Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]1.[F:9][C:10]1[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:9][C:10]1[C:24]([C:25]([F:27])([F:26])[F:28])=[N:23][CH:22]=[CH:21][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([N:2]2[CH2:5][C:4](=[CH:6][C:7]#[N:8])[CH2:3]2)[CH2:18][CH2:19]1)=[O:13]
Reactant: N#CC=C1CNC1
Reactant: O=C1CCN(C(=O)c2ccnc(C(F)(F)F)c2F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#CC=C1CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 4.5 g, 34.46 mmol), 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCO3) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product (10), which was purified by column chromatography (SiO2, 0-10% of ethyl acetate in hexane gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8%) as a white solid. For 10: 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=4.7 Hz, 1H), 7.54 (t, J=4.6 Hz, 1H), 5.29 (p, J=2.4 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.03 (m, 2H), 3.98-3.94 (m, 2H), 3.57-3.39 (m, 2H), 3.17-3.04 (m, 1H), 2.56 (tt, J=7.4, 3.5 Hz, 1H), 1.86-1.77 (m, 1H), 1.75-1.64 (m, 1H), 1.54-1.43 (m, 1H), 1.43-1.31 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 161.34, 160.73, 152.62 (d, J=269.1 Hz), 145.75 (d, J=6.1 Hz), 136.73 (qd, J=36.1, 12.0 Hz), 134.56 (d, J=16.9 Hz), 126.89, 120.58 (qd, J=275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; C17H16F4N40 (MW 368.33), LCMS (EI) m/e 369 (M++H).
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]([CH3:34])=[CH2:33])[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH3:4])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]
Reactant: CC[Zn]CC
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of diiodomethane (3.7 g, 0.013 mmol) in toluene (10 mL) was cooled in ice-salt bath. Then diethylzinc (1.1M in toluene, 10 mL, 11 mmol) was added dropwise into the above solution slowly. After the addition, the mixture was stirred for 10 min. To the resulting mixture was added a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in Example 267a (800 mg, 1.4 mmol) in toluene (10 mL). The mixture was then allowed to warm to room temperature and stirred for 3 h, quenched with aqueous NH4Cl. The organic layer was separated, washed with water, dried over Na2SO4, purified by column chromatography to give title compound (800 mg).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:21])[NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=2)[C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:21])[NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:39]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]4[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=4)[C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:40]3)=[O:16])=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CN2CCNCC2)c1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 4-(3-phenylureido)benzoate (1.00 g, 3.90 mmol) in N,N-dimethylform-amide (20 mL) was added methyl 3-(piperazin-1-ylmethyl)benzoate bis(2,2,2-trifluoroacetate) (1.25 g, 2.70 mmol), N-ethyl-N-isopropylpropan-2-amine (0.94 mL, 5.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.40 g, 2.97 mmol, HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.57 g, 2,97 mmol, EDCl). The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was taken up in ethyl acetate and washed with water (×2) and then saturated aqueous sodium chloride. The organic phase was dried on magnesium sulfate, filtered, concentrated under vacuum. Silica chromatography (10-40% ethyl acetate in n-hexanes) and recrystallisation from methanol gave the title compound (1.02 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33].CO>C(Cl)(Cl)Cl.CN(C)C=O>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)ccnc2cc1O
Reaction time: 3 h

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-methoxy-7-quinolinol (70 mg) was dissolved in chloroform (1.5 ml) and N,N-dimethylformamide (1 ml). 2,4-Difluorophenyl isocyanate (43 mg) was then added to the solution, and a reaction was allowed to proceed at room temperature for 3 hr. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (20/1) to quantitatively give the title compound.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-phenyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-(1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[O:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].[H-].[Na+].[CH3:23]I>CN(C=O)C>[N:1]([CH:4]1[CH:5]([O:20][CH3:23])[CH2:6][O:7][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1COC(c2c([N+](=O)[O-])cnn2C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol, (Intermediate 57) (182 mg, 0.65 mmol) in anhydrous DMF (5 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) portionwise over 10 min. After a further 45 min, methyl iodide (0.06 mL, 0.97 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added followed by methyl iodide (0.06 mL, 0.97 mmol) and the mixture stirred at room temperature for 48 hr. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-(5-azido-6-methoxyoxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (100 mg). A solution of this oil (100 mg, 0.37 mmol) in THF/water (5 mL/1 mL) was treated with triphenylphosphine (97 mg, 0.37 mmol) and the reaction mixture heated at 70° C. behind a blast shield for 18 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (3 mL) at 0° C. and di-tert-butyl-dicarbonate (89 mg, 0.4 mmol) and DIPEA (0.18 mL, 1.02 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 3 hr. Water (10 mL) was added and the mixture extracted with DCM (20 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave racemic tert-butyl-(3-methoxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (relative stereochemistry as shown above) as a clear oil (119 mg, 47% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.39 (dd, J=10.6, 3.6 Hz, 1H), 4.75 (br s, 1H), 4.33 (dd, J=14.2, 1.9 Hz, 1H), 4.06 (s, 3H), 3.91-3.83 (m, 1H), 3.75 (dd, J=14.2, 3.2 Hz, 1H), 3.43 (s, 3H), 3.39-3.34 (m, 1H), 2.22-2.12 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.82 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@@H:34]([CH2:37][CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH2:35][OH:36])[CH2:37][CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (S)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2449.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][N:18]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]4[CH2:34][CH2:33][NH:32][CH2:31][C:26]=4[N:27]3[CH3:30])=[CH:23][CH:22]=2)[C:17](=[O:35])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:32]1[CH2:33][CH2:34][C:25]2[C:24]3[C:28](=[CH:29][C:21]([N:18]4[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)=[CH:16][C:17]4=[O:35])=[CH:22][CH:23]=3)[N:27]([CH3:30])[C:26]=2[CH2:31]1)(=[O:2])[CH3:3]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
AcCl (0.023 mL, 0.32 mmol) was added to a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride (100 mg, 0.216 mmol), DMAP (5 mg, 0.04 mmol) and Et3N (0.09 mL, 0.6 mmol) in CH2Cl2 (20 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. H2O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4Cl solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (61 mg, 66%) as a mixture of rotomers as a white powder: mp 80-82° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J=7.5 Hz, 1H), 7.52-7.35 (m, 7H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.12-6.08 (m, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H), 3.69-3.65 (m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16 (s, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([O:30][CH3:31])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21]([O:30][CH3:31])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution mixture of methyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-5-methoxy-4-phenylbenzoate (0.034 g) in methanol (2.5 mL) and ethyl acetate (2.5 mL), 10% palladium-carbon (6.8 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.020 g of methyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-5-methoxy-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Reactant: Clc1ccc(C#CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CC1c2c(c3cc(Cl)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (220 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite and Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 6-chloro-9-((4-chlorophenyl)ethynyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (88 mg). 1H NMR (CDCl3) FREE BASE 7.51-7.43 (m, 4H), 7.39-7.36 (d, 1H), 7.30-7.22 (m, 2H), 4.05-3.97 (q, 1H), 3.24-2.80 (m, 4H), 2.60 (s, 3H), 1.68-1.58 (d, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:28]=[C:27]([C:29](OCC)=[O:30])[C:26]([O:34][CH3:35])=[CH:25][C:19]=2[C:20](OCC)=[O:21])=[CH:14][CH:13]=1.O.[OH-].[Na+]>C1COCC1>[OH:21][CH2:20][C:19]1[CH:25]=[C:26]([O:34][CH3:35])[C:27]([CH2:29][OH:30])=[CH:28][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH:8]([CH3:7])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCCC(C)CCCC(C)C)cc2)c(C(=O)OCC)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)c(-c2ccc(OCCC(C)CCCC(C)C)cc2)cc1CO
Temperature: 67 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
LiAlH4 (7.9 g, 208 mmol) was initially introduced with about 250 ml of THF under an argon blanket. Diethyl 2-[4-(3,7-dimethyloctyloxy)phenyl]-5-methoxyterephthalate (72.2 g, 149 mmol) was diluted with about 60 ml of THF in a dropping funnel and slowly added dropwise. During this addition, the reaction mixture was stirred vigorously. The batch, diluted with a further 100 ml of THF, was then refluxed at 67° C. After 2 hours, it was cooled to RT. When the reduction was complete, 8 ml of water were carefully added for work-up. 8 ml of aqueous NaOH solution (15% strength) were subsequently added, and finally 24 ml of water were added. After each addition, the mixture was stirred for about a further 15 minutes (“1:1:3 method”). The solid formed was filtered off with suction and again stirred with THF, and finally the combined organic phases were evaporated. Recrystallization from hexane/ethyl acetate (20:1) gave the product (93% yield) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:5]2[N:6]([N:22]=[N:23][N:24]=2)[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:8]=1[C:9](OCC)=[O:10].[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>CC(C)=O>[CH3:35][O:36][CH2:37][CH2:38][N:39]1[C:9](=[O:10])[C:8]2[CH:7]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[N:6]3[N:22]=[N:23][N:24]=[C:5]3[N:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:3]=2[CH2:2]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Reactant: COCCN
Solvent: CC(C)=O
Product: COCCN1CC2=C(C1=O)C(c1ccc(C#N)cc1)n1nnnc1N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-(bromomethyl)-7-(4-cyanophenyl)-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo-[1,5-a]pyrimidine-6-carboxylate (35.3 mg, 66.1 μmol) was initially charged in acetone (1.0 ml). 2-Methoxyethylamine (12.4 mg, 4 μl, 165 μmol, 2.5 eq.) was added dropwise, and the mixture was then stirred at RT overnight. After addition of more 2-methoxyethylamine (9.9 mg, 132 μmol, 2 eq.), the mixture was stirred at RT for a further 5 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (13 mg, 41% of theory).
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([N:26]([CH3:35])[C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.Cl.CCOC(C)=O.[C:43]1([CH:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([N:26]([CH3:35])[C@@H:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH:8][C:50](=[O:51])[CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@H](c1ccccc1)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccccc1)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1
Yield: 27.7 %

Procedure:
Prepared according to the method described in Examples 2(b) and 2(c) above from (R)-N2 -(Boc)-N5 -(Cbz)-N-methyl-(R)-N-(1-phenylethyl)ornithine amide (5.0 g; 10 mmol; from step (a) above) EtOAc (75 mL) then HCl/EtOAc (75 mL), 2 hours reaction time for the deprotection, then CH2Cl2 (50 mL), diphenylacetyl chloride (2.4 g; 10 mmol) followed by pyridine (3.0 mL; 37 mmol; instead of DiPEA) over 1 minute, overnight reaction time, diluted with CH2Cl2 (100 mL) for the work up procedure. The crude material was purified by chromatography on silica gel with EtOAc:hexanes (1:1) to provide 1.6 g (26%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]=[C:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C:9]2([O:19][CH2:18][CH2:17][O:12]2)[CH2:8][C@H:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCCCC1=CC(=O)CCC1C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCC[C@@H]1CC2(CC[C@@H]1C(=O)OCC)OCCO2

Procedure:
2-Butyl-4-oxocyclohex-2-ene carboxylic acid ethyl ester (9.05 g; 40 mmole), ethyleneglycol (2.73 g; 44 mmole) and p-toluenesulphonic acid (100 mg) were refluxed in benzene (80 ml) using a Dean-Stark water trap. After 12 hours the mixture was cooled, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate followed by water. Drying over MgSO4 and evaporation gave a liquid (10.80 g 100%) which was pure enough to use directly. Found: C,66.71; H,9.79, C15H26O4 requires C,66.64; H,9.69%.
Reaction SMILES: [Si:1]([N:8]1[C@H:11]([C:12]#[CH:13])[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[Si:1]([N:8]1[C@H:11]([C:12]2[CH:13]=[N:21][NH:20][N:19]=2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1c1cn[nH]n1
Temperature: 80 °C
Yield: 8.3 %

Procedure:
A mixture of 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (3.0 g) and trimethylsilylazide (15 ml) was heated at 80° C. for 20 hours. The reaction mixture was allowed to room temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane ethyl acetate=(1:1) to give 1-tert-butyldimethylsilyl-4(S)-(2H-1,2,3-triazol-4-yl)-2-azetidinone (0.3 g, 8.3%) as a pale yellow solid.