Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:57])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:57])=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1c(Br)cccc1C(=O)N1CCN(C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(C)CC4)c3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (174 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-(4-methyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-148) as a pale yellow powder (54 mg, 56%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
3,3-Dimethylacryloyl chloride (Intermediate 1, 4.16 g, 35.1 mmol) was slowly added to a solution of 4-bromoaniline (Intermediate 2, 5.00 g, 29.2 mmol) in 25 mL of methylene chloride. After stirring at room temperature for 20 min, triethylamine (2.5 mL) was added dropwise to the mixture. The resulting solution was stirred at room temperature for 3 h and then poured on 100 mL of ice-water mixture. The organic layer was separated, washed with brine (2×20 mL), dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by flash chromatography (90:10 hexane/ethyl acetate) afforded the title compound as a yellow solid (7.43 g, 100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[N:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([NH2:15])[C:11]=1[NH:12][CH2:13][CH3:14])=[O:5])[CH3:2].C(O)(=O)C.[N:24]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[N:12]([CH2:13][CH3:14])[N:24]=[N:15][C:10]=2[C:9]([O:16][CH2:17][CH3:18])=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCNc1c(N)c(OCC)nc(C)c1C(=O)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Reaction time: 8 h
Yield: 75 %

Procedure:
26.7 g. of 5-amino-4-ethylamino-6-ethoxy-2-methylpyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of acetic acid. At room temperature 7.5 g. of sodium nitrite in 20 ml. of water are added dropwise with continual stirring. The temperature is kept below 20°. The mixture is stirred overnight and then evaporated to dryness. 100 ml. of water are added to the residue which is then extracted three times with 50 ml. portions of ether. The organic layer is collected, dried over sodium sulfate, filtered and the solvent distilled off. The residue of 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from ligroin, yield 75%, m.p. 56°-58°.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]=[O:13]>O.C1(C)C=CC=CC=1>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[NH:11][C:12]([NH:1][OH:2])=[O:13]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: NO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)NO
Reaction time: 18 h
Yield: 97.1 %

Procedure:
A 500 mL side arm flask equipped with a thermometer and an addition funnel with a nitrogen inlet was charged with 100 mL of toluene and 2.00 g (0.10 mol) of 50% hydroxylamine in water. A solution of 4.41 g of 2,6-dimethylphenyl isocyanate (0.03 mol) dissolved in 50 mL of toluene was added dropwise over 15 min. External cooling was used to maintain the, internal reaction temperature below 25° C. Stirring was continued at room temp for 18 h. The solvent was removed under reduced pressure to give a white solid. The residual solvent was further co-evaporated twice with toluene, then oven dried overnight to give the desired product (5.25 g) as a white solid melting at 192-193° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19]([C:21]1[CH2:25][CH:24]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[O:23][N:22]=1)=O>CC(C)=O>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH:24]1[O:23][N:22]=[C:21]([C:19]2[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:16][CH:18]=2)[CH2:25]1
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CC(C)=O
Product: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-carbothioamide (7.33 g, 30 mmol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step C) (9.12 g, 30 mmol) in acetone (100 mL) was heated at 45° C. for 3 h, and then stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (40 mL), stirred at room temperature for 3 h and then concentrated under reduced pressure. The resulting oil was dissolved in aqueous hydrochloric acid solution (0.5 N, 200 mL) and extracted with ethyl acetate. The organic layer was basified by adding aqueous sodium hydroxide solution (10% in water), then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a thick amber-colored oil (8.62 g, weight included residual ethyl acetate).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=O)C.[ClH:39]>CO.C(Cl)Cl>[ClH:39].[OH:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 37 %

Procedure:
2M Aqueous sodium hydroxide solution (900 μl) was added to a solution of 4-(3 -acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline (290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml) and the mixture stirred for 25 minutes at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 and 95/5). The purified white solid was suspended in methanol (20 ml) and a solution of 7.5M hydrochloric acid in methanol (2 equivalents) was added. The solid was collected by filtration, washed with methanol and then pentane and dried under vacuum at 50° C. to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline hydrochloride (106 mg, 37%).
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([NH:13][C:14]([NH:16][C:17]2[C:18](=[O:37])[O:19][C:20]3[CH:33]=[C:32]4[CH2:34][CH2:35][CH2:36][C:31]4=[CH:30][C:21]=3[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])=[CH:7][C:6]=1[O:38][CH3:39])(=O)C.Cl>O1CCCC1>[OH:4][C:5]1[C:6]([O:38][CH3:39])=[CH:7][C:8]([NH:13][C:14]([NH:16][C:17]2[C:18](=[O:37])[O:19][C:20]3[CH:33]=[C:32]4[CH2:34][CH2:35][CH2:36][C:31]4=[CH:30][C:21]=3[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(NC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc(OC)c1OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of N-(4-acetoxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1]benzopyran-3-yl]urea (400 mg) in tetrahydrofuran (4 ml) was added 10% methanolic hydrochloride (4 ml). The mixture was stirred at room temperature for 8 hours and the solvent was then distilled off. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and distilled to remove the solvent. To the residue was added ethanol to give crystals of N-(4-hydroxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta [g] [1]benzopyran-3-yl]urea (330 mg, 66.7%). Recrystallization from ethanol gave colorless needles, m.p. 176°-179° C.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][NH:39][CH3:40]>CN(C=O)C>[CH3:38][N:39]([CH3:40])[C:32]1[S:33][C:29]([C:2]2([OH:1])[CH2:3][CH2:4][CH:5]([N:8]3[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[O:14])[CH2:11]3)[CH2:6][CH2:7]2)=[CH:30][N:31]=1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) and dimethylamine (Aldrich, 40% in water, 2 mL) in DMF (1 mL) was heated to 120° C. in a sealed tube overnight. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1[CH:17]=O)[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CCO>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1/[CH:17]=[C:22]1\[C:21](=[O:29])[NH:20][C:28]2[C:23]\1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:2]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c2c1C(=O)CCC2
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCc1c(/C=C2\C(=O)Nc3ccccc32)[nH]c2c1C(=O)CCC2

Procedure:
A mixture of compound 5 (0.50 mmol) and indolin-2-one (0.50 mmol) was added with EtOH (5.0 mL) and piperidine (0.1 mL). The reaction was heated at reflux for 12 h. The resultant precipitate was filtered and washed with EtOH to provide the diresed product. 1H NMR (CDCl3) δ 7.93 (s, 1 H), 7.61 (s, 1 H), 7.59 (d, 1 H, ArH), 7.19 (dd, 1 H), 7.09 (dd, 1 H), 6.89 (d, 1 H), 4.07 (q, 2 H), 3.27 (t, 2 H), 2.91 (t, 2 H), 2.74 (t, 2 H), 2.52 (t, 2 H), 2.14-2.19 (m, 2 H), 1.18 (t, 3 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH2:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28])[CH3:24]>>[CH2:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)[CH3:24]
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CCc1ccccc1CN
Product: CCc1ccccc1CNCCn1cnc(-c2cc(C(=O)O)ccn2)c1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-ethylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.11 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.6 Hz), 2.92 (2H, t, J=6.1 Hz), 3.71 (2H, s), 4.09 (2H, t, J=5.9 Hz), 7.11-7.16 (3H, m&s), 7.27 (1H, d, J=7.6 Hz), 7.44 (1H, dd, J=6.2 and 1.4 Hz), 7.69 (1H, s), 7.71 (1H, s), 8.21 (1H, s), 8.36 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:64]1(=[O:70])[CH2:69][CH2:68][CH2:67][CH:66]=[CH:65]1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:66]2[CH2:67][CH2:68][CH2:69][C:64](=[O:70])[CH2:65]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1C=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Yield: 23 %

Procedure:
[4-(Benzyloxy)phenyl]boronic acid (2 g, 8.77 mmol) was dissolved in dioxane/water (50 mL/5 mL) and Rh(acac)(C2H4)2 (68 mg, 0.26 mmol) and racemic BINAP (164 mg, 0.26 mmol) were added. The mixture was degassed 3 times and put under a nitrogen atmosphere. Cyclohexenone (1.02 mL, 10.52 mmol) was added to the yellow solution and the mixture heated at reflux overnight. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution (50 mL) added, then extracted with EtOAc (2×100 mL). The organic extracts were washed with water (100 mL) and dried. Volatile material was removed by evaporation and purification by chromatography gave the title compound (565 mg, 23%) as a solid; 1H NMR δ1.65-1.69 (1H, m), 1.78-1.93 (2H, m), 1.99-2.04 (1H, m), 2.22-2.35 (2H, m), 2.39-2.43 (1H, m), 2.65 (1H, m), 2.90-2.96 (1H, m), 5.08 (2H, s), 6.96 (2H, d), 7.20 (2H, d), 7.31-7.45 (5H, m); MS m/e MH+ 281.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole(0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)ccn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOCC2)ccn1
Yield: 62 %

Procedure:
As described for example 58c, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (61 mg, 62%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:15]1[O:52][C@H:42]([CH2:43][O:44][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][C:19]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:15]1[O:52][C@H:42]([CH2:43][OH:44])[C@@H:17]([O:18][C:19]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N6-benzoyl-5′-O-(tert-butyldimethylsilyl)-3′-O-(4,4′-dimethoxytrityl)-2′-deoxyadenosine (16.2 g) was dissolved in 200 ml of dry THF. A THF solution (31 ml) of tetrabutylammonium fluoride was added to the resultant solution and 100 ml of dry THF was further added, followed by stirring at room temperature. After 8 hours, THF was distilled off and extraction using chloroform was carried out. The extract was then washed by a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was then concentrated and purified by column chromatography (ethyl acetate/hexane/methanol) to obtain 13.8 g of the titled compound as a white powder (yield: 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Yield: 59 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene, the title compound was synthesized according to Reference Example 17a. Yield: 59%. Melting point: 165-167° C. (Ethyl acetate-hexane)
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[CH2:3][CH3:4].[OH-].[Na+].CO>O>[C:16]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH:6]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4])[CH2:15][CH2:14]2)([OH:18])=[O:17]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Yield: 97.1 %

Procedure:
A solution of methyl 2-(dipropylamino)tetralin-8-carboxylate hydrochloride (1.5 g, 4.6 mmol), sodium hydroxide (736 mg, 18.4 mmol), methanol (25 ml) and water (4 ml) was stirred overnight, The methanol was evaporated. Concentrated hydrochloric acid was added until the pH became about 6. The solution was extracted with chloroform. The organic layer was dried (sodium sulfate) and concentrated to give 1.23 g (97%) of pure 8-carboxy-2-(dipropylamino)tetralin as an oil. The hydrochloride melts at 245°-247° C., which could bse recrystallised from methanol/diethylether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH2:17])[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+](=[CH2:20])=[N-].CCCCCC>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:20][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:10][CH2:11]3)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21

Procedure:
Following general procedure O and using A 6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 41, 1.36 g, 4.6 mmol), a solution of diazomethane in diethyl ether and palladium (II)acetate (˜30 mg) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained as a clear oil (1.38 g, 100%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH:42][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]5[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=5)[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)cc1
Yield: 45 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 10 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 45% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 74% yield.