Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[CH2:6][CH2:7][C:8](O)=[O:9].C(O)C.O.C(=O)=O.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][OH:9])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: O=C(O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)hydrocinnamic acid (1.0 g, 3.5 mmol) and TEA (0.46 g, 4.5 mmol) in THF (16 mL) was cooled to −40° C. (ethanol-water/dry ice bath). To this mixture was dropwise added isobutyl chloroformate (0.56 g, 4.1 mmol) and stirring was continued for another 1.5 hours while the temperature of the cooling bath was maintained between −40° C. and −20° C. Solid NaBH4 (0.53 g, 14 mmol) was added, followed by H2O (1.3 mL). The cloudy mixture was stirred overnight while warming to room temperature. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 1 with 37% HCl and extracted with ethyl acetate. The combined organic layers were washed sequentially with saturated NaHCO3, and brine, then dried (MgSO4) and concentrated. The resulting oil was purified by flash silica gel chromatography (6:4 ethyl ether-hexane) to yield 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol.
Reaction SMILES: [O:1]=[C:2]([CH3:12])/[CH:3]=[C:4]1\[CH2:5][N:6]2[CH:9]([O:10]\1)[CH2:8][C:7]2=[O:11].[H-].C([Al+]CC(C)C)C(C)C>C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Na+].O>[OH:1][CH:2]([CH3:12])/[CH:3]=[C:4]1\[CH2:5][N:6]2[CH:9]([O:10]\1)[CH2:8][C:7]2=[O:11]
Reactant: CC(=O)/C=C1\CN2C(=O)CC2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(O)/C=C1\CN2C(=O)CC2O1

Procedure:
(E)-3-(2-Oxopropylidene)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (145 mg., 0.87 mmole) was dissolved in dry benzene (6 ml.) and the solution was stirred and ice-cooled under a dry nitrogen atmosphere while di-iso butyl aluminium hydride (20% solution in toluene, 0.7 ml., 0.98 mmole) was added dropwise. After addition, the mixture was stirred at 0° under dry nitrogen for 4 hours. The mixture was then diluted with ethyl acetate and the solution was shaken with saturated brine. The mixture was filtered, the filtrate was shaken, and the layers were separated. The ethyl acetate layer was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to give a yellow gum. The gum was chromatographed on silica gel (10 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the two diastereomers of the title compound. Both isomers were obtained as colourless oils (3 mg. each) and had identical i.r. spectra. νmax (CHCl3): 3500 and 3360 (alcohol OH), 1790 (β-lactam C=O), 1690 (olefinic C=C) cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:46][C:47]([CH2:49]O)=[O:48].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:46][C:47](=[O:48])[CH3:49])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)CO
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.2 %

Procedure:
A solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), Ph3P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) in THF (25 mL) at room temperature was treated dropwise with a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 205 mg, 48%). mp 169–170° C; 1H NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7.62 (q, J=10 Hz, 1H), 7.75 (m, 1H), 7.94 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 435 (M+H)+, (APCI−) m/z 469 (M+Cl)−; Anal. calc. for C20H16F2N2O5S.0.75H2O: C, 53.62; H, 3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([N:13]3[CH2:18][CH2:17][CH:16]([O:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.NN>C(Cl)Cl>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([N:13]3[CH2:14][CH2:15][CH:16]([O:19][NH2:20])[CH2:17][CH2:18]3)[CH2:11][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
The mixture of 2-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yloxy)isoindoline-1,3-dione (995 mg, 2.08 mmol) and hydrazine monohydrate (0.304 ml, 6.25 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 45/55 to 75/25) to give O-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yl)hydroxylamine (580 mg, 88%) as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc2[nH]ncc2cc1Br
Agent: NC(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2nn(COCC[Si](C)(C)C)cc2cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 5-bromo-6-methyl-indazole (500 mg, 2.37 mmol) in THF (6 mL) was added dicyclohexylmethylamine (0.63 mL, 3.0 mmol), followed by SEM-chloride (0.50 mL, 2.8 mmol) via syringe. The reaction mixture was stirred at room temperature for 3 hours. EtOAc (20 mL) was added followed by 0.5 N aqueous NaOH (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed consecutively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (0-33% EtOAc/heptane) to provide the title compound (639 mg, 79% yield). MS (ES+) 343.1 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 5.70 (s, 2H), 3.62 (t, J=8.10 Hz, 2H), 2.52 (s, 3H), 0.95 (t, J=8.30 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22]([C@H:24]1[C@H:29]2[C@@H:25]1[O:26][C:27]1[CH:33]=[CH:32][C:31]([O:34][Si](C(C)(C)C)(C)C)=[CH:30][C:28]=12)=[O:23])[CH3:20]>C1COCC1>[OH:34][C:31]1[CH:32]=[CH:33][C:27]2[O:26][C@@H:25]3[C@@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[C@@H:29]3[C:28]=2[CH:30]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(O)cc3[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Tetra-n-butylammonium fluoride (TBAF, 1M in THF, 4 mmol) was added dropwise to a solution of the product of Step A (7.3 g, crude) in THF (100 mL) at 0° C. The reaction was stirred at RT for 30 min. The mixture was concentrated and purified by column chromatography to afford the title compound as a solid (2.52 g, 57% for 2 steps, 72% ee).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (319 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 68%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:4][CH2:3]1.O=[C:31]1[CH2:36][O:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH3-]C#N.[Na+]>CO>[C:27]([C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[O:35][CH2:36][CH2:31][NH:32][C:33]=5[N:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:22]=2[CH:23]=1)#[N:28]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc3c(n2)NCCO3)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2R,5S)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 183, 0.14 g), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg) and 3 Å molecular sieves powder (70 mg) in methanol (8 mL) was heated at 80° C. for 1 hour. The solution was cooled to 0° C. and NaCNBH3 (33 mg) was added. After stirring at room temperature overnight, the reaction was filtered and concentrated. The residue was purified chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride to give 0.14 g.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].[OH-]>C1COCC1.O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C(C)c1ccc2c(c1)CCN2S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2c(c1)CCN2S(C)(=O)=O
Reaction time: 12 h
Yield: 80 %

Procedure:
the propanoate (1.78 mmol, 0.53 g) obtained in step b was dissolved in a THF-water mixture (5 ml, 2:1), LiOH (5.34 mmol, 0.128 g) was added and refluxing was carried out for 12 h. The reaction mixture was extracted with diethyl ether (25 ml), the aqueous phase was acidified to pH 2 with 1 N HCl and extraction was carried out with EE (3×25 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in a vacuum. It was possible to obtain 2-(1-(methylsulphonyl)indolin-5-yl)propanoic acid in an 80% yield (0.382 g).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH3:10])[CH2:1][C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(C)CCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Propargyl bromide (26.8 g, 225 mmol) was added dropwise to a mixture of N-(2-methoxyethyl)methyl amine (20 g, 225 mmol) and cesium carbonate (73 g, 225 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 14 g of (2-methoxy-ethyl)-methyl-prop-2-ynyl-amine: mass spectrum (m/e): M+H 127.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[C:9]=3[CH:8]=[CH:7][C:6]2=[O:26])[CH2:3][CH2:2]1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[CH:1]1([CH2:4][N:5]2[C:10]3[N:11]=[C:12]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[C:9]=3[CH:8]=[CH:7][C:6]2=[O:26])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(CC3CC3)c2n1
Reactant: NC(CO)CO
Product: O=c1ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc2n1CC1CC1

Procedure:
The product of Example 50, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.40 (m, 4H), 1.25 (m, 1H), 3.89 (m, 4H), 4.13 (m, 3H), 5.75 (m, 1H), 6.30 (d, 1H, J=9.8 Hz), 6.59 (br s, 1H), 7.08-7.48 (m, 5H). LC MS (m/e)=385 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.ClCCCl.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:6][C:5]=1[OH:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(N)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-amino-2-hydroxy benzoic acid methyl ester (836 mg; 5 mmol) and 4-bromobenzaldehyde (926 mg; 5 mmol) in 1 M HOAc in 1,2-dichloroethane (5 mL) was added at once NaBH(OAc)3 (1.49 g; 7 mmol) and the reaction mixture was stirred at room temperature overnight. Water (25 mL) was added and the inhomogeneous mixture was neutralized using solid NaHCO3. The organic layer was isolated, dried, evaporated to dryness and recrystallised from isopropyl ether/dichloromethane/heptane to yield 970 mg (58%) of a yellow solid. NMR and GC-MS in accordance with structure.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:27]1[CH2:31][CH:30]=[CH:29][CH2:28]1>>[N:27]1([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:31][CH:30]=[CH:29][CH2:28]1
Reactant: CC(C)CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Reactant: C1=CCNC1
Product: CC(C)CC(c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1)N1CC=CC1
Temperature: 60 °C

Procedure:
This compound was prepared from intermediate 229a and 6 equivalents of 3-pyrroline according to the procedure described in Example 171, with the exception of heating to 60° C. Received 83.3 mg (30%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][CH:29]([CH2:33][CH:34]1[CH2:39][O:38][CH2:37][CH2:36][NH:35]1)[C:30]([OH:32])=[O:31]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:34]2[CH2:33][CH:29]([CH3:28])[C:30]([OH:32])=[O:31])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(CC1COCCN1)C(=O)O
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 24.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 2-methyl-3-(morpholin-3-yl)propanoic acid hydrochloride (1.26 g, 6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.89 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([N:9]=[C:10]=S)[N:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:3][C:2]=1[Cl:1]
Reactant: S=C=Nc1ccc(Cl)c(Cl)n1
Reactant: NCC1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ccc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours, cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (1.07 mL, 6.88 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1 H), 7.84 (s, 1 H), 6.80 (s, 1 H), 3.85 (d, J=10.07 Hz, 1 H), 3.57 (d, J=10.38 Hz, 2 H), 2.98 (s, 3 H), 2.69-2.78 (m, 3 H), 2.65 (t, J=7.78 Hz, 3 H), 2.00 (s, 2 H), 1.86 (s, 2 H), 1.58 (dd, J=7.48, 2.90 Hz, 2 H), 1.56 (s, 1 H), 1.41-1.49 (m, 2 H). MS (LC/MS) R.T.=0.81; [M+H]+=327.1.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][CH:15]=[O:16]>O.C(O)(C)(C)C.CC(=CC)C>[CH3:11]/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)/[CH2:13][CH2:14][C:15]([OH:6])=[O:16]
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 l of 2-methyl-2-butene. After 2½ hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxyl)-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24].CC(C)([O-])C.[K+].C(O)(C)(C)C>C(OCC)C.O>[CH2:28]([O:27][C:20](/[C:21](=[C:6](\[C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=1)/[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)/[CH2:22][C:23]([OH:25])=[O:24])=[O:26])[CH3:29]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 20.8 %

Procedure:
341.5 g (1.16 moles) of 4-chloro-4'-methanesulfonylbenzophenone, prepared in example 2, 310 ml (1.85 moles) of ethyl succinate and 195.5 g (1.74 moles) of potassium t-butoxide are successively added to 2.5 liters of t-butanol. The temperature rises to 40°-45° C., the mixture is stirred for 7 hours at room temperature after this exothermic reaction and is then poured into iced water. After acidification to pH 3 with hydrochloric acid, the mixture is extracted with diethyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo. The oil obtained is dissolved in diethyl ether and then left overnight at room temperature. The crystals formed are filtered off and dried to provide 102 g of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonylphenyl)but-3-enoic acid as crystals with a melting point of 184°-186° C. after recrystallization from isopropanol. The evaporation of the filtrate allows the recovery of 219 g of a mixture consisting of 82% of the (E)-isomer and 18% of the (Z)-isomer.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:16]2[O:15][CH2:14][O:13][CH2:12][C:11]=2[CH:10]=[C:9]([C@H:17]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[NH:36])=[CH:33][CH:32]=2)[C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3N=[CH:28][CH:27]=[CH:26][N:25]=3)[N:19]=2)[CH:8]=1.Cl.Cl.N([C:44]1C=CC=CN=1)N>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:16]2[O:15][CH2:14][O:13][CH2:12][C:11]=2[CH:10]=[C:9]([C@H:17]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[NH:36])=[CH:33][CH:32]=2)[C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[CH:44]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:19]=2)[CH:8]=1
Reactant: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Reactant: NNc1ccccn1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccn3)c(=O)[nH]2)cc2c1OCOC2

Procedure:
The same procedure was carried out as in Examples (21i) to (21k), except that 2-hydrazinopyridine dihydrochloride was used instead of 2-hydrazinopyrimidine in Example (21i), to give the first eluting enantiomer of the title compound.