Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2cccnc2)nc2c(F)cc(Br)cc12
Solvent: Cc1ccccc1
Product: Fc1cc(Br)cc2c(Cl)nc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a suspension of 6-bromo-8-fluoro-2-(pyridin-3-yl)quinazolin-4-ol (6.16 g, 0.0192 mol) in toluene (60 mL) was added phosphorus oxychloride (5.30 ml, 0.0579 mol) at room temperature. The mixture was refluxed for 3 h. The solvent was evaporated and water was added to the residue under cooling conditions. The suspension was stirred at room temperature for 30 min, the resulting precipitate was filtered and dried to give the title compound (6.5 g, quantitative). 1H NMR (400 MHz, DMSO) δ 9.58 (d, J=1.6 Hz, 1H), 8.82 (dd, J=4.7, 1.5 Hz, 1H), 8.80-8.75 (m, 1H), 8.37 (dd, J=9.7, 1.9 Hz, 1H), 8.34-8.29 (m, 1H), 767 (dd, J=7.8, 4.6 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].CN1[CH2:28][CH2:27][CH2:26]C1=O.BrCC1CC1>O.CCN(CC)CC>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:26]4[CH2:27][CH2:28]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CCCC1=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: BrCC1CC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Naltrexone was prepared in high yield by direct N-alkylation of noroxymorphone with an alkyl halide in the presence of a protic solvent. Accordingly, 5.5 g of noroxymorphone, 16.5 mL of N-methyl-2-pyrrolidinone (NMP), and 1.65 mL of water were added to a flask (100 mL, 3 necked). The flask was flushed with nitrogen, and the reaction mixture was kept under nitrogen throughout the reaction. Next, 2.4 mL of bromomethylcyclopropane and 2.5 mL of triethylamine (NEt3) were added to the flask, which was then heated at 70° C. for 2 h. An additional 2.5 mL of NEt3 was added to the flask, and the mixture was heated at 70° C. for 7.5 h. HPLC analysis revealed that the reaction is completed with noroxymorphone at less than two percent or one percent and undesired side products such as quaternary ammonium salt and O-alkylation of phenol group were present at less than two percent or were undetectable. The mixture was cooled to room temperature, and water (82.5 g) was added to give a precipitate. The mixture was stirred for 1 h and then filtered. The solid was washed with water (2×5.5 mL) and dried under vacuum at 65° C. for 18 h to give 5.68 g of naltrexone as solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](C=C)=[C:7]([CH:21]2[C@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:25]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:23]([CH2:51][O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:22]2)[CH:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:10]=1[Cl:11])[CH:2]=[CH2:3]>C(Cl)Cl>[Cl:11][C:10]1[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[CH:8][C:7]([CH:21]2[C@H:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:25]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C@H:24]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:23]([CH2:51][O:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[O:22]2)=[C:6]2[C:5]=1[O:4][CH2:1][CH:2]=[CH:3]2
Reactant: C=CCOc1c(Cl)c(Cc2ccc(CC)cc2)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1C=C
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC=C3)cc1
Yield: 87.4 %

Procedure:
A mixture of compound 83 (145 mg, 0.17 mmol) and Grubb's 2nd generation cat. (25 mg, 0.03 mmol) in CH2Cl2 (34 mL) was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 84 (120 mg, 82%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH:9]([N:6]2[C:5]3[CH:27]=[CH:28][C:2]([NH:1][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-ylpropanoate (15 mg, 40 μmol) in dichloromethane (500 μL) was added benzenesulfonyl chloride (6.0 μL, 47 μmol) and N,N-diisopropylethylamine (8.0 μL, 46 μmol). The solution was stirred at room temperature for 48 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4), to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.50 min, MH+ 513].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)C(C)C)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([I:23])=[CH:18][N:17]=1>C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:19]([I:23])=[CH:18][N:17]=1
Reactant: NCCCO
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNc1nc(Cl)ncc1I
Yield: 95 %

Procedure:
In analogy to GP 2 reaction of 3-amino-1-propanol (0.38 ml, 5 mmol) in the presence of N-ethyldiisopropylamine (1.74 ml, 10 mmol) in 150 ml acetonitrile with 2,4-dichloro-5-iodo-pyrimidine (1.51, 5.5 mmol) provided the target compound after column chromatography in 95% yield.
Reaction SMILES: CO[CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](CCl)[CH:34]=1>CN(C=O)C>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:3][N:4]2[C:8]([C:9]3[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=3)=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:5]2)[CH:34]=1
Reactant: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(COC)n1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(Cc2cccnc2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)-pyrazole-3-carboxylate (820 mg) was dissolved in DMF (4 mL), and to the solution potassium carbonate (325 mg) and 3-picolyl chloride hydrochloride (193 mg) were added, and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the diluted residue, the resultant residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2 to 0:1) to obtain the title compound.
Reaction SMILES: COC[O:4][CH:5]([CH2:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]1=[O:38])[CH2:6][NH:7][CH:8]1[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[C:10](=[O:24])[CH2:9]1.Cl>CO.O1CCCC1>[OH:4][CH:5]([CH2:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]1=[O:38])[CH2:6][NH:7][CH:8]1[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[C:10](=[O:24])[CH2:9]1
Reactant: COCOC(CNC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)cc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(CC(O)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
6-(4-{[2-(Methoxymethoxy)-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (115 mg, 0.220 mmol) was dissolved in a mixed solvent of methanol/tetrahydrofuran (1:1,2 ml). To this solution was added 4N hydrochloric acid aqueous solution (1 ml) under cooling on ice and the mixture was stirred at 60° C. for 7 hours. The reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. To the residue was added 1N aqueous sodium hydroxide solution under cooling on ice to neutralize the residue which was then extracted using a lower layer solvent of chloroform/methanol/water (7:3:1). The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 65 mg (61%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO>[H][H]>[OH:4][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)=O
Solvent: CO
Product: CCOC(=O)CC(C)O
Yield: 26 %

Procedure:
To 3.90 g of ethyl acetoacetate were added 7.4 mg of rhodium 1,5-cyclooctadiene chloride complex compound, 22.1 mg of BCPM and 10 ml of methanol, and the mixture was charged into an autoclave. The mixture was stirred in the autoclave for 45 hours at 50° C. in hydrogen atmosphere at an initial pressure of 50 atm. It was confirmed by gas chromatography that 100% of the starting material had been converted. After distilling off the solvent, ethyl β-hydroxybutyrate was obtained almost theoretically by distillation under reduced pressure. [α]D23 =-2.67° (neat) (optical yield: 26%).
Reaction SMILES: C([NH:8][CH:9]([CH3:17])[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH:9]([CH3:17])[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(C)C(C)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)C(C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of methyl 3-(benzylamino)-2,2-dimethylbutanoate (5 g) in MeOH (150 ml) was added 10% palladium on carbon (1.5 g) at rt and the reaction mixture was stirred under hydrogen (balloon pressure) overnight at rt. After completion, the reaction mixture was filtered over a celite pad and the residue was washed with MeOH (25 ml). A saturated solution of hydrogen chloride in MeOH (50 ml) was added to the reaction mixture and allowed to stir overnight at rt. Methanol was removed under reduced pressure and the crude mass was triturated with diethyl ether (50 ml) to give the hydrochloride salt of the title compound (2.6 g). 1H NMR (400 MHz, DMSO-d6): δ 1.11-1.15 (m, 9H), 3.41-3.43 (m, 1H), 3.64 (s, 3H), 8.148 (bs, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([OH:42])[CH3:41])([CH3:34])[CH2:30][CH2:29]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)c(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 66.3 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in ethanol (4 mL) was added 10% Pd—C (60.6 mg, 0.057 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vacuum. The residue was then treated with 1M TBAF (0.949 mL, 0.949 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4,5-difluoro-2-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (85 mg, 0.126 mmol, 66.4% yield) as thick paste. 1H NMR (500 MHz, CDCl3) 6.96-6.89 (m, 1H), 6.68 (dd, J=11.7, 7.1 Hz, 1H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.31-4.09 (m, 2H), 3.93-3.81 (m, 1H), 3.44 (br. s., 2H), 2.88-2.70 (m, 4H), 2.63 (s, 4H), 2.12-1.94 (m, 4H), 1.90 (br. s., 2H), 1.57-1.42 (m, 6H), 1.41-1.31 (m, 3H), 1.27-1.18 (m, 18H). LCMS (M+H)=675.6.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)cc1F
Product: N#Cc1cc(-c2ccc(F)cc2F)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (59 mg, 73%), MS (ISP) m/z=324.4 [(M+H)+], mp 292° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [O:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Si:23]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Yield: 88.3 %

Procedure:
To a stirred solution of methyl β-D-glucopyranoside (5 g, 25.7 mmol) in 51 mL of dry DMF was added at room temperature imidazole (5.46 g, 80.2 mmol) followed by tert-butyldiphenyl-silyl chloride (11.3 mL, 43.4 mmol). The solution was heated to 50° C. for 24 hours and the DMF was removed under reduced pressure. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with H2O (1×100 mL), saturated aqueous NaCl (1×100 mL), and dried over magnesium sulfate. Concentration and flash chromatography (silica, 4% methanol in dichloromethane) provided pure target compound (9.82 g, 88%) as a white foam.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCCC1CCOc1ccccc1CCc1ccccc1
Yield: 105.8 %

Procedure:
Following a procedure similar to that described Example 38, 1.34 g of 1-t-butoxycarbonyl-2-{2-[2-(2-phenylethyl)phenoxy]ethyl}piperidine [prepared as described in Example 61(a)] were reacted with 0.269 g of lithium aluminum hydride dispersed in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.12 g (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[S:14][C:5]2[N:6]([CH3:13])[S:7](=[O:12])(=[O:11])[CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:16]#[CH:17].CO>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:13][N:6]1[C:5]2[S:14][C:2]([C:17]#[C:16][CH2:15][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)=[CH:3][C:4]=2[C:9](=[O:10])[CH2:8][S:7]1(=[O:12])=[O:11]
Reactant: CN1c2sc(I)cc2C(=O)CS1(=O)=O
Reactant: C#CCOC1CCCCO1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1c2sc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a stirring mixture of 6-iodo-1-methyl-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 34, 1.0 g), triethylamine (1.5 mL) CuI (13.8 mg), and tetrahydro -2-(2-propynyloxy)-2H-pyran (0.49g) in toluene (50 mL) at ambient temperature is added tetrakis triphenylphosphine palladium (40 mg). The resulting mixture is stirred overnight at ambient temperature. MeOH (50 mL) is added, the mixture is stirred 20 min and the solvent is removed in vacuo. The residue is partitioned between 10% HCl/H2O/EtOAc (100 ml each), and the organic layer is separated. The solvent is removed in vacuo and the residue purified by flash column chromatography (4/1, hexanes/EtOAc) to afford 0.68 g (66%) of the title compound as a white solid. Physical characteristics: 1H NMR (CDCl3) δ 1.52-1.86, 3.39, 3.55, 3.84, 4.21, 4.45, 4.81, 7.38; MS (ESI−) m/z 354 (M−H)−. Anal. Found: C, 50.70; H, 4.89; N, 3.95.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:23](=[O:24])[CH2:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 7.42 g (0.048 mol) of phenylacetyl chloride were added dropwise thereto at 0°. After stirring overnight at room temperature the mixture was poured into water, extracted with ethyl acetate, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) gave 8-chloro-4-(phenylacetyl)-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in the form of an oil.
Reaction SMILES: C([Si](C)(C)O[Si](C)(C)C=C)=C.[CH3:12][SiH:13]([CH3:15])[Cl:14].[C:16]1([O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Pt]>[O:22]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][Si:13]([CH3:15])([CH3:12])[Cl:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCOCCOc1ccccc1
Reactant: C[SiH](C)Cl
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Product: C[Si](C)(Cl)CCCOCCOc1ccccc1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
6 mg of platinum in the form of a solution of the complex with 1,3-divinyltetramethyldisiloxane are added to 290 ml (2.6 mol) of dimethylchlorosilane and the mixture is heated at reflux under a nitrogen atmosphere. 356 g of the 2-allyloxyethyl phenyl ether whose preparation is described above under a) are added dropwise over the course of about 2 hours, the temperature of the mixture being adjusted to 80° C. After 2 hours the reflux comes virtually to an end. The crude product is fractionated in vacuo, the main fraction being taken off at 95°-110° C. (2 hPa). 437 g of 3-(2-phenoxyethoxy)propyldimethylchlorosilane are obtained with an acid number of 207 (theoretically 205). The 1H NMR spectrum shows that the product contains neither starting material nor its 1-propeneoxy isomer.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:37])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:37][C:27]2[CH:28]=[CH:29][C:30]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:25]([O:24][CH3:23])[CH:26]=2)[N:6]=1)=[O:4]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CN(C)C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: COc1cc(Nc2nc(C(=O)N(C)C)cc(-c3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Yield: 51 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid dimethylamide (99 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound as yellow solid (76 mg, 51%). MS ISP (m/e): 497.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.77 (d, 2H), 7.74 (d, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 6.90 (s, 1H), 3.89 (s, 3H), 3.18 and 3.15 (2 s, 2×3H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5]Br.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)CCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCC[Si](C)(C)C)cc1

Procedure:
A solution of 20 g. 3-(trimethylsilyl)propyl bromide and 33.9 g. ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide was stirred at 100° for 18 hr. The cooled reaction was diluted with 100 ml. water, the layers were separated, and the aqueous layer was washed three times 100 ml. portions of methylene chloride. The combined organic solutions were washed with water and brine, dried with anhydrous magnesium sulfate, passed through a pad of hydrous magnesium silicate, and evaporated to 96 g. orange liquid. The liquid was dissolved into 100 ml. ethanol and the product was precipitated with 100 ml. water. The solid was filtered and dried. Crystallization from water-ethanol yielded the title compound as a white solid, m.p. 64°-66° C.