Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:35]=[CH:34][C:17]([C:18](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:17]2[CH:34]=[CH:35][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCCCCCCO
Solvent: c1ccncc1
Product: COc1ccc(C(OCCCCCCCC(=O)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 127.5 %

Procedure:
8-hydroxyoctanoic acid (100 mg, 0.59 mmol) was dissolved in 1.5 mL of pyridine. To the solution, 4,4′-dimethoxytrityl chloride (237 mg, 0.7 mmol) was added, and the mixture was stirred overnight. The completion of the reaction was confirmed by TLC. Then, the reaction solution was separated into organic and aqueous phases using methylene chloride and water. The organic phase was dried over sodium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified with a silica gel column (4 g, methylene chloride) to obtain amorphous 8-(4,4′-dimethoxytrityloxy)octanoic acid (348 mg). The obtained 8-(4,4′-dimethoxytrityloxy)octanoic acid was dissolved in 1 mL of methylene chloride. To the solution, 4-aminophenol (70.9 mg, 0.64 mmol), EDC (101.6 mg, 0.88 mmol), HOBT (79 mg, 0.886 mmol), and triethylamine (92 L) were added, and the mixture was stirred overnight. The completion of the reaction was confirmed by TLC. Then, the reaction solution was purified with a silica gel column (5 g, 30%-+50% ethyl acetate/n-hexane) to obtain the amorphous compound (148 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[OH:22])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:24][C:25]1[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-chloromethyl-4-(β-trimethylsilyl-ethoxymethoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-[4-(2-trimethylsilyl-ethoxy-methoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 530 [M-(C2H4 +CH2O)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:21][O:20][C:18]1[CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:15]=[CH:16][N:17]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCNCC2)ncn1

Procedure:
9.8 g 4-(6-methoxy-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 100 mL 4 mol/L HCl solution in dioxane for 4 h. The precipitate was filtered and dried to yield 8.1 g of the desired compound. Rt: 0.22 min (method B), (M+H)+: 195
Reaction SMILES: N#N.[N:3]([C@H:6]1[C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7]1)=[N+:4]=[N-:5].C1COCC1.[F-:34].C([N+](CCCC)(CCCC)CCCC)CCC>>[N:3]([C@H:6]1[C@@H:10]([F:34])[CH2:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7]1)=[N+:4]=[N-:5]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@H](N=[N+]=[N-])C1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, and under inert atmosphere (N2), a solution of trans-tert-butyl 3-azido-4-(tosyloxy)pyrrolidine-1-carboxylate (438 mg, 1.15 mmol) in 1M tetra-n-butyl-ammonium fluoride solution in THF (7.00 mL, 7.00 mmol) was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was extracted with CH2Cl2, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept/EA, 9:1→7:3) to afford cis-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate as a colorless oil. TLC: rf (Hept/EA, 7:3)=0.33. LC-MS-conditions 08: tR=0.81 min; [M-CH3+H]+=216.15.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNC(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.50 g) and benzoyl chloride (1.10 g) were reacted in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)-propyl]imidazol-4-yl}ethyl)benzamide, as an oil. The compound contained 8% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl)benzamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.25 g 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was dissolved in 5 mL of DMF and 0.63 g cesium carbonate was added. To this suspension was added 0.17 mL of benzyl bromide and the reaction was stirred overnight at room temperature. The reaction was allowed to settle and the DMF was decanted into a flask. The remaining residue was washed and decanted twice with ethyl acetate and these washes were added to the flask with the DMF. Water was added to the ethyl acetate and DMF and the organic layer removed. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4 and concentrated to give 0.28 g of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole which was used without further purification.
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=1)=[N+]=[N-]>C1COCC1.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15][CH2:14]3)[CH:5]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc3ncccc3c2)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Oc2ccc3c(c2)CCCN3)ncn1

Procedure:
The crude 6-azido-4-(quinolin-6-yloxy)-pyrimidine (36.4 mMol) in 324 ml of THF/acetic acid 4:1 is hydrogenated in the presence of 6 g Pd/C (10% Engelhard 4505). Then the catalyst is filtered off and the filtrate concentrated in vacuuo. The residue is put to pH 10 by addition of sat. Na2CO3 solution and extracted 3× with EtOAC. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of 40 g of SiO2 concentrate in vacuo. The resulting powder is put on top of a SiO2 chromatography column and the title compound eluated with EtOAc: MS: [M+1]+=243.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:23][CH3:24])[CH:20]=3)[C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:24][O:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:22]2
Reactant: COc1ccc2c(c1)CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(C1CCNCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-methoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 2.44 mmol) in dichloromethane (8.5 mL) was added trifluoro-acetic acid (1.7 mL) and the reaction mixture stirred at rt overnight. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the trifluoroacetate salt. MS (ISP): 247.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1>CO.[Pd]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CCOC(=O)N1CCC(Nc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2cc(F)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
A suspension of D1 (14.0 g, 45 mmol) and 5% Pd/C (3.0 g) in methanol (500 mL) in an autoclave (1000 mL) was put under an atmosphere of hydrogen (˜20 atm). The mixture was stirred at room temperature for 3 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound (12.7 g, 100% yield) as a black solid that was used without further purification. (Rf: 0.3 (ethyl acetate/hexane 7:8))
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][N:10]2[CH:14]([C:35](=[CH2:38])[CH2:36][CH3:37])[C:15]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:17][C:9]2=[N:8]1)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C:15]3([CH:14]([C:35](=[CH2:38])[CH2:36][CH3:37])[N:10]4[C:9](=[N:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[CH2:11]4)[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:32]2=[CH:31][CH:30]=1
Reactant: C=C(CC)C1N2CC(=O)N(CCOC(C)=O)N=C2CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(CC)C1N2CC(=O)N(CCO)N=C2CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of racemic (6′R, 3R, 8′S)-2′-(2-acetoxyethyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione (0.3 g, 0.54 mmol) prepared in example 7b in tetrahydrofuran (25 mL) and methanol (15 mL) was added sodium hydroxide aqueous solution (1N, 10 mL). the reaction mixture was stirred at room temperature for 2 h, then neutralized to “pH” 7 by aqueous HCl. The mixture was then extracted with ethyl acetate. The organic layer was separated, died over MgSO4, concentrated, and dried in vacuo to give racemic racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-hydroxyethyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione as a white solid (0.22 g, 79%)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].O[C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][S:16][C:11]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][S:16][C:11]=2[CH:10]=1
Reactant: O=C1CSc2cc(O)ccc2N1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc2c(c1)SCC(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N,N-dimethyl-3-aminopropanol (0.27 g, 5.2 mmol) was added to a mixture of 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (0.95 g, 5.2 mmol) and triphenylphosphine (1.37 g, 5.2 mmol) in dry tetrahydrofurane (30 ml) under nitrogen atmosphere, followed by diethyl azodicarboxylate (1 g, 5.7 mmol). The mixture was stirred at room temperature for 48 h, concentrated in vacuo, and the product was purified by silica gel chromatography using dichloromethane:methanol gradient of (9:1) to (7:3) as the mobile phase. Yield 1.1 g (75%) mp 120–121° C.
Reaction SMILES: [F:1][CH:2]([F:27])[CH2:3][O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH:15](F)[S:16]([C:19]1[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=1)(=[O:18])=[O:17].[F:28]C1C(C)(C)ON=C1S(CC1C(C(F)(F)F)=NN(C)N=1)(=O)=O.CC1(C)ON=C(S(C(F)C2C(C(F)(F)F)=NN(C)N=2)(=O)=O)C1.CC1(C)ON=C(S(CC2C(C(F)(F)F)=NN(C)N=2)(=O)=O)C1.FC(F)COC1N(C)N=C(C(F)(F)F)C=1C(F)(F)S(C1CC(C)(C)ON=1)(=O)=O.CC1(C)ON=C(S(C(F)(F)C2C(C(F)(F)F)=NN(C)N=2)(=O)=O)C1.FC(F)COC1N(C)N=C(C(F)(F)F)C=1C(F)(F)S(C1C(F)C(C)(C)ON=1)(=O)=O.FC(F)(S(C1C(F)C(C)(C)ON=1)(=O)=O)C1C(C(F)(F)F)=NN(C)N=1>>[F:1][CH:2]([F:27])[CH2:3][O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16]([C:19]1[CH:23]([F:28])[C:22]([CH3:25])([CH3:24])[O:21][N:20]=1)(=[O:18])=[O:17]
Reactant: Cn1nc(C(F)(F)F)c(C(F)S(=O)(=O)C2=NOC(C)(C)C2)c1OCC(F)F
Reactant: Cn1nc(CS(=O)(=O)C2=NOC(C)(C)C2F)c(C(F)(F)F)n1
Agent: Cn1nc(C(F)(F)F)c(C(F)(F)S(=O)(=O)C2=NOC(C)(C)C2)c1OCC(F)F
Agent: Cn1nc(C(F)(F)F)c(C(F)(F)S(=O)(=O)C2=NOC(C)(C)C2)n1
Agent: Cn1nc(C(F)(F)F)c(C(F)(F)S(=O)(=O)C2=NOC(C)(C)C2F)c1OCC(F)F
Product: Cn1nc(C(F)(F)F)c(CS(=O)(=O)C2=NOC(C)(C)C2F)c1OCC(F)F

Procedure:
3-{[5-(2,2-difluoroethoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl]fluoromethanesulfonyl}-5,5-dimethyl-4,5-dihydroisoxazole (2-2); 4-(4-fluoro-5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole (2-3); 4-[(5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonyl)fluoromethyl]-2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole (2-4); 4-(5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole (2-5); 3-{[5-(2,2-difluoroethoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl]difluoromethanesulfonyl}-5,5-dimethyl-4,5-dihydroisoxazole (2-6); 4-[(5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonyl)difluoromethyl]-2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole (2-7); 3-{[5-(2,2-difluoroethoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl]difluoromethanesulfonyl}-4-fluoro-5,5-dimethyl-4,5-dihydroisoxazole (2-8); 4-[difluoro-(4-fluoro-5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonyl)methyl]-2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole (2-9);
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:12]=[CH:13]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2cccc(O[Si](C)(C)C(C)(C)C)c21

Procedure:
In analogy to the procedure described in example 6 b], 7-(tert-butyl-dimethyl-silanyloxy)-1H-indole (EP 206225 A2) was reacted with ethyl bromoacetate in the presence of cesium carbonate in acetonitrile to give the title compound as colorless liquid.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[C:7]([O-:10])(=[O:9])[CH3:8].[Na+]>CN(C)C=O>[C:7]([O:10][CH2:5][CH:4]=[CH:3][CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: BrCC=CCBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=CCBr
Temperature: 100 °C
Reaction time: 1 h

Procedure:
93 g of 1,4-dibromobut-2-ene are treated in 250 ml of dimethylformamide with 35.5 g of anhydrous sodium acetate and stirred for 1 hour at 100°C. The mixture is extensively freed from dimethylformamide on a rotary evaporator and the residue is partitioned between water and methylene chloride. The methylene chloride phase is dried over calcium chloride, filtered and concentrated. The residue is distilled under a water-jet vacuum, whereby the fractions are collected between 95° and 105°C at 10-15 mm; nD25 =1.502. There is obtained 1-acetoxy-4-bromobut-2-ene as a colourless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]([F:29])[F:28])=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]([F:28])[F:29])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1nc2c(cc1C(F)F)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NC(=O)N2CCCc3cc(C(F)F)c(C=O)nc32)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 35, 11 mg, 0.027 mmol) in THF (0.5 ml) and H2O (0.1 ml) was added conc. HCl (0.017 ml), the reaction mixture was stirred at room temperature for 8 h, then conc. HCl (0.033 ml) was added and the reaction mixture was stirred for 20 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated to give the title compound as a colorless solid.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2cnc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:43]>C(O)C.[OH-].[Na+]>[CH3:43][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:44])=[O:2]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O

Procedure:
A solution of (2-methyl-4-{3-[3-(3-piperidin-1-yl-prop-1-ynyl)-5-(4-trifluoromethylphenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester (30 mg, 0.05 mmol) in ethanol (1 ml) and 1N NaOH (0.25 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (2 ml). Aqueous 1N HCl (0.25 ml) was added and the mixture was extracted with methylene chloride (2×10 ml). The combined organic phases were dried and evaporated to give the title compound in 25 mg (86%) yield.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
cis-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (22.3 g, 95.59 mmol) was dissolved in CH2Cl2 (240 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (25.42 g, 114.7 mmol) was added and the mixture was stirred for 30 minutes. NEt3 (19.99 mL, 143.4 mmol) was added and the mixture was slowly warmed to ambient temperature over 2 hours and stirred overnight. The mixture was diluted with CH2Cl2 and washed with 1N KHSO4 (2×100 mL) followed by washing with saturated aqueous NaHCO3 (100 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude orange solid was dissolved in minimal hot CH2Cl2 and hexanes were added with stirring until the solution became persistently cloudy. The warm mixture was cooled to ambient temperature and allowed to stand undisturbed for 1 hour. The solids were collected by filtration and the solid was successively washed with hexanes followed by 50% Et2O/hexanes and finally with hexanes again to provide the clean cis isomer of the product as a pale yellow solid (27.05 g, 68%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH3:14].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][O:13][CH3:14])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromopyridin-3-ol (25 g, 144 mmol) in DMF (300 mL) at 0° C. under N2 is added portionwise NaH (5.7 g, 144 mmol) over 5 min. The reaction was stirred 1 h, then chloro(methoxy)methane (12 g, 144 mmol) was added and the reaction stirred an additional 1 h at 0° C. Saturated sodium bicarbonate (500 mL) was added slowly and the suspension stirred 30 min and warmed to rt. The solution was extracted with EtOAc (3×400 mL), the combined organic layers washed with H2O (500 mL), saturated NaCl (500 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1>>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-n-Decyloxy-4-hydroxybiphenyl was synthesized by monoalkylating commercially available 4,4'-dihydroxybiphenyl in the presence of an equivalent amount of n-decyl p-toluenesulfonate and an akali (m.p. 149° C.).