Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (57.0 mg, 0.121 mmol) in CH2Cl2 (3 mL) at −78° C. was added a solution of boron tribromide (1 M in CH2Cl2, 0.40 mL, 0.40 mmol) dropwise. The reaction mixture was warmed to room temperature gradually over several hours and allowed to stir overnight. Water (10 mL) was added slowly to the mixture. It was then extracted with EtOAc (3×20 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hex, 3:7) provided 40 mg (72%) of 5-chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide as a white solid (mp=90-92° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28]COC)/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.Cl.[OH-].[Na+].O>O1CCCC1>[OH:28][C:27]1[CH:26]=[CH:25][C:5](/[CH:6]=[CH:7]/[C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(O)c(OC)c3)nc2n(CCC)c1=O
Yield: 32.5 %

Procedure:
Compound 194 (1.00 g, 2.33 mmol) obtained in Reference Example 133 was dissolved in 10 ml of tetrahydrofuran. To the solution was added 6 ml of 2N hydrochloric acid, and the mixture was heated under reflux for one hour. The reaction solution was neutralized with a 2N aqueous solution of sodium hydroxide under ice cooling. Water was added thereto, and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from methanol/water to give 291 mg (yield 32%) of Compound 196 as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:6])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)C(CCOCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCOCCCC1CCCCC1)C(=O)OCC

Procedure:
82.3 g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: chloroform), are obtained by the procedure described in Example (1b) from 103.6 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid ethyl ester, 11 g of paraformaldehyde, 105 ml of pyridine and 2.9 g of piperidine.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.O[C:10]1[C:11](C)=[C:12]([CH:16]=[CH:17]C=1)[C:13]([OH:15])=[O:14]>O.[OH-].[Na+]>[C:5]([O:4][C:1]1[C:16]([CH3:17])=[C:12]([CH:11]=[CH:10][CH:2]=1)[C:13]([OH:15])=[O:14])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flat-flanged vessel, 80.0 g of 3-hydroxy-2-methylbenzoic acid (purity 97.78%) are dissolved in 320.0 g of water and 120.0 g of sodium hydroxide solution (w=30%), which results in a pH of 6.9. The clear solution is cooled to 0° C. and adjusted to pH=9 by metering in sodium hydroxide solution (w=30%). Acetic anhydride and sodium hydroxide solution are now simultaneously metered in at 0-5° C. in such a way that the pH remains within the range of 8.8-9.2. 112.6 g of acetic anhydride and 172.25 g of sodium hydroxide solution (w=30%) are metered in within 2.5 h. Afterwards, the mixture is stirred for a further 1.5 h. A second flat-flanged vessel is charged with 150.0 g of water and cooled to 0° C. The reaction mixture of the first vessel and hydrochloric acid (w=37%) are simultaneously metered in at a maximum of 5° C. in such a way that a pH of 3.8-4.2 is maintained. The product precipitates out as a white precipitate. The pH is adjusted to 1 by metering in hydrochloric acid (w=37%). The product is filtered off with suction and washed with 500.0 g of water. The precipitate is dried in a vacuum drying cabinet at 60° C. for 16 h. 172.6 g of 3-acetoxy-2-methylbenzoic acid (purity 99.9%) are obtained. This corresponds to 99.28% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:17])=[O:10])[CH:4]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(C=CC(=O)O)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1cnn(C)c1

Procedure:
3-(1-Methylpyrazol-4-yl)acrylic acid (18.86 g) was added to a solution of sulphuric acid (15 ml) in methanol (150 ml), and the mixture refluxed for 2 hours, cooled, and poured onto ice. The acid was neutralised with solid sodium carbonate and the product extracted into dichloromethane, which was dried and evaporated. Crystallisation from ether/petrol gave methyl 3-(1-methylpyrazol-4-yl)acrylate (16.0 g). 1H-NMR (d6-DMSO) δ 3.77 (3H, s), 3.91 (3H, s), 6.16 (1H, d), 7.54 (1H, s), 7.56 (1H, d), 7.69 (1H, s). (APCI) M+H=167. C8H10N2O2 requires 166.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methyl 4-t-butylphenylacetate (20 mmol) was dissolved in MeOH (160 mL) and treated with water (40 mL) and LiOH monohydrate (30 mmol). The reaction was allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the remaining residue was diluted with water and neutralized to pH 4 with 1 N sulfuric acid. The resulting solids were filtered, washed with water and dried to leave 4-t-butylphenylacetic acid as an off-white solid (3.8 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1-c1c(Cl)cnn1C
Yield: 14.4 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (36 mg, 0.15 mmol) was treated with 3-Nitrophenyl isocyanate (28 mg, 0.17 mmol) in a similar manner to Example 1.53, providing 8.7 mg (15%) of Compound 110: LCMS m/z (%)=402 (M+H35Cl, 100), 404 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.61 (d, J=4 Hz, 1H), 7.58 (s, 1H), 7.58 (t, 1H), 7.41 (d, J=4 Hz, 1H), 7.19 (d, J=12 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1)[CH3:25]
Reactant: CCNCC
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and diethylamine are converted to the named compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 9.0 g. of 1-(p-fluorophenyl)-5-(p-nitrophenyl)-1H-1,2,4-triazole, 18.0 g. of sodium hydrosulfite, 40 ml. of water and 150 ml. of acetone is stirred at room temperature for 1/2 hour. The acetone is removed in vacuo and the residue extracted with hot chloroform. Cooling produces 1.1 g. of the desired product as off-white crystals, mp. 128°-130° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[Cl:16][C:17]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20]>C1COCC1>[Cl:16][C:17]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:15][C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccnc1
Reactant: COC(=O)c1cccc(Cl)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccnc1)c1cccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To lithium diisopropyl amide (20 mL, 1.5 M in cyclohexane, 30 mmol) in THF (50.0 mL) at −78° C. was added a solution of 3-picoline (2.79 g, 30 mmol) in THF (25.0 mL) drop wise and stirred at −78° C. for 0.5 hours. The dry ice bath was removed and the reaction mixture was stirred at room temperature 1 hour. The mixture was then cooled to 0° C. and a solution of methyl 2,3-dichlorobenzoate (6.15 g, 30 mmol) in THF (25.0 mL) was added drop wise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride and extracted with ethyl acetate (2×). Combined ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel (70% ethyl acetate/hexane) gave 1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethanone (1.07 g, 13%) as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>C1COCC1.C(OCC)C>[CH2:13]([NH:16][C:17]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Br:1])=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A quantity of 10.0 g (40.1 mmol) of 2-bromo-4-chlorobenzhydrazide was suspended in 100 ml of THF at 50° C. and admixed with 3.59 ml (40.9 mmol) of allyl isocyanate in solution in 50 ml of THF. Stirring was continued for 16 h at 50° C. The batch was then allowed to cool to RT and diluted with 50 ml of diethyl ether. The precipitated solid was filtered off with suction, washed with a little diethyl ether and dried in an HV. This gave 11.30 g (85% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:14]([OH:16])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:5]([C:14]([NH2:31])=[O:16])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Product: COc1ccc(-c2c(C(N)=O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
4-Cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.035 g, 0.10 mmol), HOBT (0.028 g, 0.18 mmol) and EDCI (38 mg, 0.20 mmol) were suspended in DCM (5 mL). After 50 min the reagents dissolved. To the resulting solution was added concentrated aqueous ammonia (0.2 mL, 5 mmol) and the solution was allowed to stir vigorously at rt for 2 h. The reaction mixture was concentrated and the residue was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4 filtered and concentrated to give 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxamide (66) (0.028 g, 80%). LCMS: (AA) ES+ 344. 1H NMR (400 MHz, d6-DMSO) δ: 7.32-7.35 (m, 2H), 7.06-7.09 (m, 2H), 3.82 (s, 3H), 3.76-3.78 (m, 4H) and 3.52-3.54 (m, 4H).
Reaction SMILES: O.[OH-].[Li+].C(OC([N:11]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=O)C(C)C.CO>O>[C:29]([CH:28]=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]2[C:15]([S:12]([NH:11][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=1)([OH:31])=[O:30]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
Lithium hydroxide monohydrate (87 mg) was added to a solution of N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) in tetrahydrefuran (6.2 ml) followed by methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours then evaporated to dryness. The residue was dissolved in water (50 ml), washed with ethyl acetate (50 ml), acidified with 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layer was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase separated, acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[4-(2-carboxyvinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (108 mg) as a solid, m.p. 233-235° C.: 1H NMR (d6 -DMSO): 2.2 (s, 3H), 3.8 (s, 3H), 6.55 (d, 1H), 7.35 (br s, 1H), 7.45 (d, 2H), 7.55-7.75 (m, 4H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.1 (br s, 1H); mass spectrum (+ve ESP) 427 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13](O)=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1O
Product: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinol (10.49 g, 39.40 mmol) and phosphorous oxychloride (18 ml) was heated at 110° C. for 4 h and allowed to stir at room temperature overnight. The reaction was quenched by diluting with EtOAc and carefully adding water. The organic layer was washed three times with a saturated solution of NaHCO3 in water, dried and concentrated in vacuo to afford the product as an amber oil. 1H NMR (CDCl3) δ 8.46 (1H, s), 7.95 (1H, s), 7.19-7.14 (1H, m), 7.00-6.96 (1H, m), 6.91-6.88 (1H, m), 4.03 (2H, s).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:7][C:6]=12.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:6]3[N:7]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(-c2ccn3ncc(I)c3n2)cc1
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-iodo-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.33 step 1) (195 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (101 mg, 53%). MS (ISP) 380.0 [(M+H)+]; mp 213-214° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=1)[CH3:3].Cl.[C:18](=O)([O-])[O-:19].[K+].[K+]>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15](=[NH:16])[O:19][CH3:18])[CH:6]=1)[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CN(C)Cc1ccnc(CSCCC#N)c1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)CCSCc1cc(CN(C)C)ccn1
Temperature: -5 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
3-(4-Dimethylaminomethyl-2-pyridylmethylthio)propionitrile (13.60 g) was dissolved in a mixture of dry methanol (70 ml) and dry chloroform (140 ml) and the stirred solution cooled to -5° C. under nitrogen. Dry hydrogen chloride gas was passed through the solution for 3.75 hours, keeping the temperature below 0° C. The solution was allowed to stand in a stoppered flask at ca. 4° C. for 24 hours and was added to a solution of potassium carbonate (45 g) in ice-water (500 ml). The chloroform layer was separated off and the aqueous layer extracted with chloroform (3×150 ml). The combined extracts were dried (K2CO3 and chloroform evaporated at reduced pressure to give methyl 3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate (14.02 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([Cl:12])[C:3]=1[Cl:13].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:12][C:4]1[C:3]([Cl:13])=[C:2]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1Cl
Reactant: OB(O)c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccncc2)c(Cl)c1Cl

Procedure:
The title compound was prepared from N-[4-bromo-2,3-dichlorophenyl]acetamide and pyridin-4-ylboronic acid using a similar procedure to Description 3.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:26])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:35](=[O:36])[C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:38])([F:27])[F:39])=[CH:34][N:33]=4)[CH:17]=3)[O:12][CH:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(N)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)C(F)(F)COC1
Yield: 7 %

Procedure:
The condensation of (2RS,4R)-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.3) and 5-trifluoromethyl-pyridine-2-carboxylic acid yielded the title compound (7% yield) as a light brown solid. MS (ISP): m/z=532.8 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
TFA (7.87 mL, 103 mmol) was added to a solution of tert-butyl 1-(pyrimidine-2-yl)piperidin-4-ylcarbamate (2.86 g, 10.3 mmol) in DCM (60 mL) at at 0° C. The reaction mixture was stirred for 2 h at room temperature and removed the solvent under reduced pressure. The residue was re-dissolved in DCM, and neutralized with aq. Na2HCO3. The solvents were removed by evaporation, the resulting residue was purified by column chromatography (DCM:MeOH:NH4OH=10:1:0.1) to give 1-(pyrimidin-2-yl)piperidin-4-amine (1.68 g, 92%) as a white solid. 1H-NMR (CD3OD, Varian 400 MHz) δ 1.26-1.37 (2H, m), 1.75-1.99 (2H, m), 2.76-2.98 (2H, m), 2.86-3.05 (1H, m), 4.64-4.72 (2H, m), 6.53 (1H, t, J=4.8 Hz), 8.27 (2H, d, J=4.8 Hz). m/z=179.04 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:14]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:12]([N:14]1[C:18]([O:19][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:17][C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:15]1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
1,4-difluoro-2-nitrobenzene (2.06 g, 9.85 mmol, 3 equiv) was added to a stirring mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (0.70 g, 3.28 mmol, 1 equiv) and potassium carbonate (1.36 g, 9.85 mmol, 3 equiv) in DMSO (6.57 mL). The reaction mixture was stirred at 80° C. for 20 minutes then cooled to 22° C. and diluted with water. The mixture was extracted with ethyl acetate, and then the organic layer was washed sequentially with water (two times) and saturated aqueous sodium chloride. The washed solution was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo to give the 3-[1-ethyl-5-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-3-yl]benzonitrile. The crude reaction product was taken into the next step without further purification. Calcd (M+1)+: 353.1. Found: 353.2.
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH:18]4[CH2:20][CH2:19]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:34][C:35]1([NH:39][CH3:40])[CH2:38][NH:37][CH2:36]1>>[CH:18]1([N:8]2[C:7]3[N:6]=[C:5]4[CH:21]=[C:22]([N:37]5[CH2:38][C:35]([CH3:34])([NH:39][CH3:40])[CH2:36]5)[C:2]([F:1])=[CH:3][C:4]4=[CH:13][C:12]=3[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)[CH2:19][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CNC1(C)CNC1
Agent: CS(=O)(=O)O
Product: CNC1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 79.3 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.58 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. 1.57 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 330° C.