Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a suspension of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.79 mmol) in CH2Cl2 (25 mL) at 0° C. under an N2 atmosphere, was added dropwise tert-butyl piperidin-4-ylcarbamate (2.08 g, 10.13 mmol) and triethylamine (2.20 mL, 15.8 mmol) in CH2Cl2 (10 mL). The reaction was stirred overnight, quenched with water and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to afford tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 100%—solvent residue). LC/MS: m/z 421.3 (M+H)+ at 2.70 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]([NH:25][NH2:26])=[O:24]>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1/[CH:5]=[N:26]/[NH:25][C:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:24]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: CCO
Product: O=C(N/N=C/c1ccccc1C(F)(F)F)c1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-(Trifluoromethyl)benzaldehyde (4-B) (135 μL, 1.0 mmol) was added to a partial solution of 2-naphthohydrazide (4-A) (186 mg, 1.0 mmol) in ethanol (4 mL) at 70° C. and the mixture stirred at 70° C. for 2 h. The mixture was cooled and the thick precipitate was filtered, washed with cold ethanol and dried to give N′-{(1E)-[2-(trifluoromethyl)phenyl]-methylene}-2-naphthohydrazide (4-C).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1.CCOCC>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]/[C:20]([NH:26][NH:25][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C/n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1cnccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C/n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.75 g,) in EtOAc (25 mL) and THF (12.5 mL) was added a solution of 2-hydrazinopyrazine (0.23 g) in 12 mL THF at room temperature. T3P (50% in ethyl acetate, 1.52 mL) and DIPEA (1.46 mL) were added dropwise and simultaneously and the reaction mixture was stirred for 30 min at room temperature before being quenched with ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg), affording 0.698 g of a crude solid. Trituration first with petroleum ether then with Et2O afforded 275 mg (yield: 29%) (E)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.3 (s, 1H), 9.15 (s, 2H), 8.59 (s, 2H), 8.30-8.26 (d, J=14.8 Hz, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 6.98-6.95 (d, J=13.4 Hz, 1H); LCMS for C7H12F6N7O [M+H]+ 443.31. found 444.19 (RT 2.625 min, purity: 99.06%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].CC(=CC)C.C1C[O:31]CC1.[O-]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[C:21]([OH:31])=[O:22]
Reactant: C1CCOC1
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4a (335 mg, 1.00 mmol) and 2-methyl-2-butene (1.06 ml, 10.01 mmol) were dissolved into 50 ml THF. A freshly prepared solution of 80% NaClO2 (339 mg, 3.00 mmol) and NaH2PO4.H2O (414 mg, 3.00 mmol) in 55 ml of t-BuOH/H2O 5:1 was added. The reaction mixture was stirred in room temperature for 6 hours. The reaction was quenched with water and extracted CH2Cl2. The organic phase was extracted with sat. NaHSO4. The water phase was then made acidic with HCl and extracted with CH2Cl2. the organic layer was washed with brine and dried over Na2SO2. After filtration the solvent was evaporated ant the product recrystallized from ethanol.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].CO.[BrH:15]>>[BrH:15].[BrH:15].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: NCCS
Reactant: OCc1cncs1
Agent: Br
Agent: Cl
Solvent: CO
Product: NCCSCc1cncs1

Procedure:
The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteamine hydrochloride (1.99 g.) in aqueous hydrobromic acid by the method described in Example 1(i)(a) gave 5-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide (4.85 g.), m.p. 191°-194° (from methanol).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: CC(C)(CN)CO
Solvent: CCO
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 3-amino-2,2-dimethyl-1-propanol (0.008 mL, 0.078 mmol) for 20 min. (160° C. in a microwave vessel. The reaction was further microwaved for 40 min.@160° C., cooled to ambient temperature, and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.57 (s, 6 H), 1.93 (s, 1 H), 2.91 (d, J=5.19 Hz, 2 H), 3.08 (d, J=5.62 Hz, 2 H), 3.92 (t, J=5.33 Hz, 2 H), 4.16 (s, 2 H), 4.56-4.68 (m, 3 H), 7.11-7.18 (m, 2 H), 7.35-7.41 (m, 2 H), 7.80 (s, 4 H), 8.22 (d, J=0.84 Hz, 1 H), 8.55 (d, J=0.56 Hz, 1 H), 10.02 (t, J=6.32 Hz, 1 H); ES+ MS: 573 (M+H+).
Reaction SMILES: [OH-].[K+].[N+]([C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>O>[NH2:13][C:12]1[C:11]2[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1sc2cc(OC)ccc2c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
A solution of 20.3 g (0.363 mol) of potassium hydroxide in 100 ml of water is added to a mixture of 36.3 g (0.204 mol) of 3-nitro-4-cyanoanisole and 26 g (0.245 mol) of methyl thioglycolate in 400 ml of N,N-d-methylformamide, the temperature being maintained at 0° C. The mixture is left stirring at 0° C. for 20 min and is then poured into a mixture of water and ice. The precipitate is then filtered off, rinsed with water and dried. The product is dissolved in a mixture of dichloromethane and tetrahydrofuran, the organic phase is then dried over sodium sulphate and concentrated under reduced pressure and the residue is triturated in dichloromethane. 26.2 g of product are thus obtained in the form of a light-beige powder.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[CH3:17][N:18]1[CH2:22][CH2:21][N:20]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:19]1=[O:23]
Reactant: CN1CCNC1=O
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: CN1CCN(Cc2ccc(C#Cc3ccccc3)cn2)C1=O

Procedure:
The title compound, light brown solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-methyl-imidazolidin-2-one.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16](O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([Cl:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2Cl
Yield: 86.3 %

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (0.65 g, 2.26 mmol) was dissolved in 50 mL toluene, and 1 mL of thionyl chloride was added. The reaction was refluxed for one hour, and then cooled. Solvent was removed under reduced pressure to yield 6-benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 86.3%) as a crude oil. MS: 308 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][Br:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of methyl 4-bromo-2-methylbenzoate (0.7 g, 0.003 mol), N-bromosuccinimide (0.65 g, 0.0037 mol) and benzoyl peroxide (0.038 g, 0.00016 mol) in carbon tetrachloride (30 mL) was refluxed under an atmosphere of nitrogen for 2 h. The mixture was cooled to RT, and filtered through silica gel eluting with dichloromethane followed by diethyl ether. The mixture was concentrated and the residue was purified by chromatography on silica gel with 30% EtOAc in hexanes to afford the desired product (0.86 g, 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([CH3:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6]([NH:9][CH:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:17])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(Nc1ccc(Cl)cc1[N+](=O)[O-])c1cccnc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC(Nc1ccc(Cl)cc1N)c1cccnc1
Yield: 100 %

Procedure:
A mixture of 46 parts of N-(4-chloro-2-nitrophenyl)-α-methyl-3-pyridinemethanamine monohydrochloride and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 41.5 parts (100%) of 4-chloro-N1 -[1-(3-pyridinyl)ethyl]-1,2-benzenediamine monohydrochloride as a residue.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C., after 1 h allyl bromide (1.5 eq) was added and the suspension was stirred at RT for 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (100% as crude); MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=23)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]1=[C:7]2[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCCC1

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 7,8,9,10-tetrahydro-11-(4-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.[C:17](=[O:19])=[O:18].O>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Fc1cc2[nH]ccc2cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Temperature: -75 °C
Reaction time: 2 h

Procedure:
1.56 ml (2.49 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 3.2 ml THF at −78° C. under nitrogen. 211 mg (1.24 mmol) of 5-chloro-6-fluoro-1H-indole as a 3:1 mixture of regioisomers dissolved in 0.8 ml THF were added within 15 min keeping the temperature below −70° C. After 5 min 279 mg (2.49 mmol) of potassium-tert-butylate dissolved in 1 ml THF were added within 15 min. The reaction mixture was stirred for 2 h at −75° C. to give a clear orange solution. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted twice with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 2 h and filtered to yield 121 mg (46 of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 13.6 (br, 1H), 11.3 (br, 1H), 8.00 (d, 1H), 7.42 (s, 1H), 6.52 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>CN(C)C(=O)C>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: OCCNCCO
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)c(N(CCO)CCO)c(F)c1

Procedure:
A solution of 3,4,5-trifluorobenzonitrile (5 g, 32 mmol) and diethanolamine (6 ml, 85 mmol) in N,N-dimethylacetamide was stirred for 10 days. The solvent was then evaporated, the residue partitioned between CH2Cl2 (200 ml) and H2O (200 ml), the organic layer dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOAc as eluent to give, after recrystallization from toluene, 2.7 g (35%) of pure white crystals: mp 63-65° C.; 1H NMR δ3.33 (t, 4H, NCH2, J=6 Hz), 3.48 (t, 4H, OCH2, J=6 Hz), 4.43 (bs, 2H, OH), 7.57 (dd, 2H, H2+6, JH2, F3 and H6, F5=8.5 Hz, JH2, F5 and H6, F3=2Hz=22 Hz); 19F NMR δ −116.0 (d, 2F, F3+5, JF3, H2 and F5, 6=7.5 Hz); MS m/z 265 (M+Na+, 10), 243 (M+H+, 100), 211 (M-CH2OH, 85). Anal. (C11H12N2O2F2) C,H,N.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)(=[O:8])=[O:7])[CH3:2]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([NH:3][C:4]([N:18]1[CH2:22][CH:21]([CH2:23][CH3:24])[CH:20]=[N:19]1)=[N:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:7])=[O:8])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc2c(c1)CCN2)N1CC(CC)C=N1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCNC(=NS(=O)(=O)c1ccc2[nH]ccc2c1)N1CC(CC)C=N1
Temperature: 50 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
0.42 g 2,3-Dihydro-1H-indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide was dissolved in 25 mL toluene, and 10 mol % of palladium on carbon was added. The mixture was stirred at 50° C. for 5 days, with addition of fresh catalyst (10 mol %) after 2 days. The mixture was cooled to room temperature and filtered over Hyflo. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (DCM→DCM/EA 9:1) to give 0.26 g (66%) of 1H-Indole-5-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a blue oil. 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.37 Hz, 3H), 1.08 (t, J=7.22 Hz, 3H), 1.32-1.59 (m, 2H), 2.89-3.02 (m, 1H), 3.35-3.50 (m, 2H), 3.58 (dd, J=11.44, 7.52 Hz, 1H), 3.96 (t, J=11.29 Hz, 1H), 6.54-6.58 (m, 1H), 6.85 (d, J=1.50 Hz, 1H), 6.97 (br.s., 1H) 7.23-7.29 (m, 1H), 7.42 (d, J=8.73 Hz, 1H), 7.69 (dd, J=8.73, 1.81 Hz, 1H), 8.24 (d, J=1.20 Hz, 1H), 9.43 (br.s., 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][OH:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][O:29][C:31](=[O:33])[CH3:32])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCSCCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-hydroxyethylthio)hexanamide [prepared as described in step (b) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37]O)=[NH:36])=[CH:33][N:32]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[N:17]3[N:24]=[CH:25][C:26]([C:27]4[O:28][N:37]=[C:35]([C:34]5[CH:39]=[CH:40][C:31]([NH2:30])=[N:32][CH:33]=5)[N:36]=4)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])[CH3:2]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(N)nc1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) (210 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (120 mg, 45%). MS (ISP) 536.3 [(M+H)+]; mp 263° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH2:8][C:9]([OH:11])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:35][C:36]1([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)[CH:41]2[CH:37]1[CH2:38][NH:39][CH2:40]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:35][C:36]1([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)[CH:41]2[CH:37]1[CH2:38][N:39]([C:9](=[O:11])[CH2:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:40]2
Reactant: Cc1ccsc1CCC(=O)O
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1CCC(=O)N1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.6 %

Procedure:
To a solution of 3-(3-methyl-2-thienyl)propanoic acid (J. W. McFarland et al., J. Med. Chem., 1970, 13, 113, 200 mg, 1.17 mmol) in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazole monohydrate (200 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg, 1.77 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.32 mmol) and sodium hydrogen carbonate (200 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO4), and concentrated in vacuo to afford 620 mg of a brown oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min) and then with ethyl acetate:methanol (100:0 to 0:100 over 5 min) to afford the title compound as a colourless oil (244 mg, 50%).