Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(OC)=O.[Cl:7][CH2:8][CH2:9][CH2:10][CH:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])[C:12]([NH2:14])=O.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:23])[F:24])[C:12]#[N:14]
Reactant: NC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Agent: COP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N#CC(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.6 %

Procedure:
Methyl dichlorophosphate (1.9 mL) was added dropwise at 20° C. or less to an ice-cooled solution of 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoic acid amide (3.0 g) and 1,8-diazabicyclo[5,4,0]undec-7-ene (6.4 mL) in methylene chloride (30 mL). After completion of the dropwise addition, the reaction solution was stirred at room temperature for one hour and 25 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction solution. After stirring for five minutes, the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent:heptane:ethyl acetate=49:1→19:1) to obtain 2.25 g of the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:17])=[CH:6][C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:8][CH:9]=1)[CH3:2].[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=O>C(O)CCCC>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([C:18]2[N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[CH:8][C:7]([S:10]([C:13]([F:16])([F:14])[F:15])(=[O:11])=[O:12])=[CH:6][C:5]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCCCCO
Product: CCn1c(-c2ccc(C(=O)OC)cc2)nc2cc(S(=O)(=O)C(F)(F)F)ccc21

Procedure:
N1-Ethyl-4-trifluoromethanesulfonyl-benzene-1,2-diamine (134 mg, 0.50 mmol) and methyl 4-formylbenzoate (82 mg, 1.1 equiv) were dissolved in 0.8 mL dry pentanol and heated to reflux for 18 h. The reaction mixture was then evaporated to one-third volume by blowing with a stream of nitrogen while heating. Upon cooling, the solids were collected and washed with ether to yield 155 mg upon drying. The solids may be recrystallized from EtOAc/ether to yield pure ester 35: 1HNMR (400 MHz, d6-DMSO) δ 8.48 (d, J=1.65 Hz, 1H), 8.19 (m, 3H), 8.01 (m, 3H), 4.45 (q, J=7.24 Hz, 2H), 3.92 (s, 3H), 1.36 (t, J=7.22 Hz, 3H); LCMS-APCI in/z 413 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].C1(C)C=CC=CC=1.[CH3:28][OH:29]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:29][CH3:28])=[O:10]
Reactant: CO
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1

Procedure:
1 g (0.00326 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was added to 2 mL toluene at 0° C. along with stirring, followed by dropwise addition of 1 mL titanium tetrachloride, and the reaction was stirred at 0° C. for 1 hour. Later 18 mL of methanol was added, and then the reaction was stirred for 36 hour at 29° C. and later reflux for 3 hrs. The solvent was distilled under reduced pressure and the residue was added to aq. sodium carbonate at 0° C. the product was extracted with 20 mL ethyl acetate, and the organic layer was isolated, dried over anhy. Na2SO4, concentrated and purified by column chromatography using hexane:ethyl acetate as eluent. The product obtained was stored under nitrogen atmosphere and kept in refrigerator before converting into salt. The yield of titled product was 0.157 g (12-15%).
Reaction SMILES: Cl.[C:2]1([P:8]2(=[O:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[O:14]=[P:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Reactant: O=P1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCN2CCP(=O)(c3ccccc3)CC2)cc1

Procedure:
4-Phenyl-1,4-azaphosphinane 4-oxide hydrochloride (200 mg, 0.863 mmol), tert-butyl 4-(2-bromoethyl)benzoate (246 mg, 0.863 mmol), and K2CO3 (358 mg, 2.59 mmol) were combined in MeCN (10 mL) and stirred at reflux overnight. The reaction was cooled, diluted with EtOAc, washed with water and brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded the title compound as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.88 (d, J=8.4 Hz, 2H), 7.76-7.71 (m, 2H), 7.54-7.45 (m, 3H), 7.21 (d, J=8.2 Hz, 2H), 3.09-2.99 (m, 4H), 2.85-2.80 (m, 2H), 2.77-2.73 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.98 (m, 2H), 1.55 (s, 9H). MS: cal'd 400 (MH+), exp 400 (MH+).
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[Cl:30]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:30][C:22]1[CH:23]=[C:24]([N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:10]([CH3:13])[CH2:11][OH:12])[CH:25]=[CH:26][C:21]=1[F:20]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(CO)NC(C)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CO)N(c1ccc(F)c(Cl)c1)C(C)c1ccccc1
Reaction time: 24 h

Procedure:
2-[(1-phenylethyl)amino]propan-1-ol (5-5, 0.027 g, 0.151 mmol) in CH2Cl2 (1.0 mL) was treated with Cu(OAc)2 (0.041 g, 0.227 mmol), pyridine (0.024 mL, 0.302 mmol), and 4-fluoro-3-chloro-phenylboronic acid (0.026 g, 0.149 mmol). 4 A MS (20 mg) were added and the resulting solution stirred 24 h. Upon completion, the reaction mixture was filtered and the filtrate was purified by reverse phase liquid chromatography (Semi-prep YMC C-18 Column 5% CH3CN/H2O up to 95% CH3CN/H2O) to give 2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol (5-6) as a brown oil. MS 308.3 found 308.8 (M+H+) required.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[Cl:40])(=[O:49])=[O:48])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C(O)c1ccc(NCCc2c(CCNS(=O)(=O)c3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 21 %

Procedure:
The intermediate from example 143 step 12 was treated with 2-chloro-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 21% yield.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22](O)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([Cl:29])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a nitrogen purged 3 liter 4-neck flask fitted with a condenser, mechanical stirrer, temperature probe, and connected to a 2M aqueous NaOH scrubber was added toluene (1 L), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (250 g, 0.94 mol, 1 equiv), and DMF (5 mL). 4′-Trifluoromethyl-biphenyl-2-carboxylic acid can be obtained from Aldrich, Milwaukee, Wis. The solution was heated to 60° C. and thionyl chloride (110 mL, 1.5 mol, 1.6 equiv) was added at such a rate as to maintain the temperature below 65° C. The addition was complete after 30 minutes and the reaction was heated to reflux. After 4 hours, the heating was stopped and the reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was used in the next step without further purification. The material crystallized to a solid at room temperature.
Reaction SMILES: [CH3:1][C:2]([C:4]1C=CC=[C:6](Cl)[CH:5]=1)=[O:3].O.[C:12](O)(=O)[CH:13]=O.[CH2:17](OCC)C>C(Cl)Cl.CO>[CH:13]([O:3][CH:2]([CH3:1])[CH3:4])([CH3:12])[CH3:17].[CH3:1][CH2:2][CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CCCCC
Temperature: 60 °C

Procedure:
A well stirred mixture of 3-chloroacetophenone (18.9 g, 0.1 mol) and glyoxylic acid monohydrate (9.2 g, 0.1 mol) was heated at 60° C. under vacuum (25 mmHg), over 16 hours. The residue was taken up with diethyl ether and the organic phase was extracted with saturated NaHCO3 solution, the combined aqueous layers were whased with ether, cooled at 0° C. and the pH of the solution was adjusted to 2 by addition of 37% HCl. The resulting suspension was extracted with ethyl acetate, and the combined organic extracts washed with water, drided (Na2SO4) and concentrated in vacuo to provide the crude product. Column chromatography (SiO2; CH2Cl2/MeOH 95:5) afforded the pure titled compound as colorless needles, mp.98-100° C. (Diisopropyl ether/pentane).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.BrN1C(=O)CCC1=O.[N-:29]=[N+:30]=[N-:31].[Na+].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[N:29]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(-c2cccc(C(=O)OC(C)(C)C)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(-c2cccc(N=[N+]=[N-])c2)c1
Temperature: 80 °C
Yield: 89.1 %

Procedure:
Compound 19 (2.18 g, 8.13 mmol) and N-bromosuccinimide (1.70 g, 9.50 mmol) was suspended in 60 mL of CCl4. Dibenzoyl peroxide (20 mg) was added and the mixture was refluxed for 1.5 hr. After removing the solid, the filtrate was washed with concentrated sodium bicarbonate and dried over sodium sulfate. 1H NMR showed the crude material contained 70% of monobrominated and 30% of dibrominated product. This material was dissolved in 20 mL of DMSO and sodium azide (3.70 g, 57 mmol) was added. The mixture was heated to 80° C. for 4 hr before being poured into a mixture of methylene chloride and water. The organic layer was dried and evaporated. The residue was purified by flash column chromatography (5% of ethyl acetate in hexane) to give 20 (2.14 g, 78%, two steps) as colorless oil. 1H NMR (CDCl3) δ 8.22 (s, 1H), 8.00 (d, 7.7 Hz, 1H), 7.76 (d, 8.2 Hz, 1H), 7.58 (m, 2H), 7.50 (m, 2H), 7.33 (d, 7.6 Hz, 1H), 4.43 (s, 2H), 1.62 (s, 9H). 13C NMR (CDCl3) δ 165.2, 140.5, 140.3, 135.8, 132.3, 130.7, 129.1, 128.5, 128.2, 127.8, 127.1, 126.7, 126.6, 80.9, 54.3, 27.8.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:13][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2occc2c1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Benzofuran-5-carbaldehyde (315 mg, 2.16 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (0.86 mL of 33% solution in ethanol, 6.91 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a brown oil and then dissolved in anhydrous methanol (10 mL). Sodium borohydride (83.2 mg, 2.20 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 mL) was added and the solution was concentrated. Sodium hydroxide (10 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over MgSO4, filtered and concentrated to afford benzofuran-5-yl-N-methylmethanamine (316 mg, 91%) as a light brown oil: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.56 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 3.70 (s, 2H), 3.17 (s, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][NH:9][C@H:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]([C@H:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
Acetic anhydride (66 μl, 0.70 mmol) was added drop wise to a solution of 5-{[(2R)-2-(methylamino)propyl]oxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (250 mg, 0.58 mmol, obtained as described in Example 115, preparation of starting materials) and potassium carbonate (161 mg, 1.16 mmol) in acetone (10 ml). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvents, the residue was diluted in DCM. The solution washed with aqueous sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 5% 7N ammonia-methanol in DCM) to give the title compound (230 mg, 84%); NMR Spectrum: (CDCl3) 1.28 (d, 3H), 1.94 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.90 (s, 3H), 4.30-4.10 (m, 2H), 5.38 (m, 1H), 6.92 (m, 2H), 7.08 (d, 1H), 7.14 (dd, 1H), 7.48 (d, 2H), 7.53 (s, 1H), 7.64 (t, 1H), 8.27 (d, 1H), 8.60 (s, 1H), 9.51 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=C=O.[CH2:28]([N:30]1[C:42]2[CH:41]=[CH:40][C:39]([NH2:43])=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29]>>[CH2:28]([N:30]1[C:42]2[CH:41]=[CH:40][C:39]([NH:43][C:10]([C@@H:9]3[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]3[C:6]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[O:7])=[O:12])=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: COc1cccc(N=C=O)c1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2cccc(OC)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=469.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15](Br)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li:18]CCCC.[C:23](=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:23]([O-:25])=[O:24])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+:18]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Reactant: O=C=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(C(=O)[O-])sc2C1
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolved 2-bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (650 mg, 2.036) in dry THF and the mixture was cooled to −78° C. To this was added n-BuLi in a dropwise fashion. The mixture was stirred for 30 min at 4° C. and then was re-cooled to −78° C. and solid CO2 was added in one portion. The mixture was warmed to room temperature, stirred for 1 h and was concentrated to give 132.5 mg of lithium 5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9](C2C=CC(Cl)=CC=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36].Cl[CH2:42][Cl:43]>>[Cl:43][C:42]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[C@:3]1([CH2:2][N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH2:11]2)=[CH:5][CH2:4]1
Reactant: CCCNCCC
Reactant: ClCCl
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Product: CCCN(CCC)C[C@@]1(c2ccccc2Cl)C=CC(CN2CC(=C(c3cc(F)cc(F)c3)S(C)(=O)=O)C2)=CC1

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.020 g of di-n-propylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of 1-{(R*)-(4-(chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 0.85 (t, J=7 Hz, 6H) 1.45 (mt, 4H), 2.34 (t, J=7.50SHz, 4H), 2.80 (s, 3H), 3.48 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].C(OCC)(=O)C>CN(C)C=O.C(OC(C)C)(C)C>[C:23]1(=[O:33])[N:27]([CH2:2][CH:3]2[CH2:8][N:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][N:4]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A suspension of 15 g (47.6 mmol) of 2-chloromethyl-1,4-diphenylmethyl piperazine and 8.81 g (47.6 mmol) of potassium phtalimide in 7 ml anhydrous dimethyl formamide was stirred 2 hours at 110° C. After cooling the reaction mixture was taken up with 100 ml ethyl acetate. The mineral salts were filtered off. The solvent was removed, the residue was dissolved in 150 ml ethyl acetate, washed three times with water, dried over magnesium sulfate to give a srystalline product which was resrystallized in isopropyl ether to yield 6.67 g (33%) of title compound. M.P. 124° C.
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cn2c(n1)CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CCCC2
Yield: 70.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (2.58 mmol, 428 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.717 mmol, 479 mg). DMF (10 ml) was used as the solvent. The reaction mixture was diluted with water and extracted three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated. The crude product was purified by flash chromatography. 515 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 1.78-1.94 (m, 4H), 2.76 (t, 2H), 3.95 (t, 2H), 4.24-4.31 (m, 1H), 4.33-4.46 (m, 2H), 7.01 (d, 1H), 7.43 (s, 1H), 7.84 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.08 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26](C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[Cl:40]CCl.Cl>C(OCC)C>[ClH:40].[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 44 mg, 0.08 mmol), methanol (0.1 ml), dichloromethane (0.6 ml) and 1M HCl in diethyl ether (1 ml) was kept at room temperature for 3 weeks. The mixture was concentrated to give the title compound as a white solid.