Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromonicotinaldehyde (XLV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LII) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO m/z 188 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]2)[S:21][CH:22]=1)=[O:17])[C@@H:11]([CH3:14])[CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C)C=O>[C:32]([S:34][CH:25]1[CH2:26][N:23]([C:20]2[S:21][CH:22]=[C:18]([C:16](=[O:17])[NH:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C@@H:11]([CH3:14])[CH2:12][CH3:13])[N:19]=2)[CH2:24]1)(=[O:35])[CH3:33]
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.55 g, 3.15 mmol) (obtained as described in Reference Example 38(5)) in dimethylformamide (78 ml) was added potassium thioacetate (2.16 g, 18.9 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidine (910 mg, yield 61%) as a pale brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[CH2:33]2.O>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:34]2[CH2:33][C:32]3[C:36](=[CH:37][CH:38]=[C:30]([CH2:29][NH:28][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:31]=3)[C:35]2=[O:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of (α,α,α-trifluoro-p-tolyl)acetic acid (0.33 g, 1.6 mmol) and CDI (0.27 g, 1.7 mmol) was stirred in DMF (20 ml) at 40° C. under N2 for 2 hours. After 2 hours, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol) was added. After 2 h, TEA (0.16 g, 1.6 mmol) was added to the mixture and stirring continued for 16 h at this temperature. Water (40 mL) was added, resulting in precipitation of the product. The solids were filtered, washed with water (50 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide as an off-white solid (0.22 g, 29% yield); mp 217-219° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.95 (96.06%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.63 (s, 2H), 4.25 (d, 1H, J=17.4), 4.31-4.45 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.37-7.43 (m, 2H), 7.51 (d, 2H, J=7.8), 7.67-7.70 (m, 3H), 8.74 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.9, 42.3, 47.0, 51.6, 122.0, 122.9, 124.4 (q, J=269.3), 125.0 (q, J=3.75), 127.1, 127.2 (q, J=31.5), 129.9, 130.4, 141.1, 142.3, 143.6, 167.9, 169.5, 171.0, 172.9; LCMS: MH=460; Anal. Calcd for C23H20F3N3O4+0.5 CH2Cl2: C, 56.24; H, 4.22; N, 8.37. Found: C, 56.10; H, 3.92; N, 8.50.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:18]3=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.OS(O)(=O)=O>CO>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]([O:26][CH3:2])=[O:25])[C:18]3=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2ccc3c(C(=O)O)n[nH]c3n2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1n[nH]c2nc(N3CCN(C)CC3)ccc12

Procedure:
6-(4-Methyl-1-piperazinyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate trifluoroacetate (1.82 g, 4.8 mmole) was refluxed overnight in 300 mL of MeOH containing 2 mL of concentrated H2SO4. The reaction mixture was concentrated to ca. 100 mL and then distributed between EtOAc and an aqueous NaHCO3 solution. The aqueous phase was extracted additional two times with EtOAc and then the combined organic phase was dried and concentrated. Recrystallization from MeOH gave 1.21 g (91%) of analytically pure product, mp 230° -231° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=CC(O)=[CH:12][CH:11]=1>>[C:5]([O:4][C:1]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:2]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To 1500 ml. of acetic anhydride was added portionwise 248 g. (2.0 m) of p-methoxyphenol. Following the addition, the solution was heated on a steam bath for 3 hours, then poured into 5 liters of ice water. The solvents were removed by distillation to give an amber colored liquid weighing 273 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COC(CBr)OC
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)cc(C=O)c1OCC(OC)OC

Procedure:
A heterogeneous solution of 31 g (0.134 mol) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde, 28 g (0.166 mol) of 2-bromo-1,1-dimethoxyethane and 49 g (0.150 mol) of caesium carbonate in 150 ml of dimethylformamide is heated at 160° C. for 3 hours. After returning to room temperature, the mixture is filtered. The filtrate is then evaporated under reduced pressure. The solid so obtained is taken up in 250 ml of dichloromethane and filtered again. The homogeneous solution is then washed twice with 200 ml of 0.1N hydrochloric acid each time and subsequently with 200 ml of a saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and subsequently evaporated under reduced pressure, yielding the expected product.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(OCCO)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(OCCO)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 51 %

Procedure:
A mixture of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethanol (460 mg, 1.08 mmol) and 10% palladium on activated carbon (100 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature before the catalyst was removed by filtration. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethanol (236 mg, 55.1%) as a white solid: LC/MS m/e calcd for C23H28N2O4S [M+H]+ 429.55, observed 429.5; 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (br. s., 1H), 7.90 (d, J=8.3 Hz, 3H), 7.60 (d, J=8.1 Hz, 2H), 6.53 (s, 1H), 4.33 (t, J=7.8 Hz, 1H), 4.16 (t, J=4.5 Hz, 2H), 3.90 (t, J=4.5 Hz, 2H), 3.09 (s, 3H), 2.23-2.31 (m, 1H), 2.09-2.18 (m, 1H), 1.60-1.87 (m, 5H), 1.44-1.56 (m, 2H), 1.17-1.30 (m, 2H).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][C:25]1=[O:40].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:40])[CH2:26]4)=[N:35][CH:34]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)C(=O)C2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(=O)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) and methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 0.98 mmol) in toluene (5.00 mL) at 25° C. The resulting solution was stirred at 60° C. for 24 h. The reaction mixture was added to methanol (100 mL), then treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (204 mg, 45%) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[C:28]([C:29](=[O:30])[NH:31][CH3:32])=[CH:33][CH:34]=[CH:35][C:36]=4[F:37])[C:23]([Cl:38])=[CH:22][N:21]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (76 mg, 42%). LCMS (m/e) 529 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.32 (m, 2H), 8.63-8.51 (m, 1H), 8.20 (s, 1H), 7.55-7.36 (m, 3H), 7.28 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=8.5 Hz), 4.87-4.71 (m, 1H), 4.05-3.85 (m, 2H), 3.67-3.40 (m, 2H), 2.74 (d, 3H, J=4.2 Hz), 1.97-1.81 (m, 2H), 1.33-1.00 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16].CN(C)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)OCC1CNC(C)(C)O1
Agent: CN(C)C
Solvent: c1ccccc1
Product: CC(C)OCC1CN(C(=O)C(Cl)(Cl)Cl)C(C)(C)O1

Procedure:
To 20.8 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5.5 grams of trichloroacetyl chloride. To this solution was added dropwise with cooling, 3.1 grams of trimethylamine. After washing with water, drying and removal of the benzene in vacuo, there was obtained 8.1 grams of the title compound, nD30 1.4603. Analytical data supports the structure.
Reaction SMILES: [CH:1]1[C:6](=O)C=C(C(O)=O)[O:3][C:2]=1C(O)=O.C(O[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.CC(C)=O.[O-]CC.[Na+]>>[O:3]=[C:2]([CH2:1][CH3:6])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1cc(=O)cc(C(=O)O)o1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)C(=O)CC

Procedure:
Riegel, Zwilgmeyer, Organic Syntheses Coll., Vol. II, 126 (1943) and Huang et al. CA 98(3):16549v describe the preparation of chelidonic acid. In a first step rapid addition of 1.03 equivalents of diethyloxalate and 1 equivalent of acetone to a slight excess of sodium ethoxide yields ethyl dioxovalerate as the major product. In a second step another equivalent of diethyloxalate and hot sodium ethoxide solution is quickly added to the reaction causing a Claisen condensation with ethyl dioxovalerate. Acetone diethyloxalate ester is formed and exists as a disodium complex. In a third step ethanol is distilled off resulting in a cake-like product. In a further step, disodium acetone diethyloxalate complex is converted to its hydrogenated form by rapid, cold neutralization with hydrochloric acid. In a fifth step the neutralized acetone diethyloxalate is returned to the reactor after filtering and another equivalent of HCl added to promote cyclization and refluxed. The resulting chelidonic acid is cold filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].Br[CH2:15][C:16]1[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:15][C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: COC(=O)c1cc(F)c(CBr)cc1F
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(COc2cnc(OCC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 5-chloro-6-isobutoxy-pyridin-3-ol (Preparation 1, 364 mg, 1.8 mmol) in DMSO (15 mL) was added methyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 3, 479 mg, 1.8 mmol) followed by potassium carbonate (500 mg, 3.6 mmol) and the resulting mixture stirred at room temperature for 18 hours under nitrogen. The mixture was poured onto water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined extracts were washed with water (20 mL), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the title compound (623 mg, 89%) as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C>>[C:13]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:25]=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC(C)(C)c1cc(C=O)ccc1N1CCCC1
Yield: 80.1 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 7.6 g (27 mmol) of 1-(4-bromo-2-tert-butylphenyl)pyrrolidine with 16.2 ml (40 mmol) of a 2.5M solution of n-butyllithium and 3.1 ml (40 mmol) of DMF. 5 g of 3-tert-butyl-4-pyrrolidin-1-ylbenzaldehyde are obtained in the form of a yellow oil (yield=80%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]>>[Si:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
Prepared as in Example 12-1c from 3-hydroxy-4-methoxybenzaldehyde and tert-butylchlorodimethylsilane. Yield 100%, yellowish liquid. MS 267 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[H][H].[ClH:12]>O.[Pt]=O>[ClH:12].[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: OCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: OCCC1CCNCC1

Procedure:
2-(4-pyridyl)ethanol (70. g, 0.57M) and platinum oxide (2 g) in water (600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at the pressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidine hydrochloride in quantitative yield. Treatment of 4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12M) with phosphorus tribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration with diethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidine hydrogen bromide (20.76 g, 77% yield). The solution of the 4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085M) in tetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. To this solution was added formic acetic anhydride (12.7 ml) at 0° C., followed by the addition of triethylamine (25 ml) with vigorously stirring. The reaction mixture was stirred overnight. After the reaction, it was filtered and the filtrate was stripped in vacuo to dryness and water (100 ml) was then added to the residue and the mixture was extracted with diethyl ether (3×100 ml). Removal of the solvent and purification on silica gel columns, eluted with ethyl acetate-hexane (9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde (12.06 g, 66% yield).
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([OH:36])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:40](OS(C(F)(F)F)(=O)=O)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].C(=O)([O-])O.[Na+]>ClCCl>[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([O:36][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(COC/C=C(\C)[C@@H](O)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(COC/C=C(\C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Temperature: -78 °C
Yield: 100.4 %

Procedure:
2,6-Lutidine (38.2 ml, 328 mmol) was added to an anhydrous dichloromethane (1.00 l) solution of (1S,3R,4S,5E)-4-hydroxy-7-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohept-5-en-1-yl benzoate (70.0 g, 164 mmol) at −78° C. under nitrogen atmosphere. Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (56.5 ml, 246 mmol) was added dropwise to the reaction solution over 10 minutes. After the reaction solution was stirred at −78° C. for one and a half hour, a saturated sodium hydrogen carbonate aqueous solution was added at −78° C. The reaction solution was warmed to room temperature, which was then extracted with dichloromethane. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=8:1) to obtain the title compound (89.0 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(F)cc3)nsc2c1
Product: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole, MS: 379 (M,1Br).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[CH3:21][NH:22][CH2:23][CH:24]=[CH2:25].O>CN1C(=O)CCC1>[CH2:23]([N:22]([CH3:21])[C:4]1[C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:24]=[CH2:25]
Reactant: C=CCNC
Reactant: CN1Cc2c(Cl)nc(Cl)nc2C(c2ccc(F)cc2)C1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(C)c1nc(Cl)nc2c1CN(C)CC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture of 2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Preparation V, 408 mg, 1.307 mmol) in NMP (13 mL) was added N-methylprop-2-en-1-amine (465 mg, 6.53 mmol). The resulting reaction mixture was stirred at rt overnight. Water (50 mL) was added to the mixture and stirred for 30 min. The mixture was filtered to get a light tan solid which was dried and purified by flash column chromatography eluting with 30 to 100% EtOAc/Hexane to get N-allyl-2-chloro-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (453 mg, 100% yield). LC-MS (M+H)+=347.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]([OH:26])[C:24]#[CH:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:25]#[C:24][CH:23]([C:15]2[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[OH:26])=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(C(O)C#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (444 mg) as per the general procedure to afford 3-(2,4-Diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-yn-1-ol as a yellow powder (275 mg, 80%): Rf=0.12 (9:1, CHCl3:MeOH); mp=174-176° C.; 1H NMR (DMSO-d6) δ 6.85 (s, 2H), 6.27 (s, 2H), 5.98 (d, J) 5.6 Hz, 1H), 5.53 (d, J) 5.4 Hz, 1H), 3.78 (s, 6H), 3.65 (s, 3H), 2.19 (s, 3H), 1.51 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 167.1, 164.3, 161.2, 152.7, 138.3, 136.7, 103.7, 99.1, 87.9, 79.5, 63.6, 60.0, 55.8, 22.5; HRFAB[M+Li]351.1638 (calculated C17H20N4O4Li: 351.1645).