Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[O:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:16]1[O:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:19])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (655 mg), 5-bromofuran-2-carboxylic acid (681 mg), 1-hydroxybenzotriazole hydrate (457 mg), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.069 g), and N,N-diisopropylethylamine (2.5 mL) in N,N-dimethylformamide (10 mL) was agitated until a homogenous solution was obtained, and was then allowed to stand at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The chloroform layer was dried over magnesium sulfate, filtered, and evaporated and the residue was purified by chromatography on silica gel in a solid phase extraction cartridge using ammoniated methanol/chloroform mixtures as the eluent. The compound was then dissolved in tetrahydrofuran (20 mL), excess hydrogen chloride (5 mL; 1 M solution in diethyl ether) was added, and the solution was evaporated and then recrystallised from methanol/diethyl ether to give the hydrochloride salt of the title compound as a colourless solid (538 mg); MS (ES+) 299, 301 (MH+).
Reaction SMILES: C1(CCO)CC1.[CH3:7][C:8]1([CH3:17])[C@H:13]2[CH2:14][C@@H:9]1[CH2:10][CH2:11][C@@H:12]2[CH2:15][OH:16].FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41]>>[Cl:34][C:35]1[C:36]([O:16][CH2:15][C@H:12]2[CH2:11][CH2:10][C@H:9]3[CH2:14][C@@H:13]2[C:8]3([CH3:17])[CH3:7])=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])=[O:41]
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CC1(C)[C@H]2CC[C@H](COc3cc(F)c(C(=O)NS(C)(=O)=O)cc3Cl)[C@@H]1C2

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl)methanol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compound was obtained as a colorless solid (0.03 g, 2%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.25 (d, J=12.5 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.35 (s, 3H), 2.47-2.37 (m, 1H), 2.10-2.03 (m, 1H), 1.94-1.65 (m, 5H), 1.48-1.37 (m, 2H), 1.12 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2 Hz), 159.8 (d, JC-F=255 Hz), 158.1 (d, JC-F=11 Hz), 130.7 (d, JC-F=3 Hz), 116.6 (d, JC-F=3 Hz), 113.7 (d, JC-F=14 Hz), 102.5 (d, JC-F=28 Hz), 73.1, 41.9, 41.2, 40.1, 38.8, 34.1, 26.5, 23.5, 23.1, 20.0, 17.4; MS (ES−) m/z 402.1, 404.1 (M−1).
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CCO>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:5][CH2:4]1)[CH3:2]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)CC#N)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (25 mg, 0.088 mmol) and triethylamine (0.037 mL, 0.264 mmol) were dissolved in EtOH (3 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (19 mg, 0.106 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 50% B in A and gave 16 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.03 (m, 1H), 6.86 (m, 1H), 4.53 (d, 2H, J=2.0 Hz), 3.08-3.11 (m, 2H), 2.93-2.94 (m, 2H), 2.72-2.73 (m, 2H), 2.04-2.09 (m, 1H), 1.91-1.94 (m, 1H), 1.36-1.72 (m, 4H), 0.35 (t, 3H, J=7.6 Hz). [M+H] found 352.
Reaction SMILES: [C:1]([C:4]1[O:32][C:7]([CH2:8][C:9]2[CH2:10][S:11](=O)[C@@H:12]3[C@H:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18](=[O:30])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(Cl)(=O)C>CN(C)C=O>[C:1]([C:4]1[O:32][C:7]([CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:18](=[O:30])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS[C@H]12
Reaction time: 2 h

Procedure:
To a mixture of 1.3 g of crude 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide and 1.7 g of tin-II-chloride in 20 ml of dimethylformamide are added dropwise under anhydrous conditions 6 ml of acetic acid chloride, the temperature being maintained at 0°-5°. The reaction mixture is subsequently stirred for 2 hours and worked up in a conventional manner for free acids (see Example 78). Chromatography of the crude product (silica gel, washed with hydrochloric acid; elution with a 4:1-mixture of methylene chloride and ethyl acetate) and subsequent crystallisation from methyl acetate yield the 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid, m.p. 183°-186°; thin-layer chromatogram (silica gel); Rf = 0.24 (system: n-butanol/ethanol/water 40:10:50) and Rf = 0.55 (system: chloroform/methanol 1:1); infrared absorption spectrum (in mineral oil): characteristic bands at: 2,96μ, 3,18μ, 5,65μ, 5,73μ and 5,90μ.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C(C3C=NN(CC(C)C)C=3)N=CC=4)=CC=2)CCC1.Cl[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48](=[O:49])[C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:59][CH2:58][CH2:57]4)=[CH:52][CH:51]=3)=[C:46]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:45][C:44]=12.[F:74][C:75]1[CH:82]=[CH:81][CH:80]=[C:79](B2OC(C)(C)C(C)(C)O2)[C:76]=1[C:77]#[N:78]>>[C:77]([C:76]1[C:75]([F:74])=[CH:82][CH:81]=[CH:80][C:79]=1[C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:48](=[O:49])[C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:59][CH2:58][CH2:57]4)=[CH:52][CH:51]=3)=[C:46]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[O:45][C:44]=12)#[N:78]
Reactant: CC1(C)OB(c2cccc(F)c2C#N)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: CC(C)Cn1cc(-c2nccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)cn1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccc(F)c5C#N)nccc4c3=O)cc2)CCC1
Yield: 44 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-8-(1-isobutyl-1H-pyrazol-4-yl)-2-phenyl-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted with 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile to give the title compound (40 mg, 44%). LCMS (Method I): RT=7.90 min, [M+H]+=532 (-tBu).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](OC1C=CC(OCCCBr)=CC=1)C1C=CC=CC=1.CNC>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCOc1ccc(OCc2ccccc2)cc1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Agent: CNC
Product: CN(C)CCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In the manner described above for the preparation of 1-benzyloxy-4-(3-methylaminopropoxy)benzene, 1-benzyloxy-4-(3-bromopropyloxy)benzene was reacted with dimethylamine to give 1-benzyloxy-4-(3-dimethylaminopropoxy)benzene. The product was isolated as its hydrochloride salt and crystallization from isopropanol gave the purified hydrochloride salt of 1-benzyloxy-4-(3-dimethylaminopropoxy)benzene, mp 183°-185°.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(NS(C)(=O)=O)ccc21
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 9-Ethyl-9H-carbazol-3-ylamine (210 mg, 1 mmol) and pyridine (105 μl, 1.3 mmol) in CH2Cl2 (8 ml) at room temperature was added methanesulfonyl chloride (85 μl, 1.1 mmol). After stirring overnight the reaction mixture was diluted with CH2Cl2 and washed with saturated aq. NaHCO3 and brine, then the organic layer dried (Na2SO4) and concentrated to afford the crude product. Chromatographic purification (silica, CH2Cl2) afforded the desired product as a pale yellow solid (203 mg, 70% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[N+](C1C=CC(S(O[CH2:42][C@H:43]2[CH2:45][N:44]2[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(=O)=O)=CC=1)([O-])=O.CC([O-])(C)C.[K+]>CN(C=O)C>[C:49]([O:48][C:46]([NH:44][C@@H:43]1[CH2:45][N:9]2[C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:42]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application publication WO2006/046030)(0.15 M) in DMF was treated with CsF (4 eq) in one portion; the resulting mixture was stirred for 20 min at RT then treated via dropping funnel over 30 min with a solution of tert-butyl (2R)-2-({[(4-nitrophenyl)sulfonyl]oxy}methyl)aziridine-1-carboxylate (1.3 eq) in DMF (0.5 M). The resulting solution was stirred at RT overnight. The reaction mixture was then placed into an ice bath and powdered KOtBu (1.4 eq) added slowly to the reaction mixture. After 1.5 h, the reaction was quenched with sat. aq. NH4C1 and extracted into EtOAc. The combined organic layers were washed with water and brine, before being dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 80:20) affording the product as an off-white foam (85%). (ES+) m/z 505 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25].[Br:26]Br.S(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:26])=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)nc(N)c1OC
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)nc(N)c1OC
Temperature: 60 °C
Yield: 21.1 %

Procedure:
Methyl 6-amino-2-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-methoxypyrimidine-4-carboxylate (350 mg, 0.95 mmol) was stirred in 4 mL 1,2-dichloroethane, treated with bromine (1.0 g, 6.3 mmol) and heated to 60° C. for 6 h. After cooling, the mixture was stirred with 15% sodium bisulfite solution until negative to starch-iodine paper. The mixture was diluted with ethyl acetate, washed with saturated NaCl, dried (Na2SO4), and evaporated. Purification by flash chromatography (SiO2, eluting with 0-30% ethyl acetate in hexanes) provided the title compound as white solid (75 mg, 23%).
Reaction SMILES: [CH:1]1(Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:11]([OH:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:12][C:11]2[CH:10]=[C:9]([CH:17]=[CH:16][C:13]=2[O:14][CH3:15])[CH:8]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 122.5 °C
Reaction time: 1.5 h

Procedure:
A mixture of cyclopentyl chloride (8.48 g, 0.08 moles), isovanillin (6.12 g, 0.04 moles) and potassium carbonate (1.1 g, 0.08 moles) in dimethylformamide (4.04 g) was stirred in the reactor (100 mL) at 120 to 125° C. for 1.5 hours. A sample was taken to verify the batch conversion. Result (GC): 0.5 area % isovanillin (target:≦1.0 area %). The mixture was cooled to 20° C. and filtered to remove the solid (potassium bicarbonate, potassium chloride). The wet cake was washed with methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](C2C=CC=CC=2)(O)[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1(C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2ccccc2)c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccccc1-c1cccc(C=Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18 (from above), toluene (75 mL) and a crystal of p-toluenesulfonic acid monohydrate was refluxed with H2O removal (Dean-Stark trap) for 2 hr. The mixture was cooled to room temperature and stirred overnight. The mixture was washed with saturated NaHCO3 solution (25 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (60 g) packed in hexanes. The column was eluted with hexanes (300 mL), 0.4% MTBE/hexanes (500 mL), 0.8% MTBE/hexanes (500 mL) and 1% MTBE/hexanes (1000 mL). Product fractions were concentrated under reduced pressure to give 0.6 g of an inseparable mixture of 19 and 2-(benzyoxy)-2′-methoxybiphenyl as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[CH:24][C:25]3[CH2:32][C@H:31]4[C@:33]5([CH2:37][N:36]([CH2:38][C:39]([F:42])([F:41])[F:40])[S:35](=[O:44])(=[O:43])[NH:34]5)[C@H:28]([CH2:29][CH2:30]4)[CH2:27][C:26]=3[CH:45]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:22]3[CH:23]=[CH:24][C:25]4[CH2:32][C@H:31]5[C@:33]6([CH2:37][N:36]([CH2:38][C:39]([F:42])([F:41])[F:40])[S:35](=[O:43])(=[O:44])[NH:34]6)[C@H:28]([CH2:29][CH2:30]5)[CH2:27][C:26]=4[CH:45]=3)[N:3]=[CH:4]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-n2cnc(Br)c2)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(F)cc4)cn3)cc2C1
Temperature: 100 °C
Yield: 11.9 %

Procedure:
To a degassed solution of 4-bromo-1-(4-fluorophenyl)imidazole from Step 1 (50 mg, 0.21 mmol) and the homochiral boronate from Example 24 Step 1 (100 mg. 0.21 mmol) in N,N-dimethylformamide (3 mL) and water (1 mL) was added cesium carbonate (67 mg, 0.21 mmol) followed by tetrakis(triphenylphosphine) palladium (0) (24 mg, 0.02 mmol). The reaction was heated at 100° C. for 19 hours. The cooled reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica eluting with ethyl acetate/isohexane (gradient 20 to 30 to 50% to neat ethyl acetate) followed by recrystallisation from dichloromethane/diethyl ether to give the product (13 mg, 12%).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8](Cl)=[N:9][CH:10]=1>COCCO>[Br:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: NN
Reactant: Cc1cc(Br)cnc1Cl
Solvent: O
Solvent: COCCO
Product: Cc1cc(Br)cnc1NN
Temperature: 120 °C
Reaction time: 30 h
Yield: 49.1 %

Procedure:
Hydrazine hydrate (119 mL, 2422 mmol) was added to a suspension of 5-bromo-2-chloro-3-methylpyridine (50 g, 242 mmol) in 2-methoxyethanol (250 mL). The resulting solution was stirred 30 h at 120° C. and concentrated. The yellow residue was purified by trituration with H2O to provide the title compound (24 g) as a colorless solid. tR: 0.39 min (LC-MS 2); ESI-MS: 201.9 [M+H]+ (LC-MS 2)
Reaction SMILES: [CH2:1]([N:4]1[CH:9](SC)[NH:8][C:7](=[O:12])[CH:6]=[N:5]1)[C:2]#[CH:3].Cl.C([OH:16])C>>[CH2:1]([N:4]1[C:9](=[O:16])[NH:8][C:7](=[O:12])[CH:6]=[N:5]1)[C:2]#[CH:3]
Reactant: CCO
Reactant: C#CCN1N=CC(=O)NC1SC
Agent: Cl
Product: C#CCn1ncc(=O)[nH]c1=O
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 1.34 g 2-propargyl-3-methylthio-5-oxo-2,3-dihydro-1,2,4-triazine, 5 ml conc. hydrochloric acid and 10 ml ethyl alcohol was heated under reflux for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain a yellow solid. This solid was recrystallized from ethyl alcohol to obtain 0.92 g of a white crystal.
Reaction SMILES: [C:1]([CH:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[C:10]([C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:11])[CH3:5])(O)=[O:2].[CH2:32]([NH2:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:32]([NH:39][C:1]([CH:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[C:10]([C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:11])[CH3:5])=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCN
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(C)C(=O)O)c2)c2ccccn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCNC(=O)C(C)Nc1cccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of ethyl 4- [1- [3- [(1-carboxyethyl)amino]benzoyl]indolizin-3-yl]butyrate (60 mg), heptylamine (16 mg) and 1-hydroxybenzotriazole (20 mg) in dichloromethane (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg). The mixture was stirred for 3 hours at room temperature, evaporated and dissolved in ethyl acetate (10 ml). The solution was washed with diluted hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-[1-[3-[[1(heptylcarbamoyl)ethyl]amino]benzoyl]indolizin-3-yl]butyrate (70 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][C:39]5[N:44]6[CH:45]=[C:46]([CH3:48])[N:47]=[C:43]6[CH:42]=[CH:41][CH:40]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([C:39]5[N:44]6[CH:45]=[C:46]([CH3:48])[N:47]=[C:43]6[CH:42]=[CH:41][CH:40]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4cccc5nc(C)cn45)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)c4cccc5nc(C)cn45)cc2)CCN3CC(C)C)cc1
Temperature: -20 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.50 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.27 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred at −20° C. for 18 hours, sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:1→2:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazo[1,2-a]pyridin-5-ylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 171) (110.5 mg) as yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C.Cl[Cu]>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: Cl[Cu]
Solvent: CC#N
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Example 1 was repeated using the following amounts of reagents: 5 g (0.031 mole) of 1-phenyl-3-amino-2-pyrazoline were dissolved in 25 ml of acetonitrile under addition of 0.2 g (0.00201 mole) of CuCl, under an oxygen head. Oxidation lasted about 3 hours. 2.5 g of 1-phenyl-3-aminopyrazole were obtained.