Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 6-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-nicotinic acid (49 mg, 0.15 mmol) and TBTU (53 mg, 0.17 mmol) in DMF (0.8 mL) was added DIPEA (129 μL, 0.76 mmol). Then isopropylamine (14 μL, 0.17 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (45 mg, 82%) as a light yellow solid after recrystallisation from methanol/water. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.C(O)(C)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[S:45]([NH2:48])(=[O:47])=[O:46]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([NH:48][S:45]([C:38]3[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=3[Cl:36])(=[O:47])=[O:46])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: Cc1c(C(=O)O)nc2c(Cl)cc(C(F)(F)F)cn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2nc3c(Cl)cc(C(F)(F)F)cn3c2C)c1
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
To the carboxylic acid prepared in Step B (200 mg, 0.72 mmol) was added a solution of 4-(dimethylamino)pyridine (262 mg, 2.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mmol) in a 1:1 solvent mixture of t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, 2-chloro-5-methoxybenzenesulfonamide (143 mg, 0.65 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 118 mg of the title compound, a compound of the present invention, as a white solid, m.p. 222-223° C. 1H NMR (dmso-d6) δ 10.0 (br s, 1H), 8.94 (s, 1H), 7.96 (s, 1H), 7.65 (d, 1H), 7.59 (d, 1H), 7.30 (dd, 1H), 3.87 (s, 3H) 2.71 (s, 3H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([C:13]#[N:14])=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[F:22])[N:10]=[C:9]3[NH:23][N:24]=[C:25]([CH3:26])[C:8]=23)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1>O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:10]=[C:9]2[NH:23][N:24]=[C:25]([CH3:26])[C:8]2=[C:7]([C:5]2[O:6][C:2]([N:37]3[CH2:36][CH2:35][CH:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)[CH2:39][CH2:38]3)=[CH:3][CH:4]=2)[C:12]=1[C:13]#[N:14]
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(-c3ccc(Br)o3)c12
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(-c3ccc(N4CCC(N5CCN(C)CC5)CC4)o3)c12
Yield: 52.1 %

Procedure:
A solution of 0.80 g (1.9 mmol) of 4-(5-bromofuran-2-yl)-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 3.56 g (19.4 mmol) of 1-methyl-4-(piperidin-4-yl)piperazine in 55 ml of anhydrous dioxane is refluxed for 7 days. The mixture is concentrated and the residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 5 to 10%) to yield 0.51 g (51%) of 6-(2-fluoro-4-hydroxyphenyl)-3-methyl-4-(5-(4-(4-methylpiperazine-1-yl)piperidin-1-yl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of an orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]2[N:4]([C:5]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)=[N:6][C:7]3[CH:8]=[CH:9][C:10]([C:15]#[N:16])=[CH:11][C:12]=32)[N:3]=1.[BH4-].[Na+]>O1CCCC1.CO.[Co](Cl)Cl>[NH2:16][CH2:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]=[C:5]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[N:4]3[N:3]=[C:2]([NH2:1])[N:14]=[C:13]3[C:12]=2[CH:11]=1
Reactant: N#Cc1ccc2nc(Cc3ccc4c(c3)OCO4)n3nc(N)nc3c2c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc2nc(Cc3ccc4c(c3)OCO4)n3nc(N)nc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
To a solution of 2-amino-5-benzo[1,3]dioxol-5-ylmethyl-[1,2,4]triazolo[1,5-c]quinazoline-9-carbonitrile (0.07 g, 0.20 mmol), prepared as described in Example 25, in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), were sequentially added cobalt(II) chloride (0.11 g, 0.81 mmol) and sodium borohydride (0.03 g, 0.81 mmol). The reaction was stirred at room temperature overnight, then the solvent was evaporated. The residue was dissolved in CHCl3/CH3OH 9/1 and washed with ammonium hydroxide solution (pH 12). The organic phase was dried over Na2SO4, filtered and evaporated to obtain a crude which was purified by preparative HPLC to give the title compound (0.01 g, 7% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]1.[I-].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH2:26]O[C@@H]3CCC[C@H](OCC4C=CC=C(C)C=4C(OC)=O)C3)[N:25]=2)=[CH:17][CH:16]=1>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][O:1][CH2:2][C:3]3([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]3)[N:25]=2)=[CH:19][CH:20]=1
Reactant: OCC1(CO)COCOC1
Reactant: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC1(COCc2coc(-c3ccc(F)cc3)n2)COCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g (6.7 mmol) of 5-hydroxymethyl-1,3-dioxan-5-ylmethanol and 0.5 g (16.5 mmol) of 2 were dissolved in 20 ml of dry DMF. 300 mg of 55% NaH in paraffin oil were added, and the mixture was then stirred at room temperature for 1 hour. Work-up was carried out analogously to the synthesis of compound 5b. This gave 28 as a white amorphous solid. TLC (n-heptane/ethyl acetate 1:2). Rf=0.4. C16H18FNO5 (323.33) MS(ESI) 324.2 (M+H+).
Reaction SMILES: C1(C)C=CC=CC=1.[BH4-].[Na+].[C:10]1([CH:16]([N:44]=[N+]=[N-])[CH2:17][CH2:18][C:19]2[NH:20][C:21]([CH3:43])=[C:22]([C:39]([O:41][CH3:42])=[O:40])[CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=3)[C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[C:10]1([CH:16]([NH2:44])[CH2:17][CH2:18][C:19]2[NH:20][C:21]([CH3:43])=[C:22]([C:39]([O:41][CH3:42])=[O:40])[CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=3)[C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C1=C(CCC(N=[N+]=[N-])c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(CCC(N)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
120 ml of water are added to a toluene suspension (120 ml) of sodium borohydride (30 g), hexadecyl-tributylphosphonium bromide (2.27 g) and 15 g of the less polar diastereoisomer of 2-(3-phenyl-3-azidopropyl)-3-carboethoxy-5-carbomethoxy-6 -methyl-4-(m-nitrophenyl)-1,4-dihydropyridine. The mixture is stirred for 24 hours at 70° C., then cooled to room temperature, poured into water (200 ml), extracted with ethylacetate (200 ml), washed with water up to pH 7, dried and evaporated under vacuum. The crude oil (15 g) is purified by chromatography (silice 450 g eluent ethylacetate) to give 7.69 g of the less polar diastereoisomer of 2-(3-phenyl-3-aminopropyl)-3-carboethoxy-5-carbomethoxy-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine as a glassy foam. It is dissolved in AcoEt (35 ml) and 1.87 g of maleic acid are added to give 8.2 g of the maleate salt C26H29O6N3 ·C4H4O4 (bright yellow crystal): p.f. 149-152° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:1][CH:2]1[CH2:5][N:4]([C:20]([C:19]2[CH:23]=[CH:24][N:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=[C:9]([CH:6]3[CH2:8][CH2:7]3)[N:14]=2)=[O:16])=[O:21])[CH2:3]1
Reactant: OC1CNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CC(O)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 8 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-hydroxy-azetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (8%) as light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17](=O)[N:18]([CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17]3[N:18]([CH:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:36]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: [NH4+]
Reactant: COc1cc(/C=C2\CCCN(CC(=O)c3ccncc3)C2=O)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCn3cc(-c4ccncc4)nc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-1-(2-oxo-2-pyridin-4-ylethyl)piperidin-2-one (150 mg) and ammonium acetate (555 mg) in acetic acid (2 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system→ethyl acetate-2-propanol) to obtain 121.5 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH:17]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (Example 2) (1.54 g, 6.25 mmol) in dimethylformamide dimethylacetal (15 mL) is heated at reflux for 17 h. The reaction mixture is evaporated, and the yellow residue is crystallized from hexanes to give 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-(N,N-dimethylamino)propen-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH:10]2[N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C2C1CCN2C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
The crude ester (42, 11.7 g crude, ˜11.0 mmol) was dissolved in 1:1 THF/MeOH (75 mL) and cooled to 0° C. and 1M NaOH (45 mL) was added in one portion. After 45 min, the reaction mixture was quenched with glacial HOAc (10 mL) and concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed successively with aqueous NaHCO3 (5×) and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was absorbed onto silica gel and purified by flash silica gel chromatography (2:1 to 1:2 hexanes/EtOAc) to provide 43 as a white foam (3.5 g, 88%, 2 steps): 1H NMR (300 MHz, CDCl3): δ7.39 (m, 5H), 5.15 (m, 2H), 4.40 (m, 2H), 4.13 (m, 1H), 3.54 (m, 3H), 3.35 (m, 1H), 2.83 (m, 1H), 2.11 (m, 2H), 1.49 (s, 9H) ppm. Mass spectrum, m/z [306.6] (M−t-Bu)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:28][C:26]1[O:27][C:23]2[CH:22]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:30]=[CH:29][C:24]=2[N:25]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ccc(N)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)oc3c2)cc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (163 mg, 0.744 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (105 mg, 0.709 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (164 mg, 70%), single spot at Rf 0.49 (60:40 hexane:ethyl acetate). mp 101.7-102.3° C., HPLC purity 99% (tR 2.02 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.61 (2H, m), 7.43 (1H, d, J=8.4 Hz), 7.37 (1H, d, J=1.8 Hz), 7.19 (2H, m), 6.83 (2H, m), 2.57 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.88 (3H, t, J=7.3 Hz). LCMS: 329.21 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1107.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[O:22])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)C>C(O)C.[Pd]>[CH2:14]([O:16][C:6]([O:20][CH2:12][CH3:11])([CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=1)[C:5](=[O:22])[CH3:4])[CH3:13]
Reactant: CCOC(OCC)C(=O)C=CCCc1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(CCCc1cc(OC)c(OC)c(OC)c1)(OCC)C(C)=O
Reaction time: 8 h
Yield: 178.2 %

Procedure:
To a solution of 2 g (5.7 mmol) of 6-(3,4,5-trimethoxyphenyl)-2-keto-3-hexenal-diethylacetal in 50 ml of ethanol was added 20 mg of 10% palladium on carbon and the mixture hydrogenated at 50 psi for 8 hours. The catalyst was filtered and the ethanol evaporated to yield 1.8 g of 6-(3,4,5-trimethoxyphenyl)-2-keto-3-hexanal-diethylacetal as an oil. 1H NMR (CDCl3) δ 6.38 (s, 2 H), 4.50 (s, 1 H), 3.80 (s, 6 H), 3.76 (s, 3 H), 3.60 (q, 2 H), 3.50 (q, 2 H), 2.50 (m, 4 H), 1.60 (m, 4 H), 1.20 (t, 6 H).
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:16]([O:40]C(OC)=O)=[CH:17][C:18]([O:35]C(OC)=O)=[C:19]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[C:20]=1[CH2:21][CH2:22][O:23][CH3:24])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:16]([OH:40])=[CH:17][C:18]([OH:35])=[C:19]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[C:20]=1[CH2:21][CH2:22][O:23][CH3:24])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(C(=O)OC)c2)c1CCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCc1c(O)cc(O)c(-c2cccc(C(=O)OC)c2)c1CCOC
Yield: 37 %

Procedure:
In the same manner as in Example 118, methyl 3-[5-acetyl-2,4-bis(methoxycarbonyloxy)-6-(2-methoxyethyl)phenyl]benzoate was obtained from Compound 119 (100 mg, 0.30 mmol) obtained in Example 119, using methyl chlorocarbonate (0.05 mL, 0.65 mmol), triethylamine (0.09 mL, 0.65 mmol) and tetrahydrofuran (3.0 mL); and from the resulting compound, obtained was methyl 3-[5-ethyl-2,4-bis(methoxycarbonyloxy)-6-(2-methoxyethyl)phenyl]benzoate, using sodium borohydride (45 mg, 1.2 mmol), water (2.0 mL) and tetrahydrofuran (2.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 131 (37 mg, 37%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)(=[O:9])[CH3:8]>>[CH3:15][C:13]1[N:14]=[C:10]([C:7]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)([OH:9])[CH3:8])[O:11][CH:12]=1
Reactant: Brc1nccs1
Reactant: CC(=O)c1nc(C)co1
Product: Cc1coc(C(C)(O)c2nccs2)n1

Procedure:
From 2-bromothiazole and 2-acetyl-4-methyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[C:33]([O:37][C:38]([C@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](=[O:18])[NH:47][C@@H:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)O)cc2S(=O)(=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)N[C@@H](C(=O)OC(C)(C)C)c3ccccc3)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxyethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 89; 70 mg, 0.134 mmol) and (R)-α-(t-butoxycarbonyl)benzylamine (J. Amer. Chem. Soc.; EN; 117; 44; 1995; 10879–10888; 35 mg, 0.169 mmol) in DCM (2.5 ml) was added 2,6-lutidine (29 mg, 0.268 mmol) and TBTU (56 mg, 0.174 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then diluted with DCM. The solution was washed with NaHCO3 (aq, sat), water, dried and the solvent was evaporated under reduced pressure. The residue was suspended in ether/petroleum ether and the crystals filtered to give the title compound 85 mg (89%). NMR (500 MHz) 0.79–0.86 (m, 6H), 1.04–1.28 (m, 4H), 1.35–1.56 (m, 11H), 1.60–1.77 (m, 2H), 2.82 (t, 2H), 3.13–3.25 (m, 2H), 3.72 (brs, 2H), 4.35–4.44 (m, 2H), 5.54 (d, 1H), 6.95 (d, 1H), 7.04 (t, 1H), 7.08 (d, 2H), 7.15 (s, 1H), 7.29–7.43 (m, 6H), 7.52 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CS(=O)c1ccc(C(=O)CBr)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Yield: 54.6 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (399 mg). and 2-bromo-4'-methylsulphinylacetophenone (784 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour, when the resulting suspension was chilled in ice. The collected solid was crystallised from ethanol to give the title pyrimidinone (509 mg,); m.p. 219°-220°; λmaxEtOH 233.5 nm (ε 17920), 332 nm (ε 2060), λinf 266 nm (ε 9280).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C)CC5)c34)cc2C)cn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 30% yield; NMR Spectrum: 2.10 (s, 3H), 2.19 (s, 3H), 2.30 (br s, 4H), 2.43 (s, 3H), 2.50 (hidden under DMSO, 4H), 2.79 (t, 2H), 4.43 (t, 2H), 6.96 (d, 1H), 7.17-7.24 (m, 2H), 7.61-7.64 (m, 2H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCN1CCc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(c1)CCN(CCC1CCCCN1)C2
Yield: 99.5 %

Procedure:
The protected amine 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]piperidine-1-carboxylic acid benzyl ester (D3, 14 g, 0.037 mol) was dissolved in ethanol (300 ml) and hydrogenated over 10% Pd/C for 18 hours to afford the title compound (9 g, 100%). MH+ 245.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH:13]([F:15])[F:14])[CH:12]=1)[NH2:9].Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>O1CCOCC1.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([NH:9][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:10]=[C:11]([CH:13]([F:14])[F:15])[CH:12]=1
Reactant: Nc1cc(Br)cc(C(F)F)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: FC(F)c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 105 °C
Yield: 34.3 %

Procedure:
Acetic acid (1.01 mL, 17.6 mmol) was added to a mixture of 3-bromo-5-(difluoromethyl)aniline (1.30 g, 5.86 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.14 g, 11.7 mmol) in dioxane (5.0 mL). The mixture was heated to 105° C. for 16 hrs then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with dilute aqueous NaHCO3, brine and dried. The residue was purified by chromatography on silica gel (0-15% ethyl acetate in hexanes) to yield N-[3-bromo-5-(difluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (741 mg, 2.01 mmol, 34%).