Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:3]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]([Br:1])=[CH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: Cn1c(Cc2ccccc2)nccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(Cc2ccccc2)ncc(Br)c1=O
Reaction time: 0.5 h

Procedure:
Br2 (2.62 mL, 52 mmol) was added to 2-benzyl-3-methyl-3H-pyrimidin-4-one (Step 2, 9.3 g, 47 mmol) in CHCl3 (100 mL) and sat NaHCO3 (100 mL). After 30 min, the organic layer was separated, dried (Na2SO4) and filtered through a plug of silica. The filtrate was concentrated under reduced pressure, and azeotroped with CHCl3 (2×). The crude compound was dried under high vacuum for 16 h to provide the title compound. MS (ESI pos. ion) m/z: 279.0, 281.1. Calc'd for C12H11BrN2O: 278.01.
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=CC=C[CH:19]=2)=[O:15])[CH2:13][CH2:12]C[C@H:2]1[C:3](N[C@H](C(O)=O)C)=[O:4].C(Cl)[Cl:25]>>[CH2:17]([O:16][C:14]([Cl:25])=[O:15])[CH:18]([CH3:23])[CH3:19].[CH3:14][N:1]1[CH2:2][CH2:3][O:4][CH2:12][CH2:13]1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reactant: ClCCl
Product: CC(C)COC(=O)Cl
Product: CN1CCOCC1

Procedure:
A suspension of 1.600 g (5.0 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in 80 ml of dry methylene chloride (CH2Cl2) was brought in an argon atmosphere to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in quick succession: 0.670 ml (5.13 mmoles) of isobutylchloroformate (IBCF) and 0.570 ml (5.17 mmoles) of 4-methylmorpholine (NMM), leaving the system under stirring for approximately 2 minutes.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56](Br)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(=O)([O-])[O-].[K+].[K+].C(COC)OC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C:26]3[S:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[CH:6]=[O:5])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)=[CH:28][CH:27]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C=O)[nH]5)cc4)s3)cc2[nH]1
Temperature: 110 °C
Yield: 66.2 %

Procedure:
A mixture of 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh3)4 (0.012 g) in 2.0M potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at 110° C. for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.085 g) as a bis-TFA salt: LCMS-ESI+: calc'd for C38H45N6O4S: 681.86 (M+H+); Found: 681.0 (M+H+).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:34]=[CH:33][C:32](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27].C(NCC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:30]=[CH:31][C:32]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:33][CH:34]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.082 g, 0.27 mol), diethyl amine (2 mol), copper(I)iodide (0.020 g, 0.1 mol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound was obtained as a brown oil (0.040 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](CC)[C:5]2(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.N[OH:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:24])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 85 %

Procedure:
A stirred mixture of 12.11 g (0.04 mole) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)quinazolinone and 8.34 g (0.12 mole) of hydroxylamine hydrochloride in 200 ml ethanol was refluxed for 3 days and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried to give 9.27 g (85%) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, mp 267°-269°.
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=4[F:42])=[O:30])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1.ClCCCl.[CH3:48][N:49]=[C:50]=[O:51]>O1CCCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=4[F:42])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:50]([NH:49][CH3:48])=[O:51])[CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: CN=C=O
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Agent: N#N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)N1CCC(c2c(COC)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL). Tetrahydrofuran was added dropwise until the reaction mixture was a complete solution. The solution was cooled to 0° C. and methyl isocyanate (5.2 μl, 1 eq) is added. The reaction mixture was allowed to gradually warm to rt over 17 hours. The reaction was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and purified via flash column chromatography (tetrahydrofuran). The purified fractions were collected, concentrated, stirred in hexanes and filtered. The filtrate was placed under vacuum overnight to yield the title compound (18 mg, 32.8% yield). 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.29 (t, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.2 (dd, J=12.1, 1.9 Hz, 1H), 7.1 (dd, J=8.5, 1.4 Hz, 1H), 4.22 (s, 2H), 4.06 (m, 2H), 3.42 (m, 1H), 3.15 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.57 (d, J=4.3 Hz, 3H) 2.17 (m, 2H), 1.59 (m, 2H); MS [M+H]+=633; LCMS RT=2.97 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCCCCC.C([Li])CCC.C(OC([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=O)(C)(C)C.[OH-].[Na+]>C(OCC)C.O>[F:12][C:4]1[CH:3]=[C:2]([C:34]2([OH:37])[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2cc(F)cc(C(F)(F)F)c2)CCNCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
5-Bromo-3-fluorobenzo trifluoride (APOLLO Co., 9.0 g) was dissolved in diethyl ether (110 ml), and the mixture was cooled to −78° C. An n-butyllithium hexane solution (2.71 M, 17.5 ml) was added to this solution, and the mixture was stirred at −78° C. for 1 hr. Then, 1-(tert-butoxycarbonyl)-4-piperidone (6.71 g) was added. The reaction temperature was then warmed to 0° C., and the mixture was further stirred for 1 hr. After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in 1,4-dioxane (150 ml), and 10% aqueous sulfuric acid (10 ml) was added thereto. The mixture was stirred with heating at 70° C. for 2 hr. After completion of the reaction, the reaction system was basified (pH=9) with an 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[3-fluoro-5-(trifluoromethyl)phenyl]piperidin-4-ol (9.89 g, yield 56%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O-:5].[Na+].[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:8][CH:9]=[CH:10][CH3:11]>C(O)CCC>[CH2:4]([O:5][CH:9]([CH2:10][CH3:11])[CH2:8][C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:3][CH2:2][CH3:1]
Reactant: CCCC[O-]
Reactant: CC=CCC(=O)OCCCC
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)CC(CC)OCCCC
Temperature: 65 °C
Reaction time: 6 h
Yield: 825.7 %

Procedure:
A solution of 4.8 g of sodium butylate in 74 g of n-butanol was added to 156 g of n-butyl 3-pentenoate at room temperature, and the mixture was heated to 65° C. and stirred at this temperature for 6 hours. The reaction mixture was cooled, n-butanol was distilled off, the residue was extracted by shaking with 25 ml of water, and the organic phase was dried over Na2SO4. Fractional distillation gave 95 g (41% of theory) of n-butyl 3-n-butoxyvalerate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:24][C:21]([NH:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:22])[CH3:23]
Reactant: CC(C)(C)Nc1cccnc1N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Nc1cccnc1N1CCNCC1

Procedure:
1- Benzyl-4-[3-(1,1-dimethylethylamino)pyridyl]piperazine (PREPARATION 96, 4.25 g, 13.10 mmol) is dissolved in 100 ml ethanol. Palladium (10% on carbon, 1.0 g) is added and the solution hydrogenated at 40 psi hydrogen gas. The mixture is filtered and concentrated to give the title compound, NMR (300 MHz, CD3OD) 7.53, 7.19, 6.93, 2.95, 1.39 δ.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.ClCCl>[Cl:25][CH2:26][C:27]([NH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:28]
Reactant: CCc1cc(-c2ccc(CN)s2)c(C)[nH]c1=O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(-c2ccc(CNC(=O)CCl)s2)c(C)[nH]c1=O
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][CH2:17][CH:18]1[CH2:20][CH2:19]1>CC(O)C>[BrH:16].[CH:18]1([CH2:17][N:6]2[C:5]3[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=3[S:3][C:2]2=[NH:1])[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CC(C)O
Product: Br
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CC1CC1
Temperature: 20 °C
Yield: 8.1 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and bromomethylcyclopropane (12.7 g) in 2-propanol (30 cc). The mixture is heated for 42 hours to boiling. After cooling of the reaction medium to a temperature in the region of 20° C., the precipitate is filtered off and recrystallized in a boiling mixture (30 cc) of ethyl acetate and methanol (80:20 by volume). 3-Cyclopropylmethyl-2-imino-6-trifluoromethoxybenzothiazoline hydrobromide (1.2 g), m.p. 220° C., is obtained.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]2)=[O:7])[CH2:5]CC[CH2:2]1.[CH2:27](N(CC)CC)C.C(Cl)(=O)C(C)(C)C>ClCCl>[CH3:2][C:1]([CH3:5])([CH3:27])[C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)=[O:7]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C2CCCC2)C1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.0 g (18.99 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(methoxy)phenyl]piperidine-3-carboxylate were dissolved in 50 ml of dichloromethane, and 2.88 g (28.48 mmol) of triethylamine were added at 0° C. 3.00 g (24.68 mmol) of pivaloyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[C:9]1([CH2:15][CH2:16][NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18]=O>O1CCOCC1>[CH2:16]([NH:17][CH2:18][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3])[CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: C=O
Reactant: CC(=O)c1ccsc1
Solvent: C1COCCO1
Product: O=C(CCNCCc1ccccc1)c1ccsc1

Procedure:
3-acetylthiophene (126 mg), phenylethyl amine (121 mg), and paraformaldehyde (40 mg) were reacted in dioxane (0.2 ml) at 130° C. for 2 hours.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:10]=1[O:11][CH2:12][CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1.[F:23][CH:24]([F:35])[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([F:33])[N:27]([CH3:34])[N:26]=1.O>ClCCl>[CH:15]1([N:14]([CH2:13][CH2:12][O:11][C:10]2[C:9]([Cl:8])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])[C:30]([C:29]2[C:25]([CH:24]([F:35])[F:23])=[N:26][N:27]([CH3:34])[C:28]=2[F:33])=[O:31])[CH2:16][CH2:17]1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: Clc1cccc(Cl)c1OCCNC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1nc(C(F)F)c(C(=O)N(CCOc2c(Cl)cccc2Cl)C2CC2)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
In a 13 ml Chemspeed™ vial is weighted 73 mg (0.726 mmol) of triethylamine. Then 3 ml of a 0.23 molar solution of N-[2-(2,6-dichlorophenoxy)ethyl]cyclopropanamine (0.594 mmole) in dichloromethane is added followed by 3 ml of a 0.26 molar solution of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.66 mmole) in dichloromethane and stirred at ambient temperature for 15 hrs. 1 ml of water is then added and the mixture is deposited on a basic alumina cartridge (2 g) and eluted twice by 8 ml of dichloromethane. The solvents are removed to yield 183 mg (64%) of pure N-cyclopropyl-N-[2-(2,6-dichlorophenoxy)ethyl]-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as an oil (M+H=422).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C([O:19][C:20]([C:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[CH:30][C:25]=2[O:24][N:23]=1)=O)C>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([C:22]2[C:26]3[CH:27]=[CH:28][C:29]([O:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:30][C:25]=3[O:24][N:23]=2)=[O:19])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1noc2cc(Oc3ccncn3)ccc12
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1noc2cc(Oc3ccncn3)ccc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 46 μl (0.35 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 6 ml toluene and cooled to 10° C. Then 550 μl Me3Al (2 M in toluene; 1.1 mMol) are added via syringe. After 1 h at rt, a solution of 101 mg (0.35 mMol) 6-(pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 1.25 ml THF is added and the reaction mixture stirred for 25 min in an oil bath at 110° C. Work up as described in step 1.2 gives the title compound: MS: [M−1]=419; Anal.: C,H,N,F.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][CH:11]([N:13](CC3C=CC=C(Cl)N=3)[SH:14](=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.N(C(OCC)=O)=N[C:34](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:63][C:64]1C=C[C:67]([CH:70](C2C=CC(Cl)=CC=2)[N:71]2CC(O)C2)=[CH:66][CH:65]=1.ClC1N=C(CNS(=O)=O)C=CC=1>O1CCCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][CH:11]([N:13]([C:70]3[CH:67]=[CH:66][CH:65]=[C:64]([Cl:63])[N:71]=3)[S:14]([CH3:34])(=[O:15])=[O:16])[CH2:12]2)=[CH:30][CH:29]=1
Reactant: O=[SH](=O)N(Cc1cccc(Cl)n1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=[SH](=O)NCc1cccc(Cl)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(c1cccc(Cl)n1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
N-{1-[Bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 2.4 cm3 of diethyl azodicarboxylate and 1.44 g of triphenylphosphine are added, under argon, to a solution of 1.54 g of 1-[bis(4-chlorophenyl)methyl]-azetidin-3-ol and 1.22 g of N-(6-chloropyrid-2-yl)methylsulfonamide in 120 cm3 of anhydrous tetrahydrofuran. After stirring for 20 hours at 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 30 cm, diameter 4.5 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 60-cm3 fractions. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.75 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl)-methylsulfonamide are obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 2.85 to 3.00 (mt: 2H); 2.91 (s: 3H); 3.57 (split t, J=7 and 2 Hz: 2H); 4.25 (s: 1H); 4.64 (mt: 1H); from 7.20 to 7.35 (mt: 9H); 7.36 (dd, J=8 and 1 Hz: 1H); 7.71 (t, J=8 Hz: 1H)].
Reaction SMILES: C1C=CC([C@@H](N)C(O)=O)=CC=1.[CH3:12][C:13]1([CH3:36])[S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([C@H:24]([NH2:32])[C:25]3[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:33]([OH:35])=[O:34].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O>>[CH3:36][C:13]1[CH2:12][S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([C@H:24]([NH2:32])[C:25]3[CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C:14]=1[C:33]([OH:35])=[O:34]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: N[C@@H](C(=O)O)c1ccccc1
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)C3=CCC=CC3)[C@H]2SC1

Procedure:
As an example, D-(-)-(4-hydroxyphenyl)-glycine and D-(-)-phenylglycine are key intermediates in the industrial synthesis of amoxycillin and ampicillin respectively; while D-(-)-2-amino-2-(1,4-cylcohexadien-1-yl)acetic acid may conveniently be employed in the acylation of 7-amino-cephalosporanic acid to give cefradin.