Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([Br:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:5]=2[N:6]=1.N1C=CC=CC=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>ClCCl>[Br:11][C:10]1[C:4]2[S:3][C:2]([NH:1][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])=[N:6][C:5]=2[C:7]([O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-7-bromo-4-methoxybenzothiazol (2.33 g, 9 mmol) is dissolved in dichloromethane (100 ml) and at 0° C. treated with pyridine (2.2 ml, 27 mmol) and 5-methyl-thiophene-2-carbonyl chloride (2.2 g, 13.5 mmol). The reaction mixture is allowed to warm to room temperature and after stirring for additional 18 h quenched with water (100 ml). After separation of the phases, the aqueous phases are extracted twice with ethyl acetate. The combined organic layers are then washed with brine, dried and avaporated to dryness. Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:1 to 4:1) and final recrystallization from ethyl acetate affords the product as off-white solid. (34 mg, 69%). MS: m/e=384 (M+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2ccc3nc(N)c4ncn(CC(C)C)c4c3c2)c(OC)c1

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 223–227° C.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:10][CH:7]([CH2:8][CH3:9])[CH3:6]
Reactant: CCC(C)O
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: CCC(C)O[Si](C)(C)C
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
8.06 g (74.2 mmol) of chlorotrimethylsilane were added dropwise while stirring at 0° C. to a solution of 5.00 g (67.5 mmol) of 2-butanol and 6.10 g (74.2 mmol) of 1-methylimidazole. The reaction mixture was stirred at 0° C. for a further 30 min and at 80° C. for 5 min to form a liquid biphasic mixture. Removal of the upper phase gave 8.50 g (theory: 9.88 g) of 2-trimethylsilyloxybutane as a colorless, slightly cloudy oil having a purity of 96% (GC).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]([CH3:18])[CH3:17]>CC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COc1ccc(Br)cc1
Yield: 60.2 %

Procedure:
4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL). Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutyl bromide (4 g, 29.2 mmol). The reaction is heated to reflux for four days, refilling solvent as necessary. The reaction mixture is diluted with water and extracted with ether, the organic layer is separated and concentrated in vacuo. The residue is dissolved in hexane dried with magnesium sulfate, and filtered through a plug of silica gel. The solvent is removed in vacuo to afford 1.6 g (60% yield) of the title compound as a colorless non-viscous oil. 1H NMR (CDCl3) 1.01 (d, 6H, J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H, J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[N:10]2[C:11](=[O:23])[C:12]3[NH:13][CH:14]=[N:15][C:16]=3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]2=[N:8][N:7]=1.[Br:27]N1C(=O)CCC1=O>O1CCCC1>[Br:27][C:14]1[NH:13][C:12]2[C:11](=[O:23])[N:10]3[C:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=4)=[N:7][N:8]=[C:9]3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=2[N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To the solution of 3-(3-bromobenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (210 mg, 0.50 mol) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (140 mg, 0.00076 mol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative LCMS to yield the desired product (0.15 g, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C18H19Br2N6O (M+H): 493. found: 493, 495 and 497.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: BrCCOc1ccccc1-c1nc(-c2ccccc2)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CN1CCN(CCOc2ccccc2-c2nc(-c3ccccc3)no2)CC1

Procedure:
1.72 g of 5-[2-(2-bromoethyl)oxy-phenyl]-3-phenyl-1,2,4-oxadiazole are dissolved in 50 ml of anhydrous dioxane and mixed with 2 g of N-methylpiperazine. The solution is refluxed for one hour and then concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with dichloromethane/methanol (90/10). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 1.7 g (78% of theory). m.p.: 251-253° C.
Reaction SMILES: [CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:40][C:41]([F:51])([F:50])[O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:50])[F:51])=[CH:48][CH:47]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC[Si]1(c2ccccc2)CCC(C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 78.4 %

Procedure:
A mixture of 50 g of 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylic acid, 50.0 g of triphenylphosphine and 420 ml of carbon tetrachloride was agitated under reflux for 1 hour. Then, a mixture of 32.0 g of 4-trifluoromethoxyphenol and 100 ml of pyridine was added to the mixture, followed by further addition of 1.00 g of 4-dimethylaminopyridine and agitation at room temperature for 9 hours. The resultant reaction mixture was poured into dilute hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification of the resultant residue with silica gel chromatography to obtain 60.8 g (yield: 78%) of (4-trifluoromethoxyphenyl) 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylate. The results of IR and NMR analyses are shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][S:13][C:7]4=[N:6][C:5]=3[CH3:14])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCS2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3)CC1)CCS2

Procedure:
A mixture of 3.3 parts of 6-(2-chloroethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 8 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered hot over Hyflo and the filter-cake was washed with trichloromethane. The filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 2 parts of 6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 165.6° C. (compound 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]>C(Cl)Cl.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(CO)ccc2Cl)cc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(C=O)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N-(2-chloro-5-hydroxymethyl-phenyl)-3,4-dimethoxy-benzenesulfonamide (2.53 g, 7 mmol) in DCM/THF (1:1, 16 mL) was treated with MnO2 (12.3 g, 20 eq). The mixture was stirred at RT for 6 h, filtered over Celite and concentrated. The residue purified by chromatography on SiO2 (hex/EA 1:1, EA). The product was recovered as a pinkish oil (1.95 g, 77%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[NH:43][C:44]2[C:45]([N:63]=1)=[CH:46][C:47]1[C:48]([CH3:62])([CH3:61])[C:49](=[O:60])[N:50]([CH2:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]=1[CH:52]=2>CN(C)C=O>[CH3:56][C:55]([CH3:58])([CH3:57])[C:54](=[O:59])[CH2:53][N:50]1[C:51]2[CH:52]=[C:44]3[NH:43][C:42]([NH:41][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:63][C:45]3=[CH:46][C:47]=2[C:48]([CH3:61])([CH3:62])[C:49]1=[O:60]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of benzoic acid (85.5 mg), TBTU (225 mg; 0.70 mmol) and DIPEA (240 μl) in N,N-dimethylformamide (8 ml) is stirred at RT for 5 min. Afterwards D7 (210 mg) is added and the mixture is stirred at RT for 18 h. After evaporation of the solvent the crude material is purified by RP-MPLC eluted with MeCN/water to give the desired compound (186 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]3[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]3=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)c2c1cnc1[nH]ncc21
Temperature: 65 °C
Yield: 46.5 %

Procedure:
3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (100 mg, 0.32 mmol) was dissolved in trifluoroacetic acid (5 ml) and heated to 65° C. for 24 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was treated with ethyl acetate (3 ml) and a few drops of methanol and cooled to 0° C. The mixture was filtered and washed with ice cold ethyl acetate to afford pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (28 mg, 47%) as a yellow solid. M.p.=285-300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.55 (bs, 1H), 8.98 (s, 1H), 8.50 (s, 1H); LCMS: 189 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:37][C:36]=1[Cl:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:50])[F:49])=[CH:45][CH:46]=2)=[CH:37][C:36]=1[Cl:51])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)c(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
250 mg (0.57 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 10A), 277 mg (0.68 mmol) of 4-(bromomethyl)-3-chloro-4′-(trifluoromethyl)biphenyl and 118 mg (0.85 mmol) of potassium carbonate in 10 ml of acetonitrile were heated to 110° C. and stirred at this temperature for 4 h. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). The product obtained in this manner was re-purified by preparative HPLC (mobile phase: methanol/water 9:1). This gave 182 mg (0.26 mmol, 45% of theory) of the target compound.
Reaction SMILES: [OH-].[K+].CC(O)C.[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8].[H][H]>CC(O)C>[C:10]1([C@H:7]([OH:9])[CH3:8])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: CC(=O)c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@@H](O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 100 mL of an autoclave was charged 11.7 mg (0.010 mmol) of the mixture of RuCl2[(R)-binap](dmf)n and RuCl2[(S) -binap][(S)-binaphthyldiamine]. After purging with argon, 2.8 mL of 2-propanol and 50 μL (0.025 mmol) of KOH/2-propanol (0.5M solution) were added. The resulting mixture was stirred at room temperature for 30 minutes. After addition of 0.38 mL (2.5 mmol) of 1′-acetonaphthone, stirring was conducted at room temperature for 4 hours at a hydrogen pressure adjusted to 0.8 Mpa. The reaction mixture was concentrated by distilling off the solvent under reduced pressure. The residue was filtered using silica gel, whereby 228 mg (yield: 53%) of (R)-1-(1-naphthyl)ethanol was obtained. The enantio-selectivity was 4%ee.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][N:18]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (12.9 g), 3,4-dihydro-2H-pyran (5.26 g) and p-toluenesulfonic acid monohydrate (2.38 g) in THF (300 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). 11.4 g (70%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:9]([NH:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(NCc2ccccc2)n1
Temperature: 25 °C

Procedure:
A solution of 2,4-dichloropyrimidine (0.500 g, 3.36 mmol) in isopropanol (10 mL) was cooled to 0° C., and benzylamine (0.360 g, 0.37 mL, 3.36 mmol) was added. N,N-Diisopropylethylamine (0.434 g, 0.58 mL, 3.4 mmol) was added and the mixture was allowed to warm to room temperature over 15 h. The resulting white suspension was concentrated to afford a white solid. This material was purified via column chromatography on silica gel (gradient elution with 0-50% ethyl acetate-hexane) to afford benzyl-(2-chloropyrimidin-4-yl)amine as a white solid. MS (MH+) 220.1; Calculated 219.68 for C11H10ClN3.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[F:10].[C:11]([Cu])#[N:12].C(OCC)(=O)C>CCCCCC>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: N#C[Cu]
Reactant: Cc1c(N)ccc(Br)c1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(N)ccc(C#N)c1F
Temperature: 140 °C
Yield: 67.3 %

Procedure:
A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a separatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1[M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([OH:25])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:27]1[C:31]2C=CC=CC=2N=N1.CN>ClCCl>[CH3:31][NH:27][C:23](=[O:25])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC2CCCC2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC2CCCC2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 14 %

Procedure:
To a cold (0°) solution of N-(Tertiarybutoxycarbonyl)-O-cyclopentyl-L-tyrosine (6.89 g, 20 mM) in dichloromethane (40 ml) was added 1-hydroxybenzotriazole (3.32 g, 21 mM) and dicyclohenylcarbodiimide (4.47 g, 21 mM). After 20 minutes at 0° a solution of methylamine (1.34 g, 40 mM) in dichloromethane (20 ml) was added and the reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture after filtration and washing with water, dilute (1M) sodium hydroxide, 3N citric acid and water was dried and concentrated in vacuo to an oil. Recrystallisation from ethyl acetate/hexane gave the title compound as white crystals (1 g); m.p. 152°-154°; (Found: C, 66.77; H, 8.47; N, 7.83. C20H30N2O4 requires C, 66.27; H, 8.34; N, 7.73%); δ(CDCl3) 1.40 (9H, s, C(CH3)3); 1.5-2.0 (8H, CH-cyclopentyl); 2.72 (3H, d, J=5 Hz, CONHCH3); 2.95 (2H, m, CH2Tyr); 4.22 (1H, dd, J=7 and 15 Hz,α-CH); 4.72 (1H, br, O--CH (cyclopentyl)); 5.07 (1H, br, CONH); 5.75 (1H, br, CONH); 6.78 (2H, d, J=8 Hz, C6H4); 7.10 (2H, d, J=8 Hz, C6H4).
Reaction SMILES: [H][H].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19]CC2C=CC=CC=2)=[CH:14][C:13]=1[Cl:27])(=[O:5])[CH3:4]>[Pd].C(O)C>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([Cl:27])=[CH:14][C:15]([OH:19])=[CH:16][C:17]=1[Cl:18])(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that set forth in Step D of Example 1, using excess hydrogen gas, 33.0 grams (0.086 mole) of 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butyl acetate and 0.05 gram (catalyst) of 10% palladium on carbon in 350 mL of ethanol. The yield of the subject compound was 25.4 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[CH3:22][O:21][C:19](=[O:20])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:14]=1
Reactant: COC(=O)c1cccc([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cccc([C@H]2CCCN2)c1

Procedure:
To a stifling solution of (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (830 mg, 2.582 mmol) in methylene chloride (30 mL) at room temperature add 4 M HCl in dioxane solution (12.91 mL, 51.64 mmol) and stir the reaction at ambient temp for 18 h. Concentrate the solution in vacuo at 35° C. to remove most solvent. Dilute and stir the dioxane suspension of solids with Et2O (50 mL) and hexane (50 mL). Filter the solid washing with Et2O then hexane and dry in vacuo under P2O5 to give (R)-3-pyrrolidin-2-yl-benzoic acid methyl ester HCl as a solid (577 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]2[C:10]=1[O:9][CH:8]=[CH:7]2.Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1>>[CH:11]([C:5]1[C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]([O:1][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2occc12
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccoc23)nc1

Procedure:
Using the procedure outlined in Preparation 70, 7-hydroxybenzofuran-4-carbaldehyde (preparation 73) and 6-chloronicotinonitrile gave the title compound: RT=3.40 min; m/z (ES+)=265.2 [M+H]+.