Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.[Pd]>[CH2:20]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(O)COc1ccc(CCOCC2CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: OC(CNCc1ccccc1)COc1ccc(CCOCC2CC2)cc1

Procedure:
In an alternative method, 3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (1.33 g), (see Example 5 (i) in ethanol (20 ml) was stirred at room temperature whilst a solution of benzaldehyde (1.06 g) in ethanol (20 ml) was added. The mixture was poured on to a slurry of 5% palladium on charcoal (0.5 g) in ethanol (5 ml) and hydrogenated at 344 kPa (50 p.s.i.) for 10 minutes. The mixture was filtered through diatomaceous earth and the filtrate evaporated to give a clear oil which crystallised on standing to give N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine, in quantitative yield, identical to an authentic sample by chromatography and a nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl-].[Li+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]1[C:24](OS(C(F)(F)F)(=O)=O)=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32].[CH3:62][O:63][C:64]1[CH:85]=[CH:84][C:67]([CH2:68][O:69][CH2:70][Sn](CCCC)(CCCC)CCCC)=[CH:66][CH:65]=1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.CN1CCCC1=O>[CH3:62][O:63][C:64]1[CH:85]=[CH:84][C:67]([CH2:68][O:69][CH2:70][C:24]2[C:23]([CH3:22])=[C:31]3[C:27]([C:28](=[O:32])[O:29][CH2:30]3)=[C:26]([O:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[C:25]=2[CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:66][CH:65]=1
Reactant: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1ccc(OC)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(COCc2ccc(OC)cc2)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
A mixture of lithium chloride (1.6 g), tris(dibenzylideneacetone)dipalladium (O) chloroform adduct (0.22 g), triphenylarsine (0.53 g), methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (8.0 g) and N-methylpyrrolidinone (70 ml) is heated to 55° C. p-Methoxybenzyloxymethyltributyltin (7.5 g) is added. After 3 hours the solution is added to water (200 ml), potassium fluoride (5 g) and ethyl acetate (200 ml). The organic solution is dried, filtered through celite and evaporated, and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-(p-methoxybenzyloxymethyl)-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: OCCN1CCNCC1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(CCO)CC3)cc21
Temperature: 110 °C
Yield: 61.3 %

Procedure:
As described in Example 1, 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid and 10.6 g of 1-(β-hydroxyethyl)-piperazine in 45 cm3 of DMSO (dimethylsulphoxide) were heated for 3 hours at 110° C. After evaporation of the solvent under a good vacuum, the viscous residue was taken up in 20 cm3 of isopropanol; the mixture was stirred and heated under reflux for 20 minutes. After standing for one night at 4° C., the solid was filtered off, washed with ethanol and recrystallised from methyl cellosolve (15 cm3). 3.5 g of 6-chloro-1-ethyl-7-[4-(β-hydroxyethyl)-piperazinyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 215° C., were obtained.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][F:21])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:21][CH2:20][CH2:19][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: CCOC(=O)C1CCCc2c1c1ccccc1n2CCF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCc2c1c1ccccc1n2CCF
Yield: 38.3 %

Procedure:
9-(2-Fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (30) (380 mg, 1.3 mmol) was dissolved in ethanol (3 mL) and then NaOH (520 mg) in water (5 mL) was added. The reaction was heated at reflux for 2 h. The reaction was concentrated in vacuo and the residue diluted with water and washed with dichloromethane (2×50 mL). The aqueous layer was added drop wise to 2 N HCl (50 mL) and then extracted into dichloromethane (3×50 mL). The organics were dried and concentrated in vacuo to afford 130 mg (37%) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (31) as a yellow solid which was used in the next step without purification. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.90-2.42 (4H, m, 2- and 3-CH2), 2.60-2.91 (2H, m, 1-CH2), 3.94 (1H, t, J=6 Hz, 4-CH), 4.30 (1H, t, J=6 Hz, NCH2CH2F), 4.37 (1H, t, J=6 Hz, NCH2CH2F), 4.59 (1H, t, J=6 Hz, NCH2CH2F), 4.74 (1H, t, J=6 Hz, NCH2CH2F), 7.05-7.26 (3H, m, ArH), 7.59 (1H, d, J=9 Hz, ArH).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](O)=O)[CH2:3][C:4](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].O.[OH-].[Na+]>O=P(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:7][CH2:8][C:9]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:3][C:4]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: NNC(N)=S
Reactant: CC(CCC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CCc1nnc(N)s1)Cc1nnc(N)s1
Temperature: 90 °C
Yield: 106.3 %

Procedure:
A mixture of 3-methyl adipic acid (5.00 g, 31.22 mmol) and thiosemicarbazide (5.69 g, 62.43 mmol) in POCl3 (45 mL) was heated at 90° C. for 4 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(2-methylbutane-1,4-diyl)-bis(1,3,4-thiadiazol-2-amine) (1003, 8.97 g). 1H NMR (300 MHz, DMSO-d6) δ 7.00 (s, 4H), 2.89-2.81 (m, 3H), 2.89-2.81 (m, 3H), 2.69 (dd, J=7.6, 7.6 Hz, 1H), 1.89-1.46 (m, 3H), 0.94 (d, J=6.6 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:26][O:27]CC)[N:18]([CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.[OH-].[K+]>ClCCl.ClCCCl.CO>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:26][OH:27])[N:18]([CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(Cn1c(CO)nc2c(N)nc3ccccc3c21)C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Boron tribromide (15 mL of a 1 N solution in dichloromethane) was added to a solution of 3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide (1.1 g, 3.2 mmol, Example 28) in 1,2-dichloroethane (35 mL). The reaction was heated at reflux for 35 minutes, cooled to approximately 0° C., and adjusted to pH 8 with the addition of a solution of potassium hydroxide (90 mL of a 0.5 N solution in methanol). The volatiles were removed under reduced pressure, and the residue was mixed with methanol (50 mL) and isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was stirred overnight with saturated aqueous sodium bicarbonate (35 mL). The resulting solid was isolated by filtration, combined with material from another run, and purified by column chromatography on silica gel (eluting with 20% methanol in dichloromethane containing 1% ammonium hydroxide) and dried in a vacuum oven for three hours at 60° C. to provide 3-[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as white crystals, mp 201-203° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:13][CH:14]3[CH2:16][O:15]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH2:25][NH:26][CH2:27][CH2:28][C:29]=1[CH3:30]>C(#N)C>[C:1]1([S:7]([C:10]2([CH2:13][CH:14]([OH:15])[CH2:16][N:26]3[CH2:25][C:24]([CH3:23])=[C:29]([CH3:30])[CH2:28][CH2:27]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C)CNCC1
Reactant: O=S(=O)(c1ccccc1)C1(CC2CO2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)CN(CC(O)CC2(S(=O)(=O)c3ccccc3)CC2)CC1

Procedure:
Crude 2-(1-benzenesulphonylcyclopropylmethyl)oxirane (500 mg, 2.1 mmol), potassium carbonate (580 mg, 4.2 mmol) and 3,4-dimethyl-1,2,5,6-tetrahydropyridine (470 mg, 4.2 mmol) in acetonitrile (3 ml) were heated at 60° C. for 18 hours. The mixture was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: COc1ncccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ncccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 53 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxynicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 163 mg, 53%) which was obtained as a white solid. MS: m/e=335.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH:12]([N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17]Cl)([CH3:14])[CH3:13]>>[CH:12]([N:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][CH2:17][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:13])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCl)Cc1ccccc1
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)Cc1ccccc1

Procedure:
By using isatin and the 2-(N-isopropylbenzylamino)ethyl chloride, a method analogous to that described in Reference Example 7 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform) to obtain 1-[2-(N-isopropylbenzylamino)ethyl]isatin in an oil (yield: 43.4%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:21][C:14]3=[N:15][C:16]([OH:20])=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:21][C:14]3=[N:15][C:16]([OH:20])=[C:17]([N+:22]([O-:24])=[O:23])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(O)nc3s2)cc1
Temperature: 80 °C

Procedure:
10.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 100 ml of acetic acid, and 15 ml of fuming nitric acid was added dropwise to the suspension while maintaining the temperature at 80° C. After completion of the reaction, the mixture was cooled and the precipitate was separated by filtration to obtain 7.1 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point of 245° to 246° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)=[O:22].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([C:21]([NH:20][CH3:19])=[O:22])[CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CNC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
A solution of 261 mg (1.0 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 15.1) and 245 mg (1.5 mmol) of 3-(methylamino-carbonyl)-benzaldehyde in 26 ml of methanol, 26 ml of DMEU and 180 mg (3.0 mmol) of acetic acid is stirred for 1 hour at RT. Then 440 mg (7.0 mmol) of NaCNBH3 are added and the reaction mixture is stirred for 9 days at RT. The methanol is evaporated off from the reaction solution using a rotary evaporator, the residue is poured into 0.6 liter of water and stirring is carried out overnight. The product precipitates. Filtering with suction, washing with water, stirring twice in 10 ml of boiling ethanol, cooling and filtering yield 4-(3-chloro-phenylamino)-3-[3-(methylaminocarbonyl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 252-254° C.; HPLC: TRet (Grad5-40)=16.9; FAB-MS: (M+H)+ =408.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](=O)([O-:56])[O-:55].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.O>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:54]([OH:56])=[O:55])[N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[N:7]=[CH:6]2
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Temperature: 50 °C
Yield: 44.4 %

Procedure:
To a solution of 1-(6-bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (0.691 g, 1.74 mmol) in 9:1 methanol/water v/v (11.6 mL) was added palladium (II) acetate (0.0195 g, 0.0870 mmol), 1-((3-(diphenylphosphino)propyl)(phenyl)phosphino)benzene (0.0359 g, 0.0870 mmol), and potassium carbonate (0.721 g, 5.22 mmol). The flask was evacuated and backfilled three times with carbon monoxide, and heated to 50° C. under a carbon monoxide balloon for S hours. The reaction mixture was acidified with 5N HCl and extracted twice with dichloromethane. The organic layer was concentrated, taken up in 5M NaOH, was washed twice with ethyl acetate, and then acidified to pH 1 with HCl. The organic layer was then extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylic acid (0.280 g, 44.4% yield).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[N:5]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[F:22])[N:13]=[C:12]([CH3:23])[C:11]=2[C:24]#[N:25])[C:6]([CH3:9])=[CH:7][CH:8]=1>CO>[CH3:3][C:4]1[N:5]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[F:22])[N:13]=[C:12]([CH3:23])[C:11]=2[C:24](=[N:1][OH:2])[NH2:25])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: NO
Reactant: Cc1nn(-c2ccc(O)cc2F)c(-n2c(C)ccc2C)c1C#N
Solvent: CO
Product: Cc1nn(-c2ccc(O)cc2F)c(-n2c(C)ccc2C)c1C(N)=NO
Temperature: 150 °C
Yield: 28.1 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.8 mL, 13.5 mmol) was added to 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (28 mg, 0.09 mmol) dissolved in MeOH (1.6 mL). The reaction was heated at 150° C. in the microwave for 15 min. Purification using preparative HPLC gave 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (8.68 mg, 28%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 344.14 (M+H), 342.25 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.13 (t, 1H, J=8.5 Hz), 6.68 (m, 2H), 5.76 (s, 2H), 2.40 (s, 3H) and 1.95 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:25][C:26]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:28](=[O:35])[C:27]=1[Cl:36])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=1)=[O:16])[CH2:10][CH2:9]2.ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:36][C:27]1[C:28](=[O:35])[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:26]=1[NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=1)=[O:16])[CH2:10][CH2:9]2)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(Cc1ccc2c(c1)CCN2C(=O)c1cc(Cl)nc(Cl)c1)NC1=C(Cl)C(=O)C12CCCCC2
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1cc(Cl)nc(Cl)c1)NC1=C(Cl)C(=O)C12CCCCC2

Procedure:
The title compound was prepared from the compound of Example 11 in a similar manner to the compound of Example 2 as a white lyophilised powder (64%). δH NMR (d6 DMSO) 8.80 (1H, d, J 9.6 Hz), 7.98 (1H, d, J 8.2 Hz), 7.85 (2H, s), 7.14 (2H, m), 4.57 (1H, m), 3.96 (2H, t, J 8.2 Hz), 3.21 (1H, dd, J 13.6 and 3.7 Hz), 3.04 (2H, m), 2.92 (1H, dd, J 13.6 and 10.6 Hz), 1.44 (10H, br m), m/z (ES+, 70 eV) 550 (M+H)+.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:22][NH2:23]>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([NH:23][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: CN
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Agent: Cl
Product: CNC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
In analogy to example 81.2, (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (example 81.1) was reacted with methylamine hydrochloride to give (RS)-N-(4-cyano-benzyl)-2-methylamino-2-phenyl-acetamide. Off-white amorphous solid. MS 280.1 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[CH:13]([CH2:25][O:26][CH3:27])[C:14]([NH:16][C:17]([CH3:24])([CH3:23])[C:18]#[C:19][CH2:20][O:21][CH3:22])=[O:15]>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:13]([CH2:25][O:26][CH3:27])[C:14]([NH:16][C:17]([CH3:24])([CH3:23])[C:18]#[C:19][CH2:20][O:21][CH3:22])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1ccc2ncccc2c1
Product: COCC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncccc2c1

Procedure:
In a similar procedure to Example 6 Stage 2, 6-hydroxyquinoline was reacted with 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide to give 2-(6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide as a colourless oil. 1H NMR (CDCl3) δ: 1.60(3H, s); 1.62(3H, s); 3.34(3H, s); 3.44(3H, s); 3.90-3.94(2H, m); 4.06(2H, s); 4.76-4.80(1H, m); 6.60(1H, s); 7.14-7.16(1H, m); 7.36-7.40(1H, m); 7.46-7.50(1H, m); 8.04-8.08(2H, d); 8.82-8.84(1H, m).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Br:33][C:34]([CH3:39])([CH3:38])[C:35]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:25])[CH2:3][CH2:4]2)[CH:22]=1)=[O:36]
Reactant: CC(C)(Br)C(=O)Cl
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Temperature: 110 °C
Yield: 63.3 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine (0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30 mmol). The resulting mixture was heated at 110° C. for 2 hours under microwave irradiation. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (35 mL), washed with brine and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 180 mg of the title compound as a light solid (yield was 63%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(C#N)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C#N)cc2)CC1
Yield: 89.4 %

Procedure:
A mixture of 40 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butenyl]benzonitrile, 2 g of palladium/carbon (5%) and 250 ml of ethyl acetate was stirred while gassing with hydrogen. Subsequently, the inorganic material was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 9:1). Recrystallization from ethanol gave 36 g of pure 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzonitrile with m.p. 51° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]1=2>C1C=CC=CC=1.O=[Mn]=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]1=2
Reactant: OCc1ccc2sccc2c1
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: O=Cc1ccc2sccc2c1
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Benzo[b]thiophen-5-ylmethanol (311 mg, 1.89 mmol) was dissolved in anhydrous benzene (20 mL). MnO2 (1317 mg, 15.2 mmol) was added and the reaction was stirred for 12 h. The solution was filtered through celite and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under vacuum to give the product (284 mg, 92%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.46-8.45 (m, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.94 (d, J=5.6 Hz, 1H), 7.81 (dd, J=8.4, 1.2 Hz, 1H), 7.66 (d, J=5.6 Hz, 1H).