Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CO.CCOC(C)=O.[Pt]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1N
Reaction time: 16 h
Yield: 71.7 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-[1-(2-fluoroethyl)-4-piperidinyl]piperazine (200 mg, 0.53 mmol) and platinum (sulfided, 5 wt. % on carbon, 50 mg, 0.013 mmol) in 20% MeOH/EtOAc (20 mL) was added to a high-pressure hydrogenation reaction flask. The reaction was purged with N2 and vacuum (3×). The reaction was purged with H2 and vacuum (3×). The reaction was then treated with H2 at 50 psi and stirred for approximately 16 h. The reaction was degassed, then poured through a Teflon filter, washing the solid with MeOH and DCM. The filtrate was concentrated under vacuum to give the title compound of step C (136 mg, 0.38 mmol, 74%) as a brown solid. MS (ESI): 351 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:20]1[NH:28][C:27]2[C:22](=[N:23][CH:24]=[N:25][CH:26]=2)[N:21]=1>C(OCC)(=O)C.O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:20]1[NH:28][C:27]2[C:22](=[N:23][CH:24]=[N:25][CH:26]=2)[N:21]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncncc2[nH]1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1-c1nc2ncncc2[nH]1
Temperature: 80 °C

Procedure:
An amount of 0.8 ml of morpholine was dissolved in a two-phase mixture of 40 ml of ethyl acetate and 40 ml of water. Then, 1 gm of crude 8-(2'-methoxy-4'-chlorosulfonylphenyl)-purine hydrochloride was added thereto in batches, under vigorous stirring, and the resulting mixture was heated to 80° C. for two hours. The reaction mixture was concentrated down to one-third of the volume, and the crystals precipitated were subjected to suction filtration and washed with water.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:25]=2[O:24][CH2:23]1>>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([NH:31][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([C:12]4[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=4)=[CH:15][CH:16]=3)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: CCCCCCCCc1noc(-c2ccc(CNc3ccc4c(c3)OCO4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,3-benzodioxol-5-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 408.4. HPLC (Condition A), Rt: 4.54 min (HPLC purity: 85.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]2[CH:16](OCC)[O:17]CC)=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
Another route involves reacting dimethylcyclohexanone (1A) with a prepared solution of diethoxycarbenium fluoroborate to provide 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8). The reaction is typically performed below room temperature in a solvent such as but not limited to methylene chloride. Chlorophenyl magnesium bromide is then added to a solution of 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8) to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 1-(4-Chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9) can be treated with an acid such as but not limited to HCl, to provide the aldehyde intermediate (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde) (4).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:73])([CH:68]([O:71][CH3:72])[O:69][CH3:70])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:70][O:69][CH:68]([O:71][CH3:72])[C:44]1([CH3:73])[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[N:58]([CH3:67])[S:59]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1
Reactant: COC(OC)C(C)(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(OC)C1(C)CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a solution of triphenylphosphine oxide (1.02 g) in dichloromethane (10 ml) was slowly added trifluoromethanesulfonic anhydride (0.31 ml) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-3,3-dimethoxy-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.70 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.28 g, yield 50%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1
Reactant: COc1cc(COc2nn(CCO)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(CCO)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-4-(hydroxymethyl)-1H-pyrazol-1-yl]ethanol (0.63 g), activated manganese dioxide (1.5 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (0.61 g, yield 97%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:2]3[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=3)=[CH:18][N:19]=[C:20]2[N:25]=1
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: CC(=O)Nc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 2.8 %

Procedure:
N-(6-Bromopyridin-2-yl)acetamide (0.33 g, 1.56 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with ethyl acetate on a gradient of methanol (0-5%) gave N-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide (14 mg) as an off-white solid: δH (400 MHz, DMSO) 2.19 (3H, s), 7.60 (1H, d, J 7), 7.85 (1H, d, J 7), 7.92 (1H, dd, J 8 and 8), 7.97 (1H, d, J 8), 8.90 (1H, s), 10.65 (1H, s), 10.75 (1H, d, J 7); m/z (ES+) 321 (M++H).
Reaction SMILES: BrC1C=C(Br)C2N(C(C(=O)C)=C(C3C=CC(F)=CC=3)N=2)C=1.[Br:22][C:23]1[CH:24]=[C:25]([Br:46])[C:26]2[N:27]([C:29]([C:39](=O)/[CH:40]=[CH:41]/N(C)C)=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:31]=2)[CH:28]=1.[CH:47]1([NH:52][C:53]([NH2:55])=[NH:54])[CH2:51][CH2:50][CH2:49][CH2:48]1>COC(OC)N(C)C>[CH:47]1([NH:52][C:53]2[N:55]=[C:39]([C:29]3[N:27]4[CH:28]=[C:23]([Br:22])[CH:24]=[C:25]([Br:46])[C:26]4=[N:31][C:30]=3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:40]=[CH:41][N:54]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nc2c(Br)cc(Br)cn12
Reactant: N=C(N)NC1CCCC1
Agent: CC(=O)c1c(-c2ccc(F)cc2)nc2c(Br)cc(Br)cn12
Agent: COC(OC)N(C)C
Product: Fc1ccc(-c2nc3c(Br)cc(Br)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 54 %

Procedure:
In a similar manner as described in Example 1 treatment of 1-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethanone (850 mg, 2.1 mmol) with N,N-dimethylformamide dimethyl acetal (30 mL), followed by condensation of the resulting (2E)-1-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one with cyclopentyl guanidine gave N-cyclopentyl-4-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (600 mg, 54% for two steps) as a yellow solid. 1H NMR (CDCl3): δ 9.98 (broad s, 1H), 8.13 (d, 1H), 7.71 (d, 1H), 7.68 (q, 2H), 7.14 (t, 2H), 6.40 (d, 1H), 5.61 (d, 1H), 4.36 (m, 1H), 2.0–2.2 (m, 2H), 1.4–2.0 (m, 6H); 19F NMR (CDCl3) δ −112.5; MS m/z 530 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]2[C:25](=[O:30])[NH:26][CH:27]=[N:28][CH:29]=2)[CH:18]=1>>[CH3:15][N:14]([CH2:13][C:11]1[O:12][C:8]([CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]2[NH:26][C:25](=[O:30])[C:24]([CH2:23][C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[CH:29][N:28]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: O=c1[nH]cncc1Cc1cccnc1
Reactant: CN(C)Cc1ccc(COCCCCN)o1
Product: CN(C)Cc1ccc(COCCCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)o1
Yield: 52.2 %

Procedure:
A mixture of 5-[(4-aminobutoxy)methyl]-N,N-dimethyl-2-furanmethanamine (1 g) and 2-methylthio)-5-[(3-pyridinyl)methyl]-4(3H)-pyrimidinone (1 g) was heated at 140° for 7 h. Column chromatography (silica/methanol) of the residue yielded the title compound (0.95 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1ccc(Br)cn1
Reactant: CSc1ccnc(Br)c1
Product: CS(=O)c1ccnc(Br)c1

Procedure:
The title compound was prepared from 2-bromo-4-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Br.[OH:23][C:24]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([OH:34])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Reactant: Oc1ccc2c(c1O)CCNC2
Agent: Br
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(O)c4O)C3)c3ccccc3n2)c1
Yield: 9 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide gave compound 48 (9% yield) as brown oil. 1H NMR (300 MHz, CD3OD) δ 2.83 and 3.05 (2t, 2H), 3.55 and 4.14 (2t, 2H), 3.87-3.92 (2s, 3H), 4.40 and 4.98 (2s, 2H), 6.15 and 6.64 (2d, 1H), 6.54 and 6.75 (2d, 1H), 7.08-7.12 (m, 1H), 7.41-7.47 (m, 1H), 7.69-7.74 (m, 1H), 7.88-8.21 (m, 5H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].Br[CH:13]([CH3:17])[C:14](Br)=[O:15].C(N(CC)CC)C>CC(C)=O>[CH3:17][CH:13]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:1][C:14]1=[O:15]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
2.5 g 2-hydroxyoctanoic acid (15.6 mmol) and 1.75 mL 2-bromopropionyl bromide (16.3 mmol) were stirred at 80° C. under nitrogen for 12 h. 150 mL acetone and 4.35 mL anhydrous triethylamine (31 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 250 mL ethyl acetate:hexane mixture (1:2). After filration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.00 (q, 1H), 4.89 (dd, 1H), 1.9-2.15 (br m, 2H), 1.70 (d), 1.66 (d), (3H, of 2 diastereoisomers), 1.45-1.65 (br m, 2H), 1.25-1.40 (br m, 6H), 0.90 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.53, 166.90. 166.26, 165.87, 75.80, 72.49, 72.25, 31.92, 31.45, 31.39, 30.00, 28.73, 28.50, 24.60, 24.29, 22.48, 22.44, 17.54, 15.83, 14.00. ELEM. ANAL. Calcd. for C11H18O4: C, 61.68; H, 8.41. Found: C, 61.63; H, 8.48. Yield: 45%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]([C@H:16]1[NH:21][CH2:20][CH2:19][N:18]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=3[N:24]=[C:17]12)([CH3:15])[CH3:14]>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]3[C:22]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=4[N:24]=[C:17]3[C@H:16]2[CH:13]([CH3:15])[CH3:14])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(Cl)n1)[C@@H]3C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (20.0 mg, 0.092 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added ZnCl2 (1M in diethyl ether, 0.2 mL, 0.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (31 mg, 0.09 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added to the reaction mixture via syringe over 1 min at 0° C. After addition, the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (20 mg, 42.6% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccsc4)c3O2)cc1
Yield: 77.1 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-thiophene boronic acid (0.334 g, 2.61 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.389 g (77%) of (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow solid. mp 90-92° C.; Anal. calcd. for C20H18O4S2: C, 62.15; H, 4.69. Found: C, 62.2; H, 4.72.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][CH:12]([CH:23]([CH3:25])[CH3:24])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14].Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[N:34]=[CH:35][C:28]=12>C1COCC1.CCOC(C)=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:33]1[C:29]2=[N:30][CH:31]=[N:32][C:27]([O:11][CH:12]([CH:23]([CH3:25])[CH3:24])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[O:14])=[C:28]2[CH:35]=[N:34]1
Reactant: Cc1ccc(NC(=O)C(O)C(C)C)nc1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)C(Oc2ncnc3c2cnn3-c2ccccc2Cl)C(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of LHMDS (0.999 mL, 1.00 mmol) in anhydrous THF (15 mL) was added dropwise to a stirred solution of racemic 2-hydroxy-3-methyl-N-(5-methylpyridin-2-yl)butanamide C1 (208 mg, 1.00 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes, then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine B1 (265 mg, 1.00 mmol) in anhydrous THF (3 mL) was added dropwise over 1 minute and the resulting mixture heated to 50° C. for 3 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The material was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-methyl-N-(5-methylpyridin-2-yl)butanamide (320 mg).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[CH:26]=[C:25]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([O:27][C:25]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:26]=2)[CH:37]=1
Reactant: Cc1cc(Oc2cc(Cl)ncc2C#N)cc2oc(=O)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncc2C#N)cc2oc(=O)[nH]c12

Procedure:
40 mg (0.16 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.12 mmol) 6-chloro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yloxy)-nicotinonitrile and 0.08 mL (0.47 mmol) DIPEA in 0.80 mL NMP were stirred for 1 h at 140° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with aqueous NaHCO3 solution. The precipitate formed was suction filtered and dried.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([Cl:1])=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:24])([CH3:25])[CH3:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)cc2ccccc21)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)c(Cl)c2ccccc21)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
N-Chlorosuccinimide (504 mg) was dissolved in an ethanol (9 ml) and water (1 ml) mixture of the 1-[4-(tert-butyldiphenylsilyloxy)butyl]-2-(3-pyridyl)indole (1.99 g) obtained in the same way as in Example 2(1), and the mixture was reacted at room temperature for 4.5 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic phase was washed with brine, then dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-[4-(tert-butyldiphenylsilyloxy)butyl]-3-chloro-2-(3-pyridyl)indole (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Br)(Br)([Br:31])=O>>[Br:31][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(O)n2)cc1
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Br)n2)cc1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-{4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.00 g) and phosphorus oxybromide was heated at 120° C. for 10 mins. The mixture was cooled, poured into ice-water and extracted with dichloromethane, which was dried (MgSO4) and evaporated to give an oil. Purification by column chromatography over silica gel (eluant dichloromethane) gave ethyl 2-{4-[N-(1-bromo-7-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.83 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][CH:7]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:6]2.C>C(OCCOCCOCC)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:8][C:7]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:6]2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NC(c1cccnc1)C2
Agent: [Pd]
Solvent: CCOCCOCCOCC
Product: COc1cc2cc(-c3cccnc3)nc(-c3ccccc3)c2cc1OC
Yield: 80.5 %

Procedure:
5.0 g of 3,4-dihydro-6,7-dimethoxy-1-phenyl-3-(3-pyridyl)isoquinoline in 150 ml of diethylene glycol diethyl ether are heated at 160° C. under an atmosphere of nitrogen with 2.5 g of palladium on animal charcoal (10%) for 2.5 hours. The catalyst is filtered off, the solution is evaporated in a rotary evaporator and the residue is washed with ether. 4.0 g of the isoquinoline compound of melting point 176°-177° C. are isolated.