Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:7]1.[I-:26].[Na+]>>[Cl:24][C:19]1[CH:18]=[C:17](/[CH:16]=[CH:15]/[C:14]([N:9]2[CH2:10][CH2:11][C:12](=[O:13])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][I:26])[CH2:7][CH2:8]2)=[O:25])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Temperature: 90 °C
Reaction time: 26 h

Procedure:
In analogy to the procedure described in example 6D, 4-(4-chloro-butyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at 90° C. for 26 h to give the title compound as orange foam. MS: 495.0 (MH+, 2Cl).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1Br.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>C1COCC1>[Br:6][C:7]1[CH:11]=[CH:10][CH2:9][C:8]=1[Sn:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: BrC1=C(Br)CCC1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)C1=C(Br)C=CC1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium, 1.6M in hexanes, (58 mL, 92.0 mmol) in THF (50 mL) was cooled under nitrogen to −75° C. 1,2-Dibromocyclopentene (10.00 g, 44.3 mmol) in dry THF (10 mL) was added dropwise over ˜10 minutes. The mixture was stirred at −75° C. for a further 20 minutes and then allowed to reach 0° C. The reaction mixture was then re-cooled to −75° C. and trimethyltin chloride (8.85 g, 44.3 mmol) in THF (30 mL) was added, under nitrogen, over ˜10 minutes. After stirring at −75° C. for 30 minutes the reaction was allowed to reach room temperature and then stirred for 2 hours. The reaction mixture was then evaporated down to an oil and partitioned between brine and dichloromethane (100/200 mL). After shaking thoroughly, the organic layer was dried (magnesium sulphate), filtered and evaporated to give an oil. (13.15 g, ˜80% pure).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH2:40][O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH2:39][CH2:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: BrCCCOC1CCCCO1
Product: CC(C)c1ccc(N(Cc2cnn(CCCOC3CCCCO3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.02 g) and 1-bromo-3-(2-oxanyloxy)propane (0.45 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(2-oxanyloxy)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.65 g) was obtained. This compound was dissolved in methanol (30 mL), and 4 mol/L-HCl/dioxane (0.1 mL) was added. The mixture was stirred at room temperature for 2 hr. Into the reaction mixture was poured saturated aqueous sodium hydrogencarbonate (2 mL). The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. By the reaction and treatment of the obtained residue (0.94 g) in the same manner as in Example 105, 5-hydroxy-N-{[1-(3-hydroxypropyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N=1)=O.[Si]([O:45][CH2:46][CH2:47][N:48]([CH2:81][CH:82]1[CH2:84][CH2:83]1)[C:49]([C:51]1[C:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:55]([OH:65])[N:54]=[C:53]([CH2:66][C:67]2([N:72]3[C:76]4=[N:77][CH:78]=[CH:79][CH:80]=[C:75]4[CH:74]=[CH:73]3)[CH2:71][CH2:70][CH2:69][CH2:68]2)[N:52]=1)=[O:50])(C(C)(C)C)(C)C>>[CH:82]1([CH2:81][N:48]([CH2:47][CH2:46][OH:45])[C:49]([C:51]2[C:56]([O:57][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[C:55]([OH:65])[N:54]=[C:53]([CH2:66][C:67]3([N:72]4[C:76]5=[N:77][CH:78]=[CH:79][CH:80]=[C:75]5[CH:74]=[CH:73]4)[CH2:68][CH2:69][CH2:70][CH2:71]3)[N:52]=2)=[O:50])[CH2:84][CH2:83]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (414) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (406) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (413) (170 mg, 0.26 mmol) and the product was obtained as white sticky solid (140 mg, crude).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].[CH3:19][NH2:20].[BH4-].[Na+].CC(C)=O>CO.O>[CH3:19][NH:20][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CC(O)c1ccc(Cc2ccc(C=O)cc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CNCc1ccc(Cc2ccc(C(C)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.8 g of the 4-[4-(1-hydroxyethyl)benzyl]benzaldehyde prepared in the step (c) and 3.7 ml of methylamine (40% methanolic solution) were stirred together in 20 ml of methanol at room temperature. After one hour, the resulting mixture was cooled with ice, followed by the addition of 0.93 g of sodium borohydride. The obtained mixture was stirred at room temperature for 30 minutes. 5 ml of acetone was dropwise added to the resulting mixture under cooling with ice to treat excess sodium borohydride therewith. The reaction mixture was poured into water and the resulting mixture was extracted with dichloromethane. The organic phase was washed with water and a saturated aqueous solution of common salt, dried and distilled to dryness. The residue was recrystallized from ether/isopropyl ether to give 10.2 g of the title compound as a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=O)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[CH:35][CH:36]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CN2CCN(CCOc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a solution of lithium aluminum hydride (0.29 g, 7 mmol) in a solution of anhydrous THF (16 mL) was added 1-((4-chlorophenoxy)methyl)carbonyl-4-(4-fluorobenzyl)piperazine (0.36 g, 1.0 mmol, in 3 mL of THF). The resultant mixture was stirred at ambient temperature for 9 hours. At that time 0.3 mL of water and 0.3 mL of 15% aqueous NaOH solution were added and the resulting mixture stirred at ambient temperature. After 18 hours, the mixture was filtered through a short column of Celite (THF) and the filtrate concentrated in vacuo to afford 0.12 g of 1-(2-(4-chlorophenoxy)ethyl)-4-(4-fluorobenzyl)piperazine as a clear oil; NMR (CDCl3) 7.2 (m, 4), 7.0 (m, 2), 6.8 (m, 2), 4.0 (m, 2), 3.4 (m, 2), 2.8-2.4 (m, 10) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:3]=1[CH2:4][O:5]C(=O)C.[OH-].[K+]>O>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:3]=1[CH2:4][OH:5]
Reactant: CC(=O)OCc1c(Br)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1CO
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of acetic acid 2-bromo-6-nitro-benzyl ester (536 mg, 1.96 mmol) in water (20 ml) was added KOH solution (10%, 1.5 ml). The reaction was heated under reflux overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The combined extracts were treated with MgSO4, and concentrated under vacuum to give (2-bromo-6-nitro-phenyl)-methanol (389 mg, 86%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 4.93 (d, J=7.43 Hz), 7.354 (t, J=8.10 Hz), 7.84 (dd, J=1.23 Hz, 8.17 Hz), 7.89(dd, J=1.22 Hz, 8.03 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>CC(C)=O>[CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[O:14][CH2:21][CH:23]1[O:25][CH2:24]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1c(O)cccc1[N+](=O)[O-]
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(OCC2CO2)cccc1[N+](=O)[O-]

Procedure:
10.0 g of 2-allyloxy-3-nitrophenol, 27 g of potassium carbonate and 54 ml of epichlorohydrin in 300 ml of acetone are stirred under reflux for 15-20 hours. After filtering the reaction mixture and evaporating the filtrate, crude 2-allyloxy-1-(2,3-epoxy-propoxy)-3-nitrobenzene is obtained and this can be used further as such.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:12]([O:11][CH3:10])=[O:13])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-methoxycarbonyl-5-trifluoromethylaniline gave 2-chloro-5-fluoro-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.60 (s, 1H), 8.43 (s, 1H), 8.20 (d, 1H, J=3 Hz), 7.99 (s, 1H), 3.96 (s, 3H); 19F NMR (CD3OD): −18332, −18374; and −44259; LCMS: purity: 91%; MS (m/e): 350 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+]>>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Yield: 97.4 %

Procedure:
Reaction of 2-chloronitrobenzene (10 g, 63 mmole), benzylamine (40 g, 380 mmole) and ammonium acetate (4.6 g) substantially as described in 1C above produced 14 g (98%) of title compound as orange crystals: mp 65°-67°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCCn2ccnc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1cccc(OCCCn2ccnc2)c1

Procedure:
1.35 g of 5-(3-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 16 h in 30 ml of methanol in the presence of 0.3 g of 5% palladium/carbon. After filtration through Celite, the solvent is stripped off and the residue is slurried in ether, filtered, slurried again in EA, filtered and dried. 5-(3-Hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 120°-122° C. is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH2:54]O>C1COCC1.C(OCC)(=O)C>[CH2:58]([O:57][C:53](=[O:56])[CH2:54][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]2[CH:32]=[CH:33][C:20]([CH2:19][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=3[CH3:18])=[CH:21][CH:22]=2)[CH:26]=1)[CH3:59]
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 61F (1.29 g, 2.93 mmoles), triphenylphophine (1.54 g, 5.86 mmoles), and di-t-butylazodicarboxylate (1.01 g, 4.40 mmoles) in anhydrous THF (6 mL) were treated with ethyl glycolate (0.35 mL, 3.66 mmoles). The reaction was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (hexanes to 10% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][N:16]=[C:15]([O:20]C)[C:14]=4[C:13]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1COCC1.Cl.[OH-].[Na+]>O>[O:20]=[C:15]1[C:14]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[N:12][N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:19]=2[CH:18]=[CH:17][NH:16]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 4-(1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (280 mg) in a mixed solvent of THF (15 mL) and water (1.5 mL) was added 1N hydrochloric acid (0.420 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (219 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][C:18]5[N:23]=[C:22]([CH3:24])[S:21][C:19]=5[C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:24][C:22]1[S:21][C:19]2[C:20]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17][C:18]=2[N:23]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(C)sc2-4)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(s1)-c1c(cnc3[nH]ncc13)CC2
Yield: 19 %

Procedure:
A solution of 8-(4-methoxybenzyl)-2-methyl-5,8-dihydro-4H-pyrazolo[3,4-c]thiazolo[5,4-f]isoquinoline (0.6 g, 1.65 mmol) in trifluoroacetic acid (4 mL) was heated at 100° C. for 2 hours. The reaction mixture was poured into water (50 mL) and basified with aqueous potassium carbonate to pH of 11. The reaction mixture was then extracted with dichloromethane (3×75 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give a residue, which was further purified by crystallization from methanol and isopropanol to give the desired product (0.076 g, 13%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.49 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 3.16 (t, J=7.6 Hz, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.70 (s, 3H); LCMS [M+H]: 243.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)Cl.CCN(S(F)(F)[F:24])CC>CO>[Cl:1][C:2]1[C:7]([C:8]2([F:24])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(c2cccnc2Cl)CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: FC1(c2cccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)tetrahydro-2H-pyran-4-ol (0.11 g, 0.515 mmol) in DCM (1 mL, 15.54 mmol) was added dropwise DAST (0.102 mL, 0.772 mmol) at room temperature, followed by one drop of MeOH. The resulting mixture was stirred at room temperature for 3 hr. Reaction was quenched with water and extracted with DCM. The recovered residue was advanced to the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O(C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1)C1C=CC=CC=1.[CH3:43][O:44][CH2:45][CH2:46][OH:47]>>[CH3:43][O:44][CH2:45][CH2:46][O:47][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COCCO
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Agent: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Product: COCCOc1ncnc2ccc(-c3ccc(F)cc3)nc12
Yield: 78 %

Procedure:
was synthesized from 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and 2-methoxyethanol in 78% yield, using the procedure described for the synthesis of 4-phenoxy-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine The mass spectrum characterising data is as follows: MS (m/z): 300 ([M+H]+, 100).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3nccc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=487.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[C:12]#[N:13]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:12][NH2:13]
Reactant: COc1cc(C#N)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CN)ccc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A flame dried 50 mL round bottom flask was charged with lithium aluminum hydride (0.63 g, 16.6 mmol) and to this was added tetrahydrofuran (25 mL). The solution was cooled to 0° C. and 3-methoxy-4-fluorobenzonitrile (1.0 g, 6.62 mmol) was added in one portion. The ice bath was removed after an hour and the resulting mixture was stirred for 16 h after which it was cooled to 0° C. and quenched by adding 0.63 mL water, 0.63 mL 15% NaOH and 1.89 mL water drop-wise and in succession. The mixture was stirred for 20 min and filtered. The filtrate was concentrated in vacuo to obtain 890 mg (86%) of the title compound as an oil. NMR indicated no further purification was required. NMR (300 MHz, DMSO-d6): δ 7.1 (m, 2H), 6.85 (m, 1H), 3.84 (s, 3H), 3.7 (s, 2H). 13C NMR (75 MHz, DMSO-d6): δ 150.0 (d, J=240 Hz), 146.6 (d, J=10.5 Hz), 141.1 (d, J=3.75 Hz), 118.75 (d, J=6.75 Hz), 115.1 (d, J=18 Hz), 112.5, 55.75, 45.2. HRMS: Calc'd for C8H10FNO (M+H): 156.0819; Found: 156.0818.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH:6]=1)[CH:33]=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C=O)c2)c(Cl)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of the title compound of Step B (410 mg, 1.31 mmol), hexamethylenetetramine (256 mg, 2.0 mmol) and trifluoroacetic acid (2.5 ml) under nitrogen was heated to 75° C. and stirred for about three hours. The solution was concentrated in vacuo to give a yellow viscous oil. Water (20 ml) was added to the yellow oil and the mixture was stirred for about 30 minutes at room temperature. The aqueous solution was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2×50 ml), brine (50 ml), dried, filtered and concentrated to give the title compound (440 mg) as a crude product which was used in the next step without further purification. NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.33 (s, 2H), 7.11-7.16 (m, 2H), 6.93 (d, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:32]4[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cc(F)cc(F)c4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-difluorophenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (64%).