Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:28]3[CH2:30][CH2:29]3)=[C:21]([O:23][C:24]([F:27])([F:26])[CH3:25])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:28]3[CH2:30][CH2:29]3)=[C:21]([O:23][C:24]([F:27])([F:26])[CH3:25])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(OC(C)(F)F)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(F)(F)Oc1cc(Oc2cc(F)c(C(=O)O)cc2Cl)cnc1C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl 5-chloro-4-(6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-yloxy)-2-fluorobenzoate (Preparation 270, 260 mg, 0.59 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (440 μL, 5.86 mmol). The reaction mixture was stirred over 48 hours at room temperature then concentrated in vacuo and the crude residue azeotroped with methanol (2×25 mL). The crude material was purified by silica gel column chromatography eluting with 50% ethyl acetate in heptane to afford the title compound as a white solid (200 mg, 96%).
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CC(=O)O
Product: Ic1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Over a period of 15 minutes samples of iodine (8.62 grams, 0.034 mol) and silver benzoate (7.78 grams, 0.034 mol) were added in portions to a magnetically stirred solution of 5 grams of 1-phenylpiperazine in 80 mL acetic acid. The mixture stirred for 1 hour. The solvent was evaporated and the residue partioned between 150 mL diethyl ether and 150 mL 2N sodium hydroxide. The organic layer was washed with 100 mL water, 100 mL brine, then dried over potassium carbonate and concentrated in vacuo to yield 1.0 gram (11%) of 1-(4-iodophenyl)-piperzine (110°-115° C.). The material obtained was used without further purification. 1H NMR (CDCl3, dTMS) 7.51 (2H, d, 3JHH =9 Hz, m-ArH), 6.69 (2H, d, 3JHH =9 Hz, o-ArH), 3.17 (4H, m), 3.04 (4H, m). 13 C NMR (CDCl3) 151.36, 137.73, 118.05, 81.35, 49.92, 45.95.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCCc1nc(-c2ccccc2)co1
Yield: 92.2 %

Procedure:
To a solution of ethyl 4-phenyl-2-oxazolepropionate (1.4 g) in THF (20 ml) was added sodium borohydride (0.86 g). Methanol (4 ml) was dropwise added to the mixture over a period of 10 minutes under reflux. The reaction mixture was refluxed for further 30 minutes, concentrated, made acidic and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and distilled to obtain crystals of 3-(4-phenyl-2-oxazolyl)propanol (1.07 g, 92%). Recrystallization from ether-hexane gave colorless prism crystals of mp 55°-56° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28])=[N:13][CH2:14]CCC.C(N)CCC.CN>C(O)C>[CH3:28][C:27]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:22][S:21][CH2:20][CH2:19][NH:18][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[N:13][CH3:14]
Reactant: CCCCN=C(NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C
Agent: CN
Solvent: CCO
Solvent: CCCCN
Product: CN=C(NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C

Procedure:
In a similar manner N,N'-bis-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-N"-butylguanidine may be prepared using butylamine in ethanol in place of ethanolic methylamine.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH2:54]([C:56]1[S:67][C:59]2=[N:60][C:61]([CH:65]=O)=[CH:62][C:63](=[O:64])[N:58]2[N:57]=1)[CH3:55].C(N1C(C)=C(C=O)C(C)=N1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:65][C:61]3[N:60]=[C:59]4[S:67][C:56]([CH2:54][CH3:55])=[N:57][N:58]4[C:63](=[O:64])[CH:62]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: CCc1nn2c(=O)cc(C=O)nc2s1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CCn1nc(C)c(C=O)c1C
Product: CCc1nn2c(=O)cc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nc2s1

Procedure:
The title compound was prepared on a 0.5-mmol scale analogously to example B(19): except using 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile from step 3 of example A(84) in place of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-7-carbaldehyde from step 2 below in place of 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. Yield: 10 mg (4%). 1H NMR (300 MHz, DMSO-d6): δ 1.29 (t, 3H), 1.35–1.7 (s, m overlap, 14H), 1.99 (m, 2H), 2.38 (m, 1H), 2.63 (m, overlap, 3H), 2.75 (d, 1H), 3.03 (q, 2H), 3.48 (ABq, 2H), 6.06 (s, 1H), 7.10 (m, overlap, 2H), 7.35 (m, 1H), 10.98 (s, 1H). LC-MS (APCI) calcd for C30H33FN2O3S: 564.22, found (M+H+): 565.2 m/z.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[CH3:27][N:28](C)[C:29]#N>C1COCC1>[CH3:27][N:28]([CH3:29])[C:15]1[N:3]=[C:4]([OH:14])[C:5]2[C:6]([CH:16]=1)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CN(C)C#N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1000 mg, 4.52 mmol) in THF (10 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (5316 μl, 9.04 mmol) and the solution was stirred for 0.5 h before addition of N,N-dimethylcyanamide (317 mg, 4.52 mmol) in THF (10 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl, and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate, filtered, followed by removal of solvent under vacuum to give 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 71% yield) which was carried to the next step without further purification. MS: MS m/z 219.1 (M++1).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1.C([N:40](CC)CC)C.N>C1COCC1.CO>[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH2:40])=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1
Reactant: OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.17 g) was added to (4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl}-2-bromophenyl)methanol (0.46 g) and triethylamine (0.26 g) in THF at −10° C. and the resultant mixture was stirred for 30 min. The mixture was poured into ammonia (10 ml), THF (10 ml) and MeOH (10 ml), and the resultant was stirred at room temperature overnight. After the solvents were evaporated under reduced pressure, the residue was diluted with t-BuOMe and H2O, and the organic layer was dried over MgSO4. After the solvents were evaporated under reduced pressure, the residue was purified with column chromatography to get the targeted product (0.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:15]([NH:25][C:12]([C@@H:9]1[CH2:10][CH2:11][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCN
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid (1) (90 mg; 0.447 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (72 mg; 0.470 mmol), N,N-diisopropylethylamine (116 mg; 0.895 mmol) and PyBOP (244 mg; 0.470 mmol) are added sequentially. The reaction is stirred for 4 days at room temperature, then concentrated under reduced pressure. The crude product is purified via silica gel chromatography using a gradient elution (10%→60% ethyl acetate in hexanes) affording the desired product (285). ISMS: MH+ 341.4
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](I)[CH2:32][CH3:33]>>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[N:8]([CH2:31][CH2:32][CH3:33])[C:7]=2[CH:22]=1
Reactant: CCCI
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Product: CCCN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccccc3OC)c(OC)cc21
Yield: 89 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using propyl iodide instead of hexyl bromine. The title compound (99 mg) was obtained as a white solid, yield=89%.
Reaction SMILES: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O.[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15].[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.N1C=CN=C1>[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
This compound was prepared from the corresponding methyl glucoside, Methyl 2-acetamido-2-deoxy-β-D-glucopyranoside (Carbohydrates, Ed. Collins, P. M., Chapman and Hall, New York, 1987, p. 414) by treatment with t-butyldimethylchlorosilane in DMF and imidazole. 1H NMR δ0.00 (2Xs, 6H), 0.80 (2Xs, 9H), 1.98 (s, br, 3H), 3.20-3.32 (m, 1H), 3.32-3.50 (s superimposed on m 5H), 3.59 (dd, J=12, 8, 1H), 3.76, 3.84 (ABX, JAB=18, 2H), 4.28 (d, J=8, 1H), 6.42 (d br J=4, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: BrCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCCCCCBr)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Anhydrous K2CO3 (5.50 g, 39.8 mmol) was added to a stirred solution of 4-nitrophenol (3.69 g, 26.5 mmol) and 1,8-dibromooctane (36.00 g, 132.1 mmol) in acetone. The reaction mixture was heated at reflux 12 h, then cooled to ambient temperature and filtered. The residue was washed with acetone (3×15 mL) and the combined organic layers evaporated in vacuo. The residue was dissolved in EtOAc (50 mL), the solution washed with water (2×20 mL), brine, dried over Na2SO4, filtered, volatiles evaporated in vacuo, and the residue subjected to column chromatography on silica gel (230-400 mesh) using hexanes as elutant to afford 7.75 g (23.5 mmol, 89%) of product as a low melting solid, mp 39-40° C. 1H NMR (500 MHz, CDCl3) δ 1.35-1.50 (m, 8H), 1.79-1.89 (m, 4H), 3.41 (t, J=6.5 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 6.93 (d, J=10 Hz, 2H), 8.18 (d, J=9.5, 2H); 13C NMR (125 MHz, CDCl3) δ 27.9, 28.5, 28.8, 29.0, 29.2, 32.6, 33.9, 68.7, 114.3, 125.8, 129.3, 141.2, 164.1; HRMS (EI) calculated for C14H20BrNO3 [M]+0 329.6027, observed 329.6040.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].OO>O.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>[OH:17][C:8]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][C:9]=1[C:9]1[CH:8]=[C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[OH:1]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 97.9 %

Procedure:
40 g (1 mole) of sodium hydroxide are dissolved in 170 ml of water which contains 1 g of sodium lauryl sulfate. With stirring, the solution is heated to 80° and then 103 g (0.5 mole) of 2,4-di-tert-butylphenol are added. Then 31 ml of a 30% solution of hydrogen peroxide are added dropwise in the course of 2 hours. After the reaction mixture has cooled, the product is isolated by filtration and washed with water and dried, affording 100.5 g (98% of theory) of 2,2'-dihydroxy-3,3',5,5'-tetra-tert-butyl-biphenyl with a melting point of 190°-195° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27]C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]4[CH2:26][CH2:27][CH2:32][CH2:31][CH2:30]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A suspension of 1.30 g (3.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 13 ml of N,N-dimethylformamide was treated with 1.44 g (0.017 mol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether/n-hexane. There were obtained 1.39 g (95%) of 7-chloro-8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 210°-212° (dec.).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:8]1[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccccc2Cl)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.3 mL of 2- chlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then stirred for 2 hours at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 124°-125° C.). 1H NMR (CDCl3) δ 2.63 (dd, 1 H), 3.10 (dd, 1 H), 3.68 (dd, 2 H), 6.07 (dd, 1 H), 7.3-7.65 (m, 4 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][O:28][C:29]1[CH:48]=[CH:47][C:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:40][C:35]([CH2:34][O:33][C:32]2[CH:47]=[CH:48][C:29]([O:28][CH2:27][CH2:26][O:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]3)=[O:13])=[CH:30][CH:31]=2)=[CH:36][CH:37]=1
Reactant: BrCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCOc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 4-{[4-(2-bromoethoxy)phenoxy]methyl}biphenyl.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:4]=2[CH2:3]1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>[OH-].[Na+]>[I:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:3][C:4]=2[CH:16]=1
Reactant: ClC1Cc2cc(I)ccc2Sc2ccccc21
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: Ic1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
10.1 g of 10-chloro-10,11-dihydro-2-iodo-dibenzo[b,f]thiepin and 23.3 g of piperazine are held at 120°-130° C for 1 hour. The mixture is cooled, diluted with 2-N sodium hydroxide and extracted with ether. The organic phase is washed with water until neutral and extracted with 500 ml of 2-N hydrochloric acid. The aqueous phase is made alkaline and extracted with chloroform. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. There is obtained 1-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-yl)-piperazine as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:20]([OH:25])[OH:21])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 23 (27.78, 0.14 mol), n-butyllithium (14 cm3, 10.0M in hexanes, 0.14 mol) and triisopropyl borate (52.7 g, 0.28 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2.[CH:24]([N-]C(C)C)(C)[CH3:25].[Li+].C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]([CH2:24][CH3:25])[C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(CC)C2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mmol of ethyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in tetrahydrofuran, and 50 mmol of lithium diisopropylamide followed by 50 mmol of ethyl iodide are added at -78° C. The mixture is heated to room temperature and stirred for 1 hour, and is worked up analogously to Example 1.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:19])=[C:10]2[CH:17]=[C:16]([CH3:18])[S:15][C:11]2=[C:12]([CH3:14])[N:13]=1)=[O:7])CCC.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO.Cl>[OH:19][C:9]1[C:8]([C:6]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])=[N:13][C:12]([CH3:14])=[C:11]2[S:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C)c2sc(C)cc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2s1

Procedure:
4-Hydroxy-2,7-dimethyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (30 mg, 0.11 mmol, example 5-b-A) and glycine (75 mg, 1.0 mmol) were suspended in 2.0 mL of 0.5 N NaOMe in methanol. The resultant mixture was heated to 120° C. for 10 min. using a CEM microwave reactor. The reaction mixture was cooled, and diluted with 0.25 N HCl until pH <3. The mixture was extracted two times with ethyl acetate, and the organic fractions were dried over anhydrous magnesium sulfate and concentrated to 27 mg of a pale yellow solid. MS: (−) m/z 279.01 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11](O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.C(OCC)C>[N:64]([C@@H:11]1[CH2:12][CH2:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[N+:65]=[N-:66]
Reactant: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
(trans)-4-(4-Bromophenyl)cyclohexanol (500 mg) is dissolved under argon in tetrahydrofurane (8 mL) and cooled to −5° C. Triphenylphosphine (770 mg) and di-tert-butyl-azodicarboxylate (550 mg) are added and the mixture is stirred for 5 minutes. A solution of diphenylphosphorylazide (650 μL) in tetrahydrofurane (8 mL) is added dropwise during 2 hours and the mixture is stirred at 0° C. for 48 hours. Then the mixture is diluted with diethylether, washed with saturated aqueous NaHCO3 solution and the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 99:1→70:30) to give the title compound. LC (method 4): tR=0.97 min.