Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([OH:19])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2
Reactant: Clc1ccccc1-c1cccc2[nH]ccc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2Cl)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2-chloro-phenyl)-1H-indole (2.4 g, 10.6 mmol) in t-BuOH:ethanol:acetic acid (67 mL:40 mL:21 mL) was added pyridinium tribromide (10.5 g, 32 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (52 mL). Zinc dust (3.5 g, 53 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.96 g (76%) of 4-(2-chloro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=O)OC(C)(C)C.N1(OC2[N:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH:43]=[CH:42][CH:41]=[N:40]4)=[C:35]([F:44])[CH:34]=3)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:43]=[CH:42][CH:41]=[N:40]3)=[C:35]([F:44])[CH:34]=2)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-n2cccn2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.30 M in NMP, 2.00 mL, 0.600 mmol) in NMP (2 mL) was added to 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxamide (184 mg, 0.427 mmol). DIEA (0.150 mL, 0.863 mmol) was also added. The mixture was stirred at 90 C overnight. After being cooled to room temperature, water was added to induce precipitation. The precipitate was collected, then dissolved in CH2Cl2 (5 mL) and TFA (4 mL). The solution was stirred at room temperature for 30 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (103 mg). MS 411.5 (M+H). UV λ=238.8, 304.8 nm.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:29]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16]2)=[CH:32][CH:33]=1
Reactant: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Reactant: Cn1cnc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cnc([N+](=O)[O-])c1NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 45 %

Procedure:
A mixture of 1.62 parts of 5-chloro-1-methyl-4-nitro-1H-imidazole, 3.67 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine, 1.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was cooled and poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.2 parts (45%) of 3-[(4-fluorophenyl)methyl]-N-[1-[2-[(1-methyl-4-nitro-1H-imidazol-5-yl)amino]ethyl]-4-piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine; mp. 198.7° C. (compound 11 ).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:34][CH:33]=[CH:32][CH2:31]3)[N:26]=[C:25]([CH3:35])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:34][CH:33]=[CH:32][CH2:31]3)[N:26]=[C:25]([CH3:35])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC=CC2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC=CC2)n1
Yield: 58.6 %

Procedure:
A solution of ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (140 mg) in 4:1 AcOH:water (2 mL) was stirred at room temperature until deprotection was complete. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide (68 mg, 58%). LCMS: (M+H)+: 407.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[Cu](C#N)[C:11]#[N:12].O.Cl>CN1C(=O)CCC1.C(OCC)(=O)C>[C:11]([C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1)#[N:12]
Reactant: Cc1cc(Br)ccc1O
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 133.6 %

Procedure:
A mixed solution of 10.89 g (58 mmol) of 4-bromo-cresol and 10.39 g (116 mmol) of copper cyanide in 50 ml of NMP was stirred at 190° C. for 2 hours, followed by the addition of 43 g of FeCl3.6H2O, 65 ml of water and 11 ml of concentrated hydrochloric acid. The resulting mixture was stirred at 80° C. for 30 minutes and was then allowed to cool down. Water and ethyl acetate were added to the reaction mixture, followed by separation into a water layer and an organic layer. The organic layer was dried over Na2SO4, and the solvent was then distilled off under reduced pressure. The residue as purified by column chromatography (chloroform/methanol=40/1), whereby 10.32 g of 4-cyanocresol were obtained as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([OH:29])[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([OH:29])[CH:3]=1
Reactant: COc1ccc(CCc2ccc(NC(=O)c3ccc(Cl)cc3O)cc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccc(CCc2ccc(O)c(O)c2)cc1)c1ccc(Cl)cc1O
Temperature: -78 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A dichloromethane (40 ml) solution of 4-chloro-N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2-hydroxybenzamide (0.50 g, 1.21 mmol) is cooled to -78° C. under an argon atmosphere. Boron tribromide (1.0M solution in dichloromethane, 5.5 ml, 5.5 mmol) is added, and the mixture is stirred at -78° C. for four hours, followed by stirring at ambient temperature for two hours. The solution is then recooled to -20° C. and quenched with water (5.5 ml). The mixture is allowed to stir at ambient temperature for 12 hours, after which additional water (10 ml) is added. Filtration affords 4-chloro-N-[4-[2-(3,4-dihydroxyphenyl)ethyl]phenyl]-2-hydroxybenzamide (0.42 g, 91%), mp 229°-213° C. after recrystallization from methanol/water.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3]1.C(C(C(C)(C)C)C(O)=O)(C)(C)C.[CH3:29][N:30]([CH3:33])[CH:31]=O>CN(C)C=O>[CH3:29][N:30]([CH:33]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[CH2:6][CH2:7]1)[CH3:31]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nn(C)c2c1CCCC2=O
Agent: CC(C)(C)C(C(=O)O)C(C)(C)C
Product: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
16 g (72 mmol) of ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 100 mL of dimethylformamide and 32 mL of dimethylformamide ditertbutyl acetate were added. The mixture was stirred at 60° C. for 8 hours. The solvent was then evaporated in vacuo and the product crystallized from ethanol to give the title compound (17.96 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.[CH2:44]=[O:45].Cl>O1CCOCC1>[C:6]([CH:11]1[CH:10]([C:6]2[C:7]3[CH2:8][O:45][CH2:44][NH:1][C:2]=3[N:3]=[C:4]([C:23]3[C:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[CH:27][CH:26]=[CH:25][C:24]=3[O:39][CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH:5]=2)[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])([CH3:10])([CH3:7])[CH3:5]
Reactant: C=O
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3C(C)(C)C)c3c(n2)NCOC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of tert-butyl 3-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-1-piperidinecarboxylate (0.501 g, 0.850 mmol) in 1,4-dioxane was added 37% formaldehyde solution (5.000 mL) and 1N HCl (5.000 mL). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=3/2) to give 1,1-dimethylethyl (tert-butyl)-3-{7-[2-[(cyclopropylmethyl)oxy]-6-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-1-piperidinecarboxylate as a colorless foam (0.319 g, yield; 62%).
Reaction SMILES: [S:1]1[CH:6]=[CH:5][CH2:4][N:3]=[CH:2]1.[N+:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:9])=[O:8].CS>[Cl-].[Zn+2].[Cl-].CCOCC.C(O)(C)C>[N+:7]([C:10](=[C:2]1[NH:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:9])=[O:8]
Reactant: C1=CSC=NC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: CS
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 1.25 h

Procedure:
To a mixture of 235 g of 5,6-dihydro-2-methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1958)) and 2 g of zinc chloride at approximately 115° in a nitrogen atmosphere, 263 g of ethyl nitroacetate (S. Zen, et al., Kogyo Kagaku Zasshi, 74, 70 (1971)) was added dropwise over a 1.5 hour period. The mixture was held at 110°-120°. When evolution of methyl mercaptan ceased after 45 minutes further stirring of the heated mixture, 1 g of zinc chloride was added and the mixture was stirred at about 115° for 1.25 hours. An additional 1 g of zinc chloride then was added and stirring of the mixture at about 115° was continued for 1.5 hours. The mixture then was poured into a cooled solution of 2/1 (volume) ether/isopropyl alcohol mixture. The crystallized product was collected, washed with ether and dried under reduced pressure to leave a tan solid, m.p. 100°-102°, which on recrystallization from methanol gave ethyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (1A) as a pale yellow solid, m.p. 105°-106°.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(Br)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Br)cc2)c1=O
Yield: 47 %

Procedure:
A solution of 1-(4-bromobenzyl)-6-hydrazino-3-propyluracil (4.15 g, 11.8 mM) and methyl isothiocyanate (2.7 ml, 40 mM) in DMF (50 ml) was heated at 120° C. for 24 hours. To the reaction solution was added 50% methanol (15 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless needles (2.19 g, 47%), m.p. 308°-310° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH2:29][CH2:30][CH2:31]Cl)[CH:24]=2)[CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28][CH2:29][CH2:30][CH2:31][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH:22]=[CH:21]2
Reactant: ClCCCSc1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCSc2ccc3cc(Cl)ccc3c2)C(=O)C1
Yield: 92.4 %

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (2.0 g) was dissolved in DMF (30 mL), and sodium hydride (0.5 g) was added thereto. With ice cooling, 2-chloro-6-((3-chloropropyl)thio)naphthalene (2.7 g) was added thereto, and the mixture was mixed at 60° C. for 3 hours. The reaction solution was poured into water, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (4.0 g) as a pale brown oily matter.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:23]([CH3:24])=[CH:22][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=1[CH3:25].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.CCOC(C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:25])=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([OH:16])=[O:15])=[CH:22][C:23]=1[CH3:24]
Reactant: CCOC(=O)c1cccc(/C=C/c2cc(C)c(OCOC)c(C)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1c(C)cc(/C=C/c2cccc(C(=O)O)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of (E)-ethyl 3-[4-(methoxymethoxy)-3,5-dimethylstyryl]benzoate (0.6 g, 1.762 mmol) in THF and EtOH ( 6/2 mL) was added 2N NaOH (1.762 mL, 3.524 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) at room temperature and diluted with EtOAc and acidified with 5% citric acid. The solution was washed with saturated brine and dried with Na2SO4. The solution was filtered and concentrated. (E)-3-[4-(methoxymethoxy)-3,5-dimethylstyryl]benzoic acid (0.533 g, 97%) was obtained without further purification (TLC indicated a pure compound).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[CH3:23])[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[N:56]=[CH:57][NH:58][CH:59]=2)[CH:52]=[N:51]1>CS(C)=O.C(OCC)(=O)C.[Cu-]=O>[CH3:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:58]3[CH:59]=[C:55]([C:53]4[CH:52]=[N:51][N:50]([CH3:49])[CH:54]=4)[N:56]=[CH:57]3)=[C:3]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9]1)[C:19]#[N:20]
Reactant: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(Cl)ccnc21
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Agent: O=[Cu-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Compound (154e) (1.66 g), copper(I) oxide (0.070 g), 4,7-dimethoxy-1,10-phenanthroline (0.214 g), cesium carbonate (5.46 g), polyethylene glycol (Mn=3400) (0.250 g), and 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride (1.20 g) were suspended in DMSO (15 mL), followed by stirring at 120° C. for 2 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The filtrate was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away to obtain 3-methyl-4-{4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. TFA (5.0 mL) and sulfuric acid (0.5 mL) were added to this 3-methyl-4-{4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, followed by stirring at room temperature for 2 days. The reaction solution was cooled in an ice bath and was neutralized with sodium hydroxide. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. Ethanol was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain compound (154) (0.881 g, the second stage yield: 38%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][C:12]=2[CH3:22])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:30]1([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH2:31]1>C(O)C>[CH:30]1([CH2:33][N:34]([CH2:35][CH2:36][CH3:37])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH3:19])(=[O:21])=[O:20])=[CH:13][C:12]=3[CH3:22])=[O:9])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: CCCNCC1CC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(2-methyl-4-(N-methylsulfamoyl)phenyl)pyrimidine-4-carboxamide (Intermediate 37, 80 mg; 0.235 mmol) and diisopropylamine (82 mL; 0.47 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml; 0.29 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14].[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[CH:31])([CH3:18])([CH3:17])[CH3:16]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[C:31][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-1-fluoro-4-(propylsulfonyl)benzene (Intermediate 106; 541 mg; 1.93 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 467 mg; 1.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg; 0.07 mmol) and TEA (728 μL; 5.2 mmol) was heated at 60° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with a sat. NH4Cl aqueous solution and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a brown solid.
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:11]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.OS(O)(=O)=O>O1CCCC1.O1CCCC1.O>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][OH:8])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CO)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6.44 g of 2-benzyloxy-4-tert-butylbenzoic acid benzyl ester in 10 ml of tetrahydrofuran is slowly added dropwise to a suspension, stirred at room temperature, of 0.47 g of LiAlH4 in 40 ml of tetrahydrofuran. The reaction mixture is stirred for a further 4 hours at room temperature and then, in succession, 0.96 ml of ethyl acetate, 6.4 ml of tetrahydrofuran/water=1:1 and 9.6 ml of 2N H2SO4 are added dropwise thereto. The suspension is partitioned between ethyl acetate and water/saturated sodium chloride solution, the organic phases are concentrated by evaporation and the residue is purified by means of FC (150 g of silica gel, dichloromethane/hexane=6:4). Title compound: Rf (dichloromethane/hexane=8:2)=0.24.