Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a solution of trans 3-azido-2-carbo-t-butoxymethoxy-1,2,3,4-tetrahydronaphthalene (750 mg, 2.47 mmol) in methanol (10 mL) at room temperature was added 20% palladium on carbon (60 mg). The resulting mixture was stirred under a hydrogen balloon. After 16 h, the reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated under vacuum to obtain the title compound (730 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.04-7.17 (m, 4H), 4.25 (d, J=16.7 Hz, 1H), 4.11 (d, J=16.7 Hz, 1H), 4.68 (m, 1H), 3.32-3.47 (m, 2H), 3.25 (dd, J=6.7, 16.5 Hz, 1H), 3.02 (m, 1H), 2.85 (dd, J=10.7, 16.5 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=1.CCO>O>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:2]([CH3:6])=[C:3]([CH3:4])[N:7]=2)[CH:10]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(=O)C(C)Br
Solvent: CCO
Solvent: O
Product: Cc1nc2ccc(I)cn2c1C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
To a mixture of 3-bromobutan-2-one (1.0 g) and 2-amino-5-iodopyridine (800 mg) was added EtOH (25 ml), and the mixture was heated at 70° C. for 30 h. The reaction mixture was cooled, diluted with water, and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (250 mg) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-tert-butyl-benzenesulfonamide [CAS 608523-94-0] according to general procedure II. Light yellow solid. MS (ISP) 566.2 [(M−H−]; mp 228° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH2:19][CH2:18][CH2:17]4)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:19]1[C:20]2[C:16](=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCC4)CC2)nc1Cl
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCC5)CC3)ccc2C)cn1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxamide (0.132 g, 0.4030 mmol), 6-methoxypyridin-3-ylboronic acid (0.092 g, 0.6045 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.046 g, 0.04030 mmol) in 1,2-dimethoxyethane (4.4 mL), 2 M Na2CO3 (600 μL) was added. The reaction mixture was stirred and heated at 80° C. for 22 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (0.150 g, 93.17%). ESI-MS m/z calc. 399.48, found 400.5 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:37])[C:18]([C:20]1[O:21][C:22]3[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=3[C:24]=1[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])=[CH:7]2.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:40][N:39]=[N:38][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:37])[C:18]([C:20]1[O:21][C:22]3[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=3[C:24]=1[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 3-phenylethyl-benzofuran-2-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.29 g, 4.15 mmol), prepared in the previous step, sodium azide (808 mg, 12.4 mmol) and ammonium chloride (668 mg, 12.5 mmol) in 50 mL of DMF was stirred under nitrogen at 100° C. for 5 h. By TLC starting material remained. An additional 801 mg (12.3 mmol) of sodium azide was added and the reaction stirred at 100° C. overnight. The reaction was diluted with 50 mL of water, made basic by the addition of 1 N NaOH and extracted three times with ethyl acetate. The aqueous layer was acidified with 1 N HCl. An oil precipitated. The aqueous layer was decanted and the oil partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a light brown solid, mp 56-59° C.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.Cl.[CH:39]12[O:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][NH2+:41][CH2:40]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:41]4[CH2:40][CH:39]5[O:46][CH:43]([CH2:44][CH2:45]5)[CH2:42]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CC2C[NH2+]CC1O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CC4CCC(C3)O4)CC2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.9 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol), 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (209 mg, 1.40 mmol), and DIPEA (0.49 mL, 2.80 mmol) in 1,4-dioxane was stirred at room temperature for 2.5 days. Additional 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (84 mg, 0.561 mmol) was added and the mixture refluxed for 1 hr. The solvent was removed under vacuum, and the residue was diluted with water. The resulting precipitate was dissolved in CH2Cl2 and dried (Na2SO4). The solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexanes gave 3-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane (118 mg, 87%): mp 219-221° C.; 1H NMR (CDCl3) δ 7.85 (dd, J=8.4, 0.5 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.07 (dd, J=8.1, 6.3 Hz, 2H), 2.79 (dd, J=8.1, 6.3 Hz, 2H), 2.55 (d, J=10.6 Hz, 2H), 2.38 (dd, J=10.9, 2.0 Hz, 2H), 1.83 (m, 4H); Anal. Calcd. for C28H37F2N9O5S: C, 51.8; H, 5.7; N, 19.4. Found: C, 51.8; H, 5.9; N, 19.3%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)(=[O:33])=[O:13]
Reactant: O=C(O)c1ccc(CCc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(CCc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)phenethyl)benzoic acid.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][S+](C)C)=[O:6])[CH3:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1>C(#N)C>[CH2:2]([O:4][C:5]([CH:7]1[CH:26]2[CH:25]1[CH2:24][CH2:23][C:22]2=[O:27])=[O:6])[CH3:3]
Reactant: CCOC(=O)C[S+](C)C
Reactant: O=C1C=CCC1
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1C2CCC(=O)C21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a suspension of (ethoxycarbonylmethyl)dimethylsulfonium bromide (148.5 g, 0.648 mole) in acetonitrile (1170 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (97 ml, 0.648 mole) at 22° C. and stirring was continued for 45 min. The solution was treated with 2-cyclopenten-1-one (63 ml, 0.778 mole) and stirring was continued at 22° C. and light exclusion for 4 d. The mixture was evaporated to a volume of ca. 500 ml, partitioned between 1N aqueous HCl and diethylether, the organic layer was dried, evaporated and purified over silica (150 g) using cyclohexane/AcOEt (9:1). The material was dissolved in diethylether (50 ml) and n-pentane (50 ml), briefly cooled to −78° C. until the material precipitated, filtered and the residue was dried to give the title compound as white crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[CH:16]=[C:15]([CH2:17][CH2:18][Cl:19])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[OH:20].C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[CH2:35][C:36](Cl)=[O:37].C(Cl)(=O)C(Cl)=O>O.[OH-].[Na+].CO.C(O)C>[Cl:19][CH2:18][CH2:17][C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([CH:16]=1)[C@@H:7]1[O:8][C@H:4]([CH2:3][NH:2][C:36](=[O:37])[CH2:35][C:29]2[C:28]([Cl:27])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:34])[C@@H:5]([OH:20])[CH2:6]1
Reactant: NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: O=C(Cc1c(Cl)cccc1Cl)NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O

Procedure:
0.32 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride were dissolved in a mixture of 5 ml of water and 2.5 ml of 1M sodium hydroxide solution. The mixture was shaken vigorously for 25 minutes with a benzene solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 0.22 g of the acid by treatment with oxalyl chloride). The resulting solid was removed by filtration and washed with water and then with diethyl ether to give 0.29 g of crude product of melting point 248°-249° C. (decomposition). 0.1 g of this solid was stirred successively for 1 hour each time with 1 ml of water, 2 ml of ethanol and 2 ml of methanol to give 0.03 g of 5-(2-chloroethyl)-5'-[2-(2,6-dichlorophenyl)-acetamido]-2',5'-dideoxyuridine of melting point 253°-254° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:19][C@H:20]1[O:22][CH2:21]1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:19][CH:20]2[CH2:21][O:22]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CO1

Procedure:
To a mixture of 25.2 g (0.145 mole) of 2-bromo-3-pyridinol and 30 g (0.22 mole) of potassium carbonate in 80 mL of N,N-dimethylformamide was added 30 g (0.13 mole) of (S)-glycidyl tosylate. The mixture was heated under nitrogen at 55–60° C. for 15 hours. The solvent was then removed in vacuum and replaced with 500 mL of methylene chloride, and the solution was washed with 500 mL of water and with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 17 g of the (S)-enantiomer of the title compound as a white solid. 1H-NMR (CDCl3): multiplet 8.01 δ (1H); multiplet 7.22 δ (2H); doublet of doublets 4.38 δ (1H); multiplet 4.04 δ (1H); multiplet 3.40 δ (1H); multiplet 2.95 δ (1H); multiplet 2.85 δ (1H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:15])[C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ncc(Br)cc12
Product: Clc1ncnc2ncc(Br)cc12
Temperature: 25 °C

Procedure:
6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (3.0 g) and POCl3 (15 mL) were heated at 130° C. under nitrogen for 3 h. The homogeneous dark solution was concentrated under reduced pressure and diluted with EtOAc (150 mL). The heterogeneous brown slurry was poured onto mixture of ice/aq. NaHCO3 and allowed the mixture warm to room temperature. The heterogeneous brown mixture was further diluted with EtOAc (75 mL) and separated the organic layer. The organic layer was partitioned with aq. NaCl, separated, stirred with MgSO4 and filtered through a pad of Celite® and silica gel. The pale yellow filtrate was concentrated and the crude solid was stirred in 50% EA/hexanes. 6-Bromo-4-chloropyrido[2,3-d]pyrimidine was obtained as a pale yellow crystalline solid (1.8 g, purity: 95%) upon filtration.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:14][C:13]([F:16])([F:15])[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)CO>>[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:14][C:13]([F:16])([F:15])[CH2:12]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C1
Solvent: OCC(F)(F)F
Product: C[C@@H](N)C(=O)N1CC(F)(F)C1
Temperature: 150 °C
Yield: 97.1 %

Procedure:
A 5 ml microwave vial was charged with [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (170 mg, 0.64 mmol) and 2,2,2-trifluoroethanol (2.4 ml, 32.9 mmol). The vial was flushed with argon, sealed and heated at 150° C. under microwave irradiation for 3 h. The reaction mixture was concentrated to afford 102 mg (97%) of (R)-2-amino-1-(3,3-difluoro-azetidin-1-yl)-propan-1-one as a brown oil which was used without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:20]([CH2:39][CH3:40])=[N:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:42]([O:49][NH:50][C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:24]2[CH:25]=[C:26]3[C:21]([C:20]([CH2:39][CH3:40])=[N:19][N:18]3[CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:22][CH:23]=2)=[O:28])=[CH:38][CH:37]=1)=[O:35])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc12
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)NOCc4ccccc4)cc3)ccc12
Reaction time: 18 h
Yield: 66.4 %

Procedure:
140 mg (0.728 mmol, 1.1 equiv) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added in one portion to a room temperature solution of 250 mg (0.662 mmol, 1.0 equiv) 4-[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-benzoic acid, 106 mg (0.662 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride, 101 mg (0.662 mmol, 1.0 equiv) 1-hydroxybenzotriazole hydrate, and 194 μL (1.39 mmol, 2.1 equiv) triethylamine in 25 mL CH2Cl2. After 18 hours, the reaction mixture was diluted with 150 mL ethyl acetate, washed 1×25 mL each 1N HCl, H2O, brine, and dried over Na2SO4. The crude product was purified on a silica gel column (2% CH3OH/CH2Cl2, flash) to give 212 mg (66%) of white crystalline solid: mp 194-198° C.; Anal. calcd for C28H30N4O3: C, 72.17; H, 7.10; N, 11.61. Found: C, 71.62; H, 6.47; N, 11.85.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H](C(O)=O)N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH:22][CH:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:21])[CH3:20].C1(C(C2C=CC=CC=2)Br)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C:19]([NH:22][C:23]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:21])[CH3:20]
Reactant: N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: BrC(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(c1ccccc1)c1ccccc1

Procedure:
As a production method of 3,3-diphenylalanine, U.S. Pat. No. 4,766,109 describes, as shown in the following reaction scheme, a method comprising reacting diethyl acetamidomalonate with diphenylbromomethane in ethanol in the presence of sodium ethoxide to give diethyl 2-acetamido-2-(diphenylmethyl)malonate, subjecting the compound to hydrolysis in the presence of hydrogen bromide, neutralizing the reaction mixture with aqueous sodium hydroxide solution, and purifying the compound using a column to give 3,3-diphenylalanine, but the yield thereof is not concretely described.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH:37]([NH2:39])[CH3:38]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH:37]([CH3:38])[CH2:36][N:35]([CH3:40])[CH3:34])=[O:23])(=[O:15])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: CC(N)CN(C)C
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CC(CN(C)C)NC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0333 cm3 of 1-(dimethylamino)-2-propylamine. 49 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (d, J=6.5 Hz, 3H), from 2.10 to 2.25 (mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8 Hz, 1H), 2.98 (s, 3H), 3.80 (mt, 2H), 4.14 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.46 (d, J=8 Hz, 4H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.16 (broad d, J=8 Hz, 1H)].
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][CH:14]=[N:15][C:16]=3[CH3:17])[C:9](=[O:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:18]
Reactant: C1COCCN1
Reactant: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Solvent: CCO
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(N3CCOCC3)c21
Temperature: 10 °C
Yield: 70.4 %

Procedure:
A mixture of 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (26 mg, 0.1 mmol) and morpholine (100 mg, 1.15 mmol) in ethanol (1.5 mL) was heated in a sealed tube at 10° C. for 3 hours. The reaction solution was evaporated to dryness and treated with cold ethanol. The yellow precipitate was filtered to give 22 mg (70.5%) of the title compound. MS-EI 312 [M+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12](OC(=O)C)(=[O:14])[CH3:13].P(=O)(O)(O)O>CCCCCC>[C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])[CH3:13]
Reactant: CCOC(=O)CCCCCO
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)CCCCCOC(C)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
240 g of ethyl 6-hydroxy-hexanoate are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. A mixture of 180 g of acetic anhydride and 3 g of 85% phosphoric acid is added dropwise thereto within a half hour while stirring. During the addition the temperature is held at 25° C. by cooling. Thereafter, the reaction mixture is heated slowly to 50° C. and held at this temperature for 3 hours. After cooling the mixture is treated with ice-water and taken up in 500 ml of hexane. The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution and thereupon neutral with water. After drying over sodium sulphate the solvent is distilled off. 282 g of crude product are obtained. Fractional distillation gives 223 g (yield 73.7% of theory) of chemically pure ethyl 6-acetoxy-hexanoate; 190 g thereof can be used as an olfactorily pure product without further treatment.