was isolated by chromatography (silica gel, gradient CH2Cl2 to CH2Cl2/MeOH 9:1) to give 2-[3-(3-acetylamino-phenyl)-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (115 mg) as off-white solid. MS 418.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[C:18]#[C:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:36][C:29]1[CH2:30][CH2:31][CH2:32][C:33]([CH3:34])([CH3:35])[C:28]=1/[CH:27]=[CH:26]/[C:25](/[CH3:37])=[CH:24]/[CH:23]=[CH:22]/[C:21](/[CH3:38])=[CH:20]/[CH:19]=[CH:18]\[CH:17]=[C:16](/[CH3:39])\[CH:15]=[CH:14]\[CH:13]=[C:12](/[CH3:40])\[CH:11]=[CH:10]\[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C#C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C\C=C(C)\C=C\C=C(C)\C=C\C2=C(C)CCCC2(C)C)C(C)(C)CCC1

Procedure:
Two moles of β-C19 -aldehyde (I) are condensed with acetylenedimagnesium bromide to give the C40 -diol (II). The C40 -diol is converted into 15,15' didehydro-β-carotene (III) by allylic rearrangement with simultaneous dehydration. The product is partially hydrogenated over Lindlar catalyst to give mainly 15-cis-β-carotene (IV) which is isomerized to all-trans-β-carotene by treatment in high boiling petroleum ether. While several methods of obtaining β-carotene from vitamin A have been proposed, the conditions required in these methods are extreme, the reagents are expensive, and, worst of all, the yields are low.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Ca+2].[OH-].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl>O1CCOCC1>[CH2:22]([O:21][C:19]([C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]n(-c2ccc(F)cc2)c(=O)c1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
2-(4-Fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (20.3 g, 0.105 mol) and calcium hydroxide (17.2 g, 0.232 mol) were suspended in anhydrous 1,4-dioxane (200 mL). The resulting suspension was heated at 50° C. for 20 minutes. The heated suspension was cooled to 10° C. and a solution of benzyl chloroformate (14.9 mL, 0.105 mol) in dioxane (10 mL) was added. The resulting reaction mixture was heated at 90° C. for 3 hours. Upon completion of the reaction, the reaction mixture was slowly cooled to 0° C. After adding 1 M hydrochloric acid, the mixture was stirred at room temperature overnight. Then, the produced solid was collected by filtration, washed with cold ethanol and ether, and dried in vacuum to give the target compound (22.88 g, 66% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH:15]([OH:17])[CH2:14][CH2:13][CH:12]1[C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21]1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][C:15](=[O:17])[CH2:14][CH2:13][CH:12]1[C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1CC(O)CCC1C(=O)N1CCC(c2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCC(C(=O)N2CCC(c3ccccc3)C2)C(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of alcohol compound from Step 2 (400 mg) was added Dess-Martin reagent (500 mg) and the mixture was stirred at rt for 3 h. After the reaction was complete the mixture was diluted with methylene chloride followed by the addition of 0.1 N NaOH aqueous solution
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:20]([O:22][CH3:23])=[O:21].O>C1COCC1>[CH3:23][O:22][C:20]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: COC(=O)Cl
Reactant: COc1ccc(CCN)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 4-methoxy-phenethylamine (5.81 mL, 39.7 mmol) in anhydrous THF (200 mL) was added Et3N (6.6 mL, 48 mmol). The solution was cooled to 0° C. and methyl chloroformate (15.38 mL, 199 mmol) was added slowly via syringe. The reaction was stirred at 0° C. for 2 hours and then allowed to warm to room temperature and stirred overnight. To the reaction mixture was added H2O (50 mL) and the resulting solution was extracted into Et2O (1×100 mL) and then into EtOAc (2×75 mL). The combined organic fractions were washed with brine (200 mL) and 1 M HCl (200 mL), dried over Na2SO4, filtered and concentrated under vacuum, affording 7.98 g (96%) of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].O[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1>>[F:1][C:2]1[C:7]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Cc1cc(CO)ccn1
Product: Cc1cc(COc2ccc(F)c(C(N)=O)c2F)ccn1
Yield: 34 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method C, scheme 3. The required building block, 4-hydroxymethyl-2-methylpyridine, was synthesised according to the literature method, shown in Scheme 23 (Ragan, J. A., Jones, B. P., Meltz, C. N., Teixeira J. J. Jr.; Synthesis 2002, 483-486. Yield 34%, mp 185-186° C., HPLC-MS (method 1): m/z 279 [M+H]+, Rt=2.50 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCCCCCC(C(=O)OCC)n1cnc2cc([N+](=O)[O-])ccc21
Yield: 22.9 %

Procedure:
5-Nitrobenzimidazole (0.109 moles, 17.8 g.) was reacted with sodium hydride (0.122 moles, 4.9 g of 60% in mineral oil) and ethyl 2-bromooctanoate (0.102 moles, 22 ml) as in Example 11 to produce a mixture of the 5 and 6 isomer. The isomers were separated to yield 7.8 g of ethyl 2-(5-nitro-1H-benzimidazol-1-yl)octanoate.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[O:3].F.C(F)([F:17])=O>>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([NH:1][C:2]([F:17])=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C(F)F
Agent: F
Agent: *C(F)(F)C(*)(F)F
Product: O=C(F)Nc1cccc(C(F)(F)F)c1
Temperature: 24 °C
Reaction time: 96 h

Procedure:
3-(Trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 187 parts of 1-isocyanato-3-(trifluoromethyl)benzene and 370 parts of hydrogen fluoride added over a period of about 15 minutes at about 4° C. The reaction mixture was then sealed in a polytetrafluoroethylene reaction vessel, heated to about 24° C., and maintained thereat, with agitation, for about 96 hours. The reaction vessel was then opened to atmospheric pressure and most of the hydrogen fluoride and carbonyl fluoride gases removed. The remaining organic product was analyzed by gas chromatographic techniques, using n-pentadecane as an internal standard, indicating a yield of 41 parts of 3-(trifluoromethyl)benzenamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(O)C>[C:1]([O:5][C:6]([NH:8][N:9]([CH2:16][CH:15]=[CH2:14])[CH:10]1[CH2:11][CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NNC1CCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: C=CCN(NC(=O)OC(C)(C)C)C1CCC1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.88 g, 4.72 mmol) was dissolved in ethanol (45 mL). Allyl bromide (0.82 mL, 9.44 mmol), potassium carbonate (0.65 g, 4.72 mmol), and lithium iodide (0.063 g, 0.47 mmol) were added sequentially. The reaction was stirred at reflux for 18 h. The mixture was cooled to 25° C., concentrated in vacuo, taken up in water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-20% ethyl acetate in hexanes) afforded the desired product, N′-allyl-N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.98 g, 4.34 mmol, 92%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.36 (9H, s), 1.50-1.62 (2H, m), 1.82-1.88 (4H, m), 3.13 (2H, d, J=6.0 Hz), 3.34-3.39 (1H, m), 5.03 (1H, d, J=10.0 Hz), 5.14 (1H, d, J=16.8 Hz), 5.71-5.81 (1H, m), 7.59 (1H, bs). LC-MS (ESI) calcd for C7H14N2 (free hydrazine) 126.20, found 127.0 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([N:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:3]=1.C([O-])=O.[NH4+]>CC(O)C.O.[Pd]>[CH:17]1([N:12]([CH2:13][CH:14]2[CH2:15][CH2:16]2)[C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-chloro-6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 11, 4.77 g; 14.7 mmol) in 150 ml of iPrOH was treated with 780 mg of palladium (10% on C). The suspension was degassed and a solution of ammonium formate (6.96 g; 110 mmol) in 20 ml of water was added. After stirring at RT for 45 minutes, the suspension was filtered on a pad of Celite, the remaining residue was twice rinsed with 50 ml of iPrOH and the combined filtrates were evaporated under reduced pressure. The remaining colorless residue was partitioned between 150 ml of MTBE and 150 ml of water. Both layers were separated. The organic phase was once washed with 100 ml of brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as colorless oil (4.14 g, 97%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:27]([F:30])([F:29])[F:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:31].O1CCOCC1>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:27]([F:30])([F:29])[F:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:10]1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(C(F)(F)F)c23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(C(F)(F)F)c23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Intermediate 33a (16.3 mg) prepared in Step A mentioned above was added with 4 N hydrogen chloride/1,4-dioxane solution (2 ml, Kokusan Chemical), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (13.3 mg).
Reaction SMILES: Cl.[C:2]1([NH:8][S:9]([C:12]2[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[C:14]([NH2:20])[CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=O)=[CH:25][CH:24]=1)#[N:22]>P(Cl)(Cl)(Cl)=O>[C:2]1([NH:8][S:9]([C:12]2[CH:19]=[CH:18][C:15]3[N:16]([CH3:17])[C:30]([CH2:29][C:26]4[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[N:20][C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccc(S(=O)(=O)Nc2ccccc2)cc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(S(=O)(=O)Nc3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1a from 4-phenylaminosulphonyl-2-amino-N-methyl-aniline-hydrochloride and 4-cyano-phenylacetic acid in phosphorus oxychloride.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([NH:10][C:11](=[O:27])[O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:6]([CH3:28])[NH:5]1)([CH3:3])[CH3:2].[CH3:29]I>CN(C=O)C>[CH:1]([N:4]1[C:8](=[O:9])[C:7]([NH:10][C:11](=[O:27])[O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:6]([CH3:28])[N:5]1[CH3:29])([CH3:3])[CH3:2]
Reactant: Cc1[nH]n(C(C)C)c(=O)c1NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)n(C(C)C)n1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2-isopropyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)carbamate (2.109 g, 5.59 mmol) in DMF (30 mL) was added methyl iodide (2.80 mL, 44.7 mmol). The reaction mixture was stirred at 90° C. overnight. The resulting mixture was quenched with IPA and water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:33](=[O:35])[CH3:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:18][CH2:19][C:20]1[N:21]=[C:22]([C:33](=[O:35])[CH3:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:24]=1
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)c1nc(CO)cn1COCC[Si](C)(C)C
Reaction time: 1 h
Yield: 108.7 %

Procedure:
The compound obtained in (2) (24.4 g) was dissolved in THF (200 mL), tetrabutylammonium fluoride (hereinafter sometimes referred to as TBAF) (a 1.0 M THF solution, 62.7 mL) was added under stirring, and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=25%→100%) using an amino column (trade name: Hi-Flash Column 5L Amino, manufactured by Yamazen Corporation) to give the title compound (14.1 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[S:11][C:12]([Br:15])=[CH:13][CH:14]=2)[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[N:6]=1)=O.[BH4-].[Na+]>CO>[Br:15][C:12]1[S:11][C:10]([CH:8]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[N:6]=[C:5]([CH2:3][OH:2])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 5-(5-bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (15.1 g, 37.6 mmol) prepared in Step 3 in methanol (125.3 mL), was slowly added sodium borohydride (6.4 g, 169.2 mmol) at 0° C. The reaction mixture was stirred at 80° C. for 18 hours, concentrated under reduced pressure, acidified by a 1N hydrochloric acid solution, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 12.9 g of the titled compound as a yellow liquid.