Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:43][CH2:42][C:15]([CH3:44])([O:16][CH2:17][CH:18]=[CH:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[CH:27][C:26]([CH3:40])=[CH:25][CH:24]=2)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[CH:27][C:26]([CH3:40])=[CH:25][CH:24]=2)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)COCc1cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCC=CC[C@H](C)O2
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1)COCc1cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10.5 %

Procedure:
To a solution of (2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (0.020 g, 0.033 mmol) in ethanol (1 mL) was added Hoveyda-Grubbs catalyst 2nd generation (4.13 mg, 6.59 μmol). Sodium borohydride (6.24 mg, 0.165 mmol) was added and the mixture was stirred at rt. After 45 min, the reaction was quenched by careful addition of water. The product was extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetic acid (2.1 mg, 9.94% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.14 (s, 1H), 7.04-6.95 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 4.83 (d, J=12.5 Hz, 1H), 4.62-4.42 (m, 3H), 4.39-4.26 (m, 1H), 3.47-3.31 (m, 3H), 2.85-2.74 (m, 1H), 2.64 (br. s., 1H), 2.42-2.33 (m, 1H), 2.23 (s, 3H), 2.02-1.30 (m, 14H), 1.28-0.96 (m, 15H). LCMS (M+H) calcd for C34H49N4O6: 609.36. found: 609.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][CH2:26][OH:27])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15](=[O:16])[NH:17][C@H:18]2[C@@H:19]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][C:45]3=[O:46])[NH:20][C:21]2=[O:22])[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCO)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCOC2=O)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Prepared according to PCT Int. Appl. 2011061760. A solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-(((2-hydroxyethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (92 mg, 0.161 mmol) in Chloroform (806 μl) was treated with CDI (131 mg, 0.806 mmol) After stirring at rt for 3 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (91 mg, 95%) as an orange oil. LCMS: Rt=0.86 min, m/z=597.2 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl-].Cl[C:3](Cl)=[N+:4]([CH3:6])[CH3:5].[CH2:8]([N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15]/[C:14]/1=[N:23]/[NH2:24])[CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>C(Cl)Cl>[CH3:5][N:4]([CH3:6])[C:3]1[N:15]2[C:16](=[O:22])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:13]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[N:23][N:24]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(N(C)C)nnc12
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To methylene chloride (10 mL) was added [B] N-(dichloromethylene)-N-methylmethanaminium chloride (0.21 g, 1.3 mmol). After stirring for 5 mins, (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.10 g, 0.42 mmol) was added, and the mixture was stirred at rt for 5 hrs. LCMS analysis showed product as a major peak was formed. 1N NaOH was carefully added to neutralize the acid, and the mixture was extracted with methylene chloride three times. The combined organic layers were dried by MgSO4, filtered and concentrated in vacuo to yield the desired product (84 mg, 69%). LCMS calculated for C13H20N7O (M+H): 290.2. found 290.1.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.040 g, 0.13 mmol) was treated with 4-chlorophenyl isocyanate (0.023 g, 0.15 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 67 (0.034 g, 0.08 mmol, 56%) as a white solid. LCMS m/z (%)=449 (M+H79Br35Cl, 22), 451 (M+H81Br35Cl, 100), 453 (M+H81Br37Cl, 26). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 3.98-4.18 (m, 2H), 3.71 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]([N:13]=[N+]=[N-])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[F:12]>CCOC(C)=O.[Pd]>[CH3:1][C@H:2]([NH2:13])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[F:12]
Reactant: C[C@@H](Cc1cc(F)cc(F)c1F)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](N)Cc1cc(F)cc(F)c1F
Yield: 58.1 %

Procedure:
To a solution of (1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethyl azide (930 mg, 4.32 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silicagel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethylamine (475 mg, 58%) as pale yellow oil. ESI-MS: m/z (MH+) 190.1. 1H NMR (300 MHz, CDCl3): δ 7.04 (m, 1H), 6.83 (m, 1H), 4.06 (s, 2H), 3.42 (m, 1H), 2.92 (m, 2H), 1.29 (d, J=6.21 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11](=[O:13])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:8])=[CH:14][CH:15]=1)#[N:2]
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C(=O)NCC(=O)O)cc1
Product: N#Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from (4-cyano-benzoylamino)-acetic acid (CA [90290-83-8]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 436.1 (MH−, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.NCCC(NC1SC(C2C=CN=C(NC3C=CC(Cl)=CC=3)N=2)=C(C)N=1)=O.ClCCN1CCOCC1>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:35][CH2:34][CH2:33][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Agent: Cc1nc(NC(=O)CCN)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Agent: ClCCN1CCOCC1
Solvent: CC#N
Product: Cc1nc(NC(=O)CCNCCN2CCOCC2)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 2-morpholin-4-yl-ethylamine (or 3-amino-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 4-(2-chloro-ethyl)-morpholine. Anal. RP-HPLC: tR=11.5 min (10-70% MeCN, purity >97%). 1H-NMR (DMSO-D6) δ: 1.52 (d, 2H, J=7.0 Hz, CH2), 2.48 (m, 2H, CH2), 2.52 (s, 3H, CH3), 3.05-3.11 (m, 4H, CH2), 3.25-3.28 (m, 6H, CH2), 4.08 (m, 2H, CH2), 7.13 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.29 (m, 2H, Ph-H), 7.82 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:30]>CCCCCC>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][Cl:30]
Reactant: CC(C)(C)C#CCCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CC(C)(C)C#CCCCl

Procedure:
This preparation illustrates further procedures for preparing alkynylamines. In this preparation 0.1 mole of 5,5-dimethylhex-3-yn-1-ol is mixed with 0.1 mole of triphenylphosphine in 40 ml. of carbon tetrachloride and then heated, under nitrogen, at 60° C for 4 hours. The mixture is then poured into 200 ml. of hexane, stirred, and then filtered and the filtrate concentrated by evaporation under vacuum. The concentrate is then chromatographed on silica gel eluting with 5% ethyl acetate-95% vol. hexane, affording 5,5-dimethylhex-3-yn-1-yl chloride. b. 0.069 Mole of 5,5-dimethylhex-3-yn-1-yl chloride is treated according to the procedures described in paragraph (b) of Preparation A, affording 1-azido-5,5-dimethylhex-3-yne. c. 0.069 Mole of 1-azido-5,5-dimethylhex-3-yne is treated according to the procedure described herein in paragraph (c) of Preparation A affording 1-amino-5,5-dimethylhex-3-yne.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][C:14](=[O:39])[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23](=O)[NH:24][CH2:25][C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[CH2:6]([O:13][C:14](=[O:39])[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:5]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)OCc1ccccc1

Procedure:
Ammonium acetate (26 g, 0.34 mol) was added to a solution of {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester (5.4 g, 0.0113 mol) in acetic acid. The resulting homogeneous mixture was refluxed overnight and then concentrated under reduced pressure. The residue was partitioned between 10% NaOH and EtOAc (1:1) and the EtOAc layer was washed with 10% NaOH (3×) and brine. The EtOAc was dried (Na2SO4) and concentrated under reduced pressure to give {4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-carbamic acid benzyl ester. 1H NMR (CDCl3): δ 1.02–1.18 (m, 2H), 1.46–1.62 (m, 3H), 1.86–1.96 (m, 2H), 2.12–2.21 (m, 2H), 2.74 (m, 1H), 3.10 (t, J=6 Hz, 2H), 4.91 (t, 1H, N—H), 5.10 (s, 2H), 7.22 (s, 1H), 7.32–7.37 (m, 5H), 7.45 (d, J=4.9 hz, 2H), 7.87 (m, 1H), 7.95 (s, 1H). MS 458 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:7][CH:6]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(OCC)(=O)C>[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:7][CH:6]=1)[CH3:19]
Reactant: CCNCC
Reactant: NC(=O)Cc1ccc(OCCBr)c2ccoc12
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(CC(N)=O)c2occc12
Yield: 99 %

Procedure:
Combine 2-[4-(2-Bromoethoxy)benzofur-7-yl]acetamide (0.102 g, 0.342 mmol) with neat diethyl amine (3 ml, excess), and heat at 55° C. for 18 hours. Dilute the mixture with ethyl acetate and wash with water and brine. Dry over sodium sulfate, filter, and concentrate to give 0.098 g (99%) of the title compound as a brown solid. Mass spectrum: electrospray (m/z) 264 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: COc1cccc(N)c1
Solvent: CCO
Product: COc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 72.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.0 ml (26.0 mmol) m-anisidine was heated to reflux under N2. Removed heat at 4.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried with hexane and collected crystals. Washed with water, dried in vacuo. Dissolved 5.94 g of crude product in 320 ml boiling ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving about 5 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=291.1.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][C:19]1[C:24](=[O:25])[N:23]2[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]2=[N:21][C:20]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]4=[N:21][C:20]=3[CH3:31])[CH2:6][CH:5]=2)=[CH:8]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
A solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)indole (25 g, 0.126 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (33 g, 0.139 mol) and potassium carbonate (17.5 g, 0.127 mol) in acetonitrile (500 ml) and water (100 ml) was heated under reflux for 18 h. After cooling the precipitate was collected and washed with water, isopropyl alcohol and petroleum ether respectively. Yield 38 g (76%) of a pale yellow solid. M.p.: 210-212° C.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:30])=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.CN1CCOCC1.ClC(OCC(C)C)=O>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([NH:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:30])=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1)=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)ccc12

Procedure:
Boc-Gln-AMC was prepared by coupling anhydrous Boc-Gln-OH (7.03 g, 28.5 mmol) to 7-amino-4-methylcoumarin (AMC) by the mixed anhydride coupling procedure outlined above. First, a solution of a mixed anhydride of Boc-Gln-OH was prepared by reacting Boc-Gln-OH with an equivalent of N-methylmorpholine and an equivalent of isobutyl chloroformate, and the resulting solution was added to AMC (5.00 g, 28.5 mmol) dissolved in 30 mL DMF. After the resulting reaction was complete, the reaction mixture was filtered and the filtrate concentrated. Product (5 g) was separated from the filtrate and dissolved in 75 mL hot methanol. This solution was then concentrated to about 30 mL and cooled. Solid AMC was separated from the solution by filtration, and the remaining filtrate was further concentrated to a volume of about 5 mL. This concentrated solution was then diluted with 30 mL chloroform, and the resulting solution applied to a 4 cm column containing about 30 g silica gel. Residual AMC was eluted from the column with additional chloroform, and product Boc-Gln-AMC (0.97 g) was then recovered from the column by elution with 2% methanol in chloroform. Recrystallization of product from methanol provided 0.46 g of purified Boc-Gln-AMC, mp 260.5-207°. TLC with methanol:chloroform (1:9) indicated a single spot, Rf 0.28.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O)[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3])[C:9]#[N:10]
Reactant: CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCNc1ccc(C#N)cc1N
Reaction time: 2 h

Procedure:
To a Parr bottle containing 4-n-propylamino-3-nitrobenzonitrile (7.63 g, 37.2 mmol) in ethyl acetate (38 mL) is added 5% Pd/C (50% wet, 633 mg). The Parr bottle is sealed in a mechanical shaker, evacuated, and then purged with nitrogen followed by hydrogen. The system is pressurized to 50 PSI of hydrogen at room temperature and mechanical shaking engaged. After 2 hours, shaking is stopped, and the system purged with nitrogen prior to opening the vessel. The reaction mixture is filtered through celite, concentrated in vacuo, and the obtained solid recrystallized by dissolving in ethyl acetate (15 mL), heating, and adding hexanes (15 mL), to give 3-Amino-4-n-propylaminobenzonitrile as gray crystals. 1H NMR (CDCl3) δ 7.14 (1H, dd), 6.92 (1H, d), 6.56 (1H, d), 3.98 (1H, br s), 3.30 (2H, br s), 3.12 (2H, t), 1.75-1.65 (2H, m), 1.03 (3H, t). LRMS calcd 175.23, found 176.2 (MH+).
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OS(O)(=O)=O>C1COCC1>[CH2:10]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 35 %

Procedure:
A solution of 3-ethoxy-2-cyclopenten-1-one (5 g, 0.89 mol) in THF (70 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 mL) under N2 and stirred for 6 h. The resulting mixture was poured into a solution of 30% H2SO4 and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give the title compound (3.1 g, 35%) as a colorless oil. NMR(CDCl3):3.45(s, 2H, benzylic protons), 5.83 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][C:48]1[N:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([NH:56][CH:54]([C:51]3[CH:52]=[N:53][C:48]([O:47][CH3:46])=[CH:49][CH:50]=3)[CH3:55])=[O:20])[N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccc(C(C)N)cn1
Reactant: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(C)NC(=O)c2nc(NC(=O)Nc3ccc(C)c(F)c3)cn2C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg (0.2 mmol) of 4-({[(4-methyl-3-fluorophenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylic acid (Example 18A) are dissolved in 4 ml of DMF and, after addition of 150 mg (0.39 mmol) of HATU and 36 mg (0.3 mmol) of DMAP, stirred at room temperature for 15 minutes. 60 mg (0.39 mmol) of [1-(6-methoxypyridin-3-yl)ethyl]amine are added to this solution and the mixture is stirred overnight. The reaction mixture is purified by preparative HPLC. The correct fractions are evaporated in vacuo.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[F:13][C:14]([F:41])([F:40])[S:15]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([CH:29](O)[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=[O:17])=[O:16].O>C(OCC)C>[F:41][C:14]([F:40])([F:13])[S:15]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([CH:29]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=[O:17])=[O:16]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
13.21 ml of triethylamine and 7 ml of methanesulfonyl chloride are successively added to a solution, cooled to 0° C. with an ice bath, of 13.8 g (30.53 mmol) of 2-trifluoromethanesulfonyloxy-8-(1′-hydroxy-2′-tert-butyldimethylsilyloxyethyl)quinoline in 300 ml of ethyl ether. The mixture is stirred for 30 min at 0° C. and then for 10 min at ambient temperature and is hydrolyzed by the addition of 300 ml of water. Extraction is carried out with ethyl acetate (3×250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is dissolved in 200 ml of chloroform and 45 ml of diethylamine and the mixture is brought to reflux for 16 h. 200 ml of water are added and extraction is carried out with ethyl acetate (3×150 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 8/2) to provide 14 g of 2-trifluoromethane sulfonyloxy-8-(1-diethylamino-2-tert-butyldimethylsilyloxyethyl)quinoline in the form of a yellow oil. (Yield: 90%)