Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.C1COCC1.CO.O.Cl>C1COCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(C)=O)c(CC=C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Lithium hydroxide (85 mg, 2.02 mmol) was added to a mixture of methyl ester 7 (106 mg, 0.405 mmol) in 0.5 mL of a 3/1/1 THF/MeOH/H2O solution. The reaction mixture was stirred at reflux for 14 hours, cooled to room temperature, and diluted with THF (1 mL). The solution was acidified the solution to pH=3 by the dropwise addition of 6 M HCl. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated to afford acid 8 (63 mg, 75%) as a red oil that was suitable for use without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CO
Reactant: Cc1nccnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C
Yield: 83 %

Procedure:
A solution of 3-methylpyrazine-2-carboxylic acid (10 g, 72.4 mmol) in 80 mL methanol and sulfuric acid, 95% (5 ml, 90 mmol) was heated to 60° C. for 4 h. The solution was concentrated to remove MeOH, the residue was dissolved in 50 mL of water and neutralized with 10% aq Na2CO3 solution to pH 12. The resulting solution was extracted with ethyl acetate. The combined organics were dried and concentrated to give crude methyl 3-methylpyrazine-2-carboxylate (9.1 g, 83% yield) which was used for next step without further purification.
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:18]([CH3:34])[C:19]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[C:27]=2[Cl:31])[CH:22]=1)=[O:20].[C:35]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:31].[ClH:1].[C:8]1([CH2:3][CH2:9][N:11]2[CH2:12][CH2:13][N:14]([CH:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[C:27]=4[Cl:31])[CH:22]=3)=[O:20])[CH3:34])[CH2:15][CH2:16]2)[CH:35]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(CCc4ccccc4)CC3)ccc2c1Cl
Yield: 83.2 %

Procedure:
A mixture of N-(1-phenylethyl)piperazine dihydrochloride (0.79 g, 3 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.64 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in acetone was treated according to general preparation 2 to give 1.06 g of compound (IV-43) as white solid, yield 65%, mp 231-232° C. M+ 437.
Reaction SMILES: CS(O[CH2:6][C:7]([C:20]#[N:21])([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)=O.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN(C)C=O>O>[ClH:18].[C:20]([C:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)#[N:21]
Reactant: c1c[nH]cn1
Reactant: CCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Product: Cl
Temperature: 135 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 2-cyano-2-(2,4-dichlorophenyl)hexyl methane sulfonate (100 g., 0.29 mole), imidazole (100 g., 1.5 mole) and N,N-dimethylformamide (5 ml.) is heated with stirring at 135° C. overnight. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate. The drying agent is filtered and into the ethereal solution is bubbled dry hydrogen chloride gas. The white solid which precipitates is collected and dried to give 70.4 g. (68%) of the expected product, which is identified by nmr.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:26][S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([S:27]([Cl:26])(=[O:29])=[O:28])[CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a mixture of 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 59, 5.0 g, 13.8 mmol) and 5 mL of CH2Cl2 was added dropwise chlorosulfonic acid (8.0 g, 69.0 mmol, 5.0 eq) with ice-bath cooling. The mixture was stirred at 0° C. for 30 min. The resulting thick oil was poured onto crushed ice with vigorous stirring. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated by evaporation to give a thick oil, which was purified by column chromatography (CH2Cl2) to yield 3-(5-chlorosulfonyl-2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 60, 4.7 g, 74%) as a light brown oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[N:9][S:10][CH:11]=1)(=O)=O.S1C=CC=C1[CH2:17][C:18]([O-:20])=O.[Na+].[S:22]1C=CN=N1>O1CCCC1.CCOCC>[C:18]([S:22][CH2:6][C:7]1[N:8]=[N:9][S:10][CH:11]=1)(=[O:20])[CH3:17]
Reactant: O=C([O-])Cc1cccs1
Reactant: c1csnn1
Reactant: CS(=O)(=O)OCc1csnn1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)SCc1csnn1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (2 mL) of sodium thiolacetate [prepared from thiolacetic acid (0.38 mL, 5.3 mmol) and sodium bicarbonate (0.445 g, 5.3 mmol)]. The resulting mixture was stirred at 23° C. for 1 h and diluted with ether (75 mL). The organic solution was washed with water (3×3 mL), dried (MgSO4) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4×19 cm) with 50% ether in hexane as eluting solvent to give 0.60 g (75%); ir (film)νmax : 1675 (C=O) cm-1 ; 1Hmr (CDCl3)δ: 2.37 (3H, s, CH3), 4.58 (2H, s, CH2), 8.44 (1H, s, H of thiadiazole). Anal. calcd for C5H6N2OS2 : C 34.47, H 3.47, N 16.08, S 36.80; found: C 34.48, H 3.83, N 16.28, S 36.80.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:36]2[C:37]([C:42]3C=CC=CN=3)=[N:38]OC=2C)C=1)=O.C(N)(C)C>>[CH:37]([NH:38][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:42])[CH3:36]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)no1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)on1
Yield: 88 %

Procedure:
As described for example 14e, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (21 mg, 0.36 mmol), to the title compound (95 mg, 88%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=361.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14].O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.2 mol, 23 ml) was added dropwise to a solution of 4penten-1-ol (0.2 mol, 20 ml) in pyridine and stirred overnight at room temperature. The reaction mixture was poured into 100 mlof water and the organic layer separated. The product mixture was washed, sequentially, with dilute HCl, saturated aqueous Na2CO3, and water. The organic layer was dried over anhydrous Na2CO3 and the product distilled: bp 90°-98° (1.0 mmHg); yield 26.9g, (71%); NMR (neat) δ 1.5 (broad m, 4, alkyl), 3.8 (t, 2, --OCH2 --), 4.6 (m, 2, =CH2), 5.2 (m, 1, =CH--), 7.3 (m, 5, ArH).
Reaction SMILES: [NH2:1][C@H:2]1[C@H](C)[CH2:5][N:4]([C:8](OC(C)(C)C)=O)[CH2:3]1.[CH2:15]=O.[BH-](O[C:27]([CH3:29])=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1COCC1.Cl.O1CCOCC1>[CH3:5][N:4]([CH3:8])[C@H:3]1[C@H:27]([CH3:29])[CH2:15][NH:1][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@@H]1CNC[C@H]1N(C)C
Reaction time: 8 h

Procedure:
A solution of commercially available 1,1-dimethylethyl(trans)-3-amino-4-methyl-1-pyrrolidinecarboxylate (1 g, 5 mmol) and formaldehyde (0.69 mL, 25 mmol, 37% in water) in THF (20 mL) was stirred at room temperature for 1 hour. NaBH(OAc)3 (7.4 g, 35 mmol) was added and the reaction was stirred overnight. 1 M NaOH (20 mL) was added and the layers were allowed to separate. The aqueous phase was extracted with ether and the combined organics were dried over sodium sulfate, filtered and concentrated to yield a crude residue. This material was dissolved in 4 M HCl in dioxane (24 mL) and stirred for 3 hours. Evaporation of the solvent yielded (trans)-N,N,4-trimethyl-3-pyrrolidinamine in quantitative yield. LCMS: (M+H)+: 129.1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1CCCC1=O>O>[C:7]1([C:5]2[S:4][CH:3]=[C:2]([NH2:1])[CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc(-c2ccccc2)c1
Temperature: 160 °C
Yield: 45.3 %

Procedure:
A mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.50 g, 10.7 mmol), 3.5 mL of N-methylpiperazine and 12 mL of N-methylpyrrolidinone is heated at 160° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into 100 mL of water. The solids are collected by filtration washing with 50 mL of water. Ethyl acetate and hexane are added and the filtrate is decanted off from the gummy black residue. The filtrate is concentrated to provide 850 mg of 5-phenyl-3-thienylamine as a yellow solid, mp 76-78° C.; 1H NMR (DMSO-d6) δ 4.87 (s, 2H), 5.98 (d, J=1.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.28 (m, 1H), 7.37 (t, J=7 Hz, 2H), 7.53 (d, J=7 Hz, 2H); MS 176.2 (M+H)+.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19]OS(C)(=O)=O)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].[N-]=[N+]=[N-].[CH:34]12CC(C=C1)C=[CH:35]2>CN(C)C=O.C(OC(=O)C)C.O1CCOCC1>[S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][CH:17]([CH2:19][N:27]4[CH:35]=[CH:34][N:29]=[N:28]4)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cc(F)c(C3=CCSCC3)c(F)c2)C(=O)O1
Reactant: C1=CC2C=CC1C2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1OC(Cn2ccnn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 60 °C
Yield: 30.2 %

Procedure:
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (1.1 g, 5.7 mmol) was dissolved in dry N,N-dimethylformamide (5 ml) and sodium azide (0.35 g, 5.43 mmol) was added. It was heated at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethylacetate, washed with water and dried over magnesium sulfate. Solvent was removed under vacuum to give an oil. The crude intermediate azide was not characterized. It was taken up in 1,4-dioxane (20 ml), bicyclo[2.2.1]hepta-2,5-diene (1.0 g, 10.9 mmol) was added and it was refluxed for 12 hours. Solvent was removed under vacuum and the residue chromatographed on silica gel with 5% methanol in dichloromethane to give the title compound (0.62 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C)C=O>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(OC)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)n(Cc4ccccc4)c4ccccc43)CC2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (50 mg) obtained in Example 1 was dissolved in N,N-dimethylformamide (1 ml), added with sodium hydride (60% in oil, 7.4 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (22 μl) and further stirred at 60° C. for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was washed with water (10 ml) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 33 mg of the title compound. Yield: 57%.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.C[CH:10](OC1C=CC=CC=1)[C:11]([NH:13][C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@H]12)=O>>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH2:10][CH2:11][NH2:13]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(Oc1ccccc1)C(=O)N[C@@H]1C(=O)N2[C@@H]1SC(C)(C)[C@@H]2C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Plasmid pAJ 201 was introduced into Brevibacterium lactofermentum AJ 12019 (NRRL B-15346) (auxotrophy for homoserine) by the transformation method described in (4). The results obtained by examination of lysine productivity with the thus-obtained transformant AJ 12073 (FERM-P 7205) are shown in Table 3. The cultivation was carried out by charging in a shoulder-equipped flask 20 ml of medium containing 10 g/dl of glucose, 5.5 g/dl of ammonium sulfate, 0.1 g/dl of KH2PO4, 0.1 g/dl of MgSO4 . 0.001 g/dl of FeSO4 . 4H2O, 0,001 g/dl of MnSo4 . 4H2 0, 200 μg/l of thiamine hydrochloride, 2.5 mg/dl of nicotinamide, 105 mg/dl of soybean protein hydrolysate (as total nitrogen), and 5 g/dl of calcium carbonate, the pH of which had been adjusted to 8.0, while shaking at 31.5° C. for 72 hours. After completion of the cultivation, lysine in the culture liquid was quantitatively determined with high speed liquid chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.[CH2:16](Cl)[C:17]#[CH:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH2:27][CH2:28]CC>O.CCOCC>[CH2:16]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:28][C:27]#[CH:26])=[O:7])=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: C#CCCl
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(=O)c1ccc(OCC#C)cc1
Reaction time: 72 h

Procedure:
A mixture of 8.0 g. of p-hydroxybenzoic acid, 125 ml. dimethylformamide, 13.0 g. of propargyl chloride and 24.0 g. of anhydrous potassium carbonate is heated at 75° for 32 hours and then is allowed to stand at room temperature for 3 days. Ether (150 ml.), pentane (100 ml.) and water (100 ml.) is added, the organic layer is separated and washed in turn with water (2 × 50 ml.) and saturated aqueous sodium chloride (1 × 50 ml.) and then is dried over calcium sulfate. Solvent is removed by rotary evaporation to yield propargyl 4-propargyloxybenzoate, m.p. 44.5-45.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([N:17]=[C:22]=[O:23])=[CH:15][C:14]=2[Cl:21])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Temperature: 105 °C

Procedure:
2 g (5.8 mmol) of 4-(3-chloro-5-difluoromethoxy-2-pyridyloxy)-3,5-dichloroaniline were dissolved in 25 ml of anhydrous toluene, 2.9 g (29 mmol) of phosgene gas were introduced at 0° C., and the mixture was slowly warmed to 105° C. Excess phosgene was expelled using inert gas, the solvent was concentrated by evaporation, and the residue was dried in a high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1Br.[CH3:17][Si:18]([CH3:35])([CH3:34])/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1/[CH:20]=[CH:19]/[Si:18]([CH3:35])([CH3:34])[CH3:17]
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 57.2 %

Procedure:
Ethyl 6-amino-5-bromo-2-cyclopropylpyrimidine-4-carboxylate (0.5 g, 1.747 mmol, see WO 2005063721 for preparation) and tetrakis (triphenylphosphine) palladium(0) (0.214 g, 0.185 mmol) were added to a 20 mL Biotage microwave reaction vessel. The vessel was sealed and purged with nitrogen gas. (E)-trimethyl(2(tributylstannyl)vinyl)silane (0.96 g, 2.466 mmol) in dioxane (8.74 ml) was added and the reaction mixture was heated at 120° C. for 6 h. The cooled reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto silica. Purification by flash chromatography (SiO2, 0-40% EtOAc:Hex gradient) provided the title compound as a tan solid (0.305 g, 57% yield): mp 99-101° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 9H), 0.85-0.94 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.91 (tt, J=7.0, 5.6 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.03 (d, J=19.1 Hz, 1H), 6.70 (d, J=19.2 Hz, 1H), 7.01 (s, 2H); ESIMS m/z 306 ([M+H]+), 304 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:25][C:26]5[CH2:27][NH:28][CH2:29][CH2:30][C:31]=5[N:32]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:33](=O)[CH3:34].[BH3-]C#N.[Na+].CO.C(OCC)(=O)C>C1COCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:25][C:26]5[CH2:27][N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][C:31]=5[N:32]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC=O
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1nc2c(s1)CNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCc2nc(COc3cc4ncnc(Nc5ccc(Cl)c(Cl)c5)c4cc3OC)sc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.5 %

Procedure:
N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine (0.249 g, 0.510 mmol) was taken up in 50% THF/MeOH (10 mL) and the solution was cooled with an ice bath. Acetaldehyde (0.057 mL, 1.0 mmol), followed by NaCNBH3 (0.038 g, 0.61 mmol) were added. The solution was allowed to warm to room temperature. After 4 h, additional acetaldehyde (0.050 mL, 0.89 mmol) and NaCNBH3 (0.040 g, 0.64 mmol) were added and the solution was stirred for 12 h. An additional 0.050 mL (0.89 mmol) of acetaldehyde and NaCNBH3 (0.020 g, 0.32 mmol) were added. The solution was poured into 10% MeOH/ethyl acetate (100 mL) and washed once with H2O (100 mL). The organic layer was dried (Na2SO4); filtered and the solvent was removed in vacuo. The crude product was purified via preparative HPLC (reverse phase, CH3CN/H2O/NH4OAc/AcOH). The solvents were removed, the product was taken up in MeOH and treated with 4.0M HCl/dioxane (0.025 mL), and lyophilized to provide 0.036 g (12%) of N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([OH:14])[CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:21].[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CCOC(C)=O
Product: Cl
Product: OC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Temperature: 25 °C

Procedure:
Through a solution of N-t-butoxycarbonyl-3-(3,4-dichlorophenyl)-3-hydroxy piperidine (150 mg, 0.44 mmol) in ethyl acetate (5 ml) cooled to 0° C. is bubbled HCl (g) for 5 min. The reaction mixture is stirred at 25° C. until reaction completion. The reaction mixture is concentrated in vacuo and flushed with ethyl acetate/concentrated 3 times to provide 3-(3,4-dichlorophenyl)-3-hydroxy piperidine hydrochloride which is converted without further purification to 3-(3,4-dichlorophenyl)-3-hydroxy piperidine-1-carboxylic acid {4-[(2,2-dimethyl-propionylamino)-methyl]-phenyl}-amide using N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide as described in example 1a.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 18.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.005 g of product in 19% yield: LCMS (ESI) m/z 418 (MH+).