Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([C:10]#[N:11])[CH:6]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]#[N:20])[CH:13]=2)[C:5]([C:21]#[N:22])=[C:4]1[CH3:23])[CH3:2].O.[NH2:25][NH2:26]>C(O)CCC>[CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([C:10]#[N:11])[CH:6]([C:12]2[CH:13]=[C:14]3[C:15](=[CH:16][CH:17]=2)[NH:26][N:25]=[C:19]3[NH2:20])[C:5]([C:21]#[N:22])=[C:4]1[CH3:23])[CH3:2]
Reactant: CCN1C(C)=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C1C
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CCN1C(C)=C(C#N)C(c2ccc3[nH]nc(N)c3c2)C(C#N)=C1C

Procedure:
A mixture of 1-ethyl-4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (1 eq), from Synthetic Example 8, and hydrazine hydrate (110 eq) in n-butyl alcohol (75 mL) was kept at 80° C. for 5 hr. The mixture was cooled and concentrated. To the residue, sodium bicarbonate solution (sat.) was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to afford 1-ethyl-4-(3-amino-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (Cpd. No. 294, Table 7). 1H-NMR (400 MHz, DMSO-D6): δ=11.43 (s, 1H), 7.51 (s, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 5.37 (s, 2H), 4.32 (s, 1H), 3.67 (q, 2H), 2.27 (s, 6H), 1.18 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[CH:55]=[C:54]2[CH3:61]>O.CCOC(C)=O.CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:55]=[C:54]2[CH3:61]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: COc1ccc2c(c1)c(C)cn2N
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(C)cn2NC(=O)c1cnc(-c2cccc(F)c2)nc1C
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
A microwave vial (20 mL) is charged with 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (657 mg, 2.83 mmol), HOTT (1.16 g, 3.11 mmol), DIPEA (1.35 mL, 7.73 mmol) and DMF (6 mL). The mixture is stirred at 23° C. under N2 for 15 min. 5-Methoxy-3-methyl-indol-1-ylamine (456 mg, 2.59 mmol) is added and the vial is capped. The resulting mixture is heated in a microwave (Biotage-Initiator) at 150° C. for 6 min. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 45% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methoxy-3-methyl-indol-1-yl)-amide (327 mg, 32%) as a solid. MS: 391 (M+H); 1H NMR (300 MHz, d6-DMSO): δ 11.75 (s, 1H), 9.19 (s, 1H), 8.32 (d, 1H), 8.18-8.16 (m, 1H), 7.66-7.62 (m, 1H), 7.45 (td, 1H), 7.30 (d, 1H), 7.22 (s, 1H), 7.05 (d, 1H), 6.85 (dd, 1H), 3.81 (s, 3H), 2.76 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][CH2:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)NC(=O)CC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2ccc(OC3CCNCC3)cc2N1
Temperature: 25 °C

Procedure:
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)piperidine-1-carboxylate (0.2 g, 0.58 mmol) was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (1.3 mL). The resulting mixture was stirred at ambient temperature until all the starting material had been consumed, at which time the volatiles were removed by evaporation to dryness under reduced pressure. The residue was neutralized by addition of excess saturated NaHCO3 aq. and the mixture evaporated to dryness under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH3:15]>CO>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH2:15])=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: N
Reactant: Fc1ccc(-c2cnc(Cl)nc2)cc1
Solvent: CO
Product: Nc1ncc(-c2ccc(F)cc2)cn1

Procedure:
2-Chloro-5-(4-fluorophenyl)pyrimidine (376 mg) in 7M of ammonia in methanol (10 mL) in a sealed tube was heated at 50° C. overnight. After concentration, the product was obtained (360 g) which was used in the next reaction step without further purification. LCMS: (M+H)=190.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:14]=2[N:15]=[CH:16][N:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:4][C:3]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=4[F:1])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(C(=O)c1cccc(NCc3cc(F)ccc3F)c1)cn2C1CCCC1
Yield: 57.7 %

Procedure:
2,5-difluorobenzaldehyde (88.1 mg, 0.62 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mmol) and AcOH (18.6 mg, 0.31 mmol) in MeOH (10 mL). After 5 min NaCNBH3 was added. After 3 h the reaction was quenched with 1N NaOH. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a white solid (80 mg, 58%). MS: 448.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[NH2:14].[N:16]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.Cl>[OH:2][C:3]1[C:4]2[C:5](=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=2)[NH:14][N:16]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(O)n[nH]c2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Aminoterephthalic acid dimethyl ester (5 g, 23.9 mmol) were dissolved in 40 ml of water and 6 ml of conc. hydrochloric acid. At 0° C., sodium nitrite (1.65 g, 23.9 mmol) in 5 ml of water were added dropwise at below 10° C. After 30 min at room temp., sodium sulfite (11.02 g, 87.42 mmol) in 40 ml of water were added. After stirring for 1 h, 10 ml of conc. hydrochloric acid were added, and the mixture was left to stand overnight. It was then heated at 80° C. for 24 h, cooled and adjusted to pH 5.5 with sodium hydroxide solution. The precipitate was filtered off with suction and dried.
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(O)c1CN
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
2-Hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 0.43 mmol) was dissolved in ethanol (10 mL) and warmed to 60° C. before it was treated with rancy nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resultant mixture was allowed to stir at 60° C. for 2 hours. The cooled reaction mixture was filtered through celite and rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 56%) as a white solid. LRMS (M+H+) m/z: calcd 168.09. found 168. HPLC purity (214 nm): 73%. 1H NMR (300 MHz, d6-DMSO): δ 6.04 (s, 1H), 3.77 (s, 3H), 3.42 (s, 2H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Product: COc1c(I)cc(NC(=O)NC(C)C)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and isopropyl isocyanate were reacted in the same manner as Example 15 Part A to give the title compound
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11]([Cu])#[N:12]>CN1C(=O)CCC1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:11]#[N:12]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
To NMP (40 ml) were added 3-bromo-4-fluorobenzaldehyde (10 g, 0.05 mol) and CuCN (5 g, 0.055 mol). The resulting mixture was heated at 170 for 24 h until the reaction finished (monitored by TLC), and cooled to 80, 10 g of celite was added and stirred for 1 h at this temperature. The reaction mixture then was cooled to room temperature, and partitioned between ethyl acetate (250 ml) and water (125 ml), the organic phase was washed with water and brine, dried, filtered, and concentrated to give the crude. Then the crude was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=4:1) to afford target compound (8 g, 100%) as a light yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=2[CH:21]=1)(=O)=O.[CH3:30][C:31]1([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:36][C:35]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[N:40][C:34]=2[NH:33][C:32]1=[O:50].ClC1N2N=C(N)N=C2C=C(Cl)C=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH2:19]([NH:18][C:16](=[O:17])[NH:15][C:13]1[S:14][C:10]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:8][C:7]([C:38]3[CH:39]=[N:40][C:34]4[NH:33][C:32](=[O:50])[C:31]([CH3:30])([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:36][C:35]=4[CH:37]=3)=[CH:21][C:11]=2[N:12]=1)[CH3:20]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Reactant: CCOC(=O)C1(C)Oc2cc(B3OC(C)(C)C(C)(C)O3)cnc2NC1=O
Agent: Nc1nc2cc(Cl)cc(Cl)n2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc4c(c3)OC(C)(C(=O)OCC)C(=O)N4)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
To the solution of 2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl trifluoromethanesulfonate (0.5 g, 1.12 mmol) and ethyl 2-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-carboxylate (0.4 g, 1.12 mmol) in 1,4-dioxane:MeOH (5:3 mL) was added potassium phosphate (0.36 g, 1.68 mmol) at rt and the mixture degassed for 15-20 min by purging N2 followed by the addition of dichloro(1,1-bis(diphenylphosphino)(ferrocene)palladium (II) (0.091 g, 0.11 mmol). The reaction was degassed for another 15-20 min then heated to 80° C. for 5 h. After completion of reaction (by TLC), the reaction was cooled to rt, diluted with EtOAc (500 mL), passed through celite, the filtrate concentrated under reduced pressure and the crude residue purified over 100-200 M silica-gel using eluent 2.3% MeOH: DCM to obtain the desired product as an off-white solid (0.25 g, 42%). 1H NMR (DMSO-d6): δ 1.06-1.13 (m, 6H), 1.77 (s, 3H), 3.21 (q, J=7.20, 2H), 4.14 (m, 2H), 6.87 (br s, 1H), 7.45 (m, 1H), 7.97-8.03 (m, 2H), 8.09 (s, 1H), 8.29 (s, 1H), 8.55 (s, 2H), 8.80 (d, J=4.0 Hz, 1H), 10.62 (br s, 1H) and 11.73 (br s, 1H). MS: 533.24 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.N1C=CC=CC=1.[CH3:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>ClCCl>[Cl:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:24]([C:22]3[S:23][C:19]([CH3:18])=[CH:20][CH:21]=3)=[O:25])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc3c(Cl)cccc3s2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-4-chlorobenzothiazol (92 mg, 0.50 mmol) is dissolved in dichloromethane (10 ml) and treated with pyridine (0.060 ml, 0.75 mmol) and 5-methyl-thiophene-2-carbonyl chloride (97 mg, 0.60 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then evaporated to dryness. The residue is redissolved in ethyl acetate and water, the phases are separated and the organic layer extracted with brine. After dryin with sodium silfate, the solvent is removed in vacuo Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:4 affords the product as white solid.(88 mg, 57%). MS: m/e=308 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:24]([O:26][CH3:27])=[O:25])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)CN(C(=O)OC)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (4.35 g, 20 mmol) in acetone (50 mL) was added a solution of triethylamine (5.5 mL, 4.05 g, 40 mmol) in acetone (10 mL) followed by methyl chloroformate (4.0 mL, 4.91 g, 52 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solvent was evaporated and the residue was stirred with a mixture of water (40 mL) and concentrated hydrochloric acid (0.4 mL) for 8 h at ambient temperature. The mixture was extracted with ethyl acetate (40 mL) and the solution in ethyl acetate was extracted with cold aqueous sodium hydroxide solution [prepared from ice (20 g) and aqueous sodium hydroxide solution (1N, 40 mL)]. Concentrated hydrochloric acid (3 mL) was added to the aqueous layer and the mixture was extracted with ethyl acetate (40 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine (3.84 g, 70%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[N:10]2[C:6]([S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:5][C:4]=1[CH3:15])=[O:2].[CH3:16][Mg]Br.C(O)(=O)C>O1CCCC1>[OH:2][CH:1]([C:3]1[N:10]2[C:6]([S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:5][C:4]=1[CH3:15])[CH3:16]
Reactant: C[Mg]Br
Reactant: Cc1nc2sc3ccccc3n2c1C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc2sc3ccccc3n2c1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Formyl-2-methylimidazo[2,1-b]benzothiazole, 4.3 g, was suspended in 40 ml of dry tetrahydrofuran. Under ice cooling, a tetrahydrofuran solution (0.02 mol) of methyl magnesium bromide was added to the suspension in a nitrogen flow followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was acidified with diluted acetic acid. The solvent was removed under reduced pressure followed by extraction with ethyl acetate. The residue obtained from the ethyl acetate phase was crystallized with ether to give 4.1 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]([NH2:21])=[N:3]1
Reactant: Cn1nc(N2C(=O)c3ccccc3C2=O)c(C#Cc2ccccc2)c1-c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nc(N)c(C#Cc2ccccc2)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of 2-[1-methyl-5-phenyl-4-(2-phenylethynyl)pyrazol-3-yl]isoindoline-1,3-dione (300 mg, 0.74 mmol), ethanol (5 mL) and hydrazine hydrate (56 μL, 1.11 mL) was stirred in a sealed tube at 90° C. for 1 h and cooled to room temperature. The reaction mixture was filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, isohexane/ethyl acetate 7:3 to 1:1) yielding the title compound as a solid (150 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:15]1([C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:22][CH2:23][CH2:24][CH2:25]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][N:3]([CH3:2])[CH2:25][CH2:24][CH2:23][NH:22][C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCCOc1ccccc1OC
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN(C)CCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 15.5 h

Procedure:
8.05 g (0.0370 mol) of N-methyl-2-(2-methoxyphenoxy) ethylamine hydrochloride, 15.5 g (0. 0407 mol) of N-triphenylmethyl-3-bromopropylamine, (0.0925 mol) of potassium carbonate and 75 ml of N,N-dimethylformamide are introduced, under argon, into a 500 ml, three-necked, round-bottomed flask. The mixture is stirred for 15.5 h at 90° C. The reaction mixture is treated with a mixture of water and ice and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]=1[C:7]([O:9]CC)=[O:8].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(F)cnn1C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1ncc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 62 h
Yield: 23.3 %

Procedure:
To a solution of ethyl 4-fluoro-1-(1-methylethyl)-1H-pyrazole-5-carboxylate (100 mg) in 1,4-dioxane (2 ml) was added 2M hydrochloric acid (2 ml) and the mixture heated at reflux under nitrogen for 58 h, allowed to stand at room temperature for 62 h, then heated at reflux under Nitrogen for 72 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. Toluene (15 ml) was added and the solvent removed in vacuo to give a white solid that was dried in a vacuum oven overnight to give the title compound (20 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:9].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[C:15]1([N:13]2[CH:14]=[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:9])[CH:11]=[N:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1ccccc1O
Product: CCOC(=O)COc1ccccc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 67 %

Procedure:
Prepared from (2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (264 mg, 1.0 mmol) and ethyl bromoacetate according to GP2 to give 235 mg (67%) of the title compound as white solid: 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.67 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.10 (ts, J=7.4, 0.8 Hz, 1 Hz), 7.29-7.36 (m, 1H), 7.41-7.53 (m, 4H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ 14.3, 61.7, 65.4, 112.2, 118.8, 119.3, 119.7, 120.0, 122.1, 125.8, 127.6, 129.7, 129.9, 130.1, 130.6, 131.8, 132.1, 136.3, 139.7, 142.8, 155.0, 168.9, 188.7.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH3:32])[N:26]=[C:25]([S:33][CH2:34][C:35]3[N:36]=[C:37]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[S:38][CH:39]=3)[C:24]=2[C:47]#[N:48])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH3:32])[N:26]=[C:25]([S:33][CH2:34][C:35]3[N:36]=[C:37]([C:40]4[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[S:38][CH:39]=3)[C:24]=2[C:47]#[N:48])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)N)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.18 g (3.091 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(methylamino)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 17A) were initially charged in 45 ml of dichloromethane. 4.76 ml (61.821 mmol) of trifluoroacetic acid were added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated on a rotary evaporator and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 2.04 g (92% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([CH2:13][C:14]([OH:16])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:11]([C:13](=[CH:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:14]([OH:16])=[O:15])#[N:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: N#CC(=Cc1c(Cl)cccc1Cl)C(=O)O
Yield: 4.9 %

Procedure:
A stirred mixture of 2,6-dichlorobenzaldehyde (609 mmol, 106.5 g), cyanoacetic acid (609 mmol, 51.8 g), ammonium acetate (122 mmol, 9.38 g), pyridine (1065 mmol, 86 ml, 84 g) and toluene (468 ml) was stirred at reflux using a Dean-Stark apparatus until one equivalent of water was collected (NB Oil bath temperature should not exceed 120° C. to avoid decarboxylation at this stage—lag Dean-Stark well). The reaction mixture was allowed to cool and the solid precipitate filtered and stirred with 10% aqueous HCl. The solid was again collected by filtering to afford pure 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (7.21 g). The filtrate was concentrated in vacuo to give the crude 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (˜135 g). Recrystallisation from toluene afforded pure 2-cyano-3-(2,6-dichlorophenyl)acrylic acid (101 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[Br:27][C:28]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:29]=1[O:30][N:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH:34](O)[CH2:33][C:32]1([CH3:41])[CH3:40]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O:16][CH:34]3[CH2:35][C:36]([CH3:38])([CH3:37])[N:31]([O:30][C:29]4[CH:42]=[CH:43][C:44]([Br:46])=[CH:45][C:28]=4[Br:27])[C:32]([CH3:41])([CH3:40])[CH2:33]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Br)cc1Br
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Product: CC(C)(C)c1cc(CCC(=O)OC2CC(C)(C)N(Oc3ccc(Br)cc3Br)C(C)(C)C2)cc(-n2nc3ccc(Cl)cc3n2)c1O

Procedure:
The title compound is prepared according to the procedure of Example 3 using 3-(5-chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid and 1-(2,4-dibromophenoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine.