Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[OH:31])[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.O.CN(C=O)C>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][O:31][C:19]3[CH:20]=[CH:21][C:22]4[C:23]([C:27]([F:30])([F:29])[F:28])=[N:24][O:25][C:26]=4[C:18]=3[CH2:15][CH2:16][CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2cccc3[nH]ccc23)ccc2c(C(F)(F)F)noc12
Temperature: 110 °C
Yield: 77.7 %

Procedure:
4-(3-Chloropropoxy)-1H-indole (0.100 g, 0.48 mmol), 7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-ol (0.117 g, 0.48 mmol), potassium carbonate (0.099 g, 0.72 mmol), potassium iodide (0.016 g, 0.10 mmol), and DMF (5 mL) were mixed and heated at 110° C. for 1.5 hours. The mixture was cooled to room temperature. Water (10 mL) and ethyl acetate (10 mL) were added and the resultant mixture was stirred for five minutes. The organic layer was separated and aqueous layer was extracted again with ethyl acetate (10 mL). The organic layer was combined, washed with water (6×20 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give an oily residue, which was purified by filtering through a short silica column using hexane/dichloromethane (50/50) as an eluant to afford 6-[3-(1H-indol-4-yloxy)-propoxy]-7-propyl-3-trifluoromethyl-benzo[d]isoxazole (0.156 g, yield: 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21]N(C=O)C>O.C(Br)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:21][C:17]1[CH:16]=[CH:15][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: CN(C)C=O
Reactant: CCCCCC
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
4-Methoxy-2-methyl-1H-indole (1 g, 6.2 mmol) was added to 248 mg (6.2 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 0.74 mL (6.2 nmol) of benzyl bromide was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.3 g(84% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole, melting at 96-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11])=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[C:11][C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#CC(C)(C)CCOc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)C(F)(F)F)CCOc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.5 g (11.2 mmol) of 5-(4-chlorophenoxy)-3,3-dimethyl-1-pentyne in 25 ml of anhydrous tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere is added 4.5 ml of 2.5M n-butyllithium in hexanes. The mixture is stirred at -78° C. for 1 hour and then is transferred by canula to a solution of 3.19 g (22.4 mmol) of ethyl trifluoroacetate in 10 ml of tetrahydrofuran cooled to -78° C. After the addition is complete, the reaction is stirred at -78° C. for 0.5 hour, is allowed to warm to 0° C. and then is quenched with saturated ammonium chloride followed by 0.1N hydrochloric acid. The layers are separated and the organic phase is washed with saturated sodium bicarbonate and brine. The organic extract is dried over magnesium sulfate, filtered and evaporated. The residue is subjected to flash chromatography on silica gel using hexane:ethyl ether (93:7) as eluting solvent. The appropriate fractions are combined and evaporated to give a light tan oil: IR (film) 2200, 1710 cm-1 ; NMR (CDCl3) δ1.42 (6H, s), 2.04 (2H, d, J=6.5 Hz), 4.1 (2H, t, J=6.6 Hz), 6.81 (2H, d, J=9.0 Hz), 7.23 (2H, d, J=9.0 Hz)
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>C(O)C>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixed solution of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (12.02 g (56.9 mmol)) and toluene (96.0 ml) was added dropwise thionyl chloride (8.11 g (68.2 mmol)), so that the internal temperature did not exceed 25° C., which was stirred for about 90 minutes at room temperature. Ethanol (24.0 ml) was added to this mixed solution to obtain a 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:27]1[CH:31]=[CH:30]N=C1)(N1C=CN=C1)=O.[CH:32](N(CC)C(C)C)(C)[CH3:33]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:27][CH2:31][CH2:30][CH2:32][CH3:33])=[O:17])=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCNC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of 4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoic acid (22.2 g, 83.6 mmol) (EP0836839, p60) carbonyldiimidazole (21.36 g, 131.7 mmol), and N,N-diisopropylethylamine (20 mL, 115.1 mmol) in dichloromethane (600 mL) was stirred at room temperature for 2 hours. nButylamine (10 mL, 101.18 mmol) was then added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 10% citric acid (2×50 mL), saturated sodium hydrogen carbonate solution (200 mL), water (200 mL) and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to give a cream powder. The powder was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 99:1, to afford the title compound (17.5 g, 65%). LRMS Cl m/z 383.3 [M+NH4]+, m.p.=118° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydro-pyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), ethyl isocyanate (0.00310 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD): δ=1.13 (t, J=7.2 Hz, 3H), 1.87 (d, J=6.8 Hz, 3H), 2.48 (br. s., 2H), 3.22 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 4.06 (d, J=2.5 Hz, 2H), 6.25 (br. s., 1H), 6.43-6.56 (m, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.65 (s, 1H), 8.16 (s, 1H). MS (ES+): m/z 493.02/495.04 (100/68) [MH+]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (600 mg, 2.0 mmol) was reacted with tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (340 mg, 39%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][NH:30][CH2:29][C:28](=[O:32])[N:27]([CH2:33][CH3:34])[C:26]=3[CH:35]=2)[N:15]=1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[CH3:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][N:30]([CH2:1][CH3:2])[CH2:29][C:28](=[O:32])[N:27]([CH2:33][CH3:34])[C:26]=3[CH:35]=2)[N:15]=1)=[O:7]
Reactant: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
Acetaldehyde (20 mg, 0.45 mmol) was added to a solution of 3-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (42.5 mg, 0.09 mmol) in THF:DCE (1:2) at 0° C. After 15 minutes, 100 mg of sodium triacetoxyborohydride was added and the mixture was stirred for 2 hours at 0° C. and 1 hour at room temperature. Evaporation and chromatography on preparative TLC with methylene chloride and methanol (100:7) gave 31 mg of 3-[5-chloro-2-(1,4-diethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (50%): 1H NMR (300 MHz, CD3OD) δ 8.42 (d, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.44 (d, 1H), 7.42 (s, 1H), 7.27 (d, 1H), 3.9 (q, 2H), 3.64 (s, 2H), 3.22 (s, 2H), 2.87 (s, 3H), 2.75 (q, 2H), 2.05 (s, 3H), 1.18 (m, 6H); MS (m/e): 500.4 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([OH:28])=O)[CH2:21]4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:65])([F:64])[O:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[CH:58][CH:57]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:61][CH2:60][C:59]5[CH:62]=[CH:63][C:56]([O:55][C:54]([F:53])([F:64])[F:65])=[CH:57][CH:58]=5)=[O:28])[CH2:21]4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)[C@H]1CCCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CCCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 23 %

Procedure:
To a solution of 3.3 (491 mg, 1.280 mmol) and TEA (535 μL, 3.84 mmol) in DCM (6402 μL) was added HATU (536 mg, 1.409 mmol) followed by 4-(trifluoromethoxy)benzylamine (Apollo Scientific Ltd., 215 μL 1.409 mmol) The reaction was stirred at room temperature for 40 hours. The reaction then was concentrated and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5 to 5% MeOH in DCM, to provide 3 as a light purple solid in 23% yield. 1H NMR (300 MHz, CD3OD) δ ppm 1.62 (br. s., 1H) 1.79-1.93 (m, 2H) 1.93-2.10 (m, 1H) 2.54 (br. s., 1H) 3.12 (br. s., 4H) 3.35-3.52 (m, 2H) 3.81 (br. s., 4H) 4.22-4.37 (m, 4H) 6.45 (d, J=7.31 Hz, 1H) 6.99 (d, J=8.62 Hz, 2H) 7.21 (d, J=8.04 Hz, 2H) 7.33 (t, J=8.40 Hz, 4H) 7.65 (d, J=7.31 Hz, 1H); M+H 557.24764.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25]([OH:27])=O)[C:4]=12.[Cl-].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([N:41]2[CH2:46][CH2:45][NH2+:44][CH2:43][CH2:42]2)=[N:39][N:38]=[N:37]1.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=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25](=[O:27])[N:44]3[CH2:43][CH2:42][N:41]([C:40]4[N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)[N:37]=[N:38][N:39]=4)[CH2:46][CH2:45]3)[C:4]=12
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CC[NH2+]CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (15 mg, 0.039 mmol), 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-ium chloride (11.43 mg, 0.043 mmol), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (13.71 mg, 0.043 mmol) and N,N-diisopropyl ethylamine (0.022 ml, 0.124 mmol) in DMF (1 ml) was stirred overnight at room temperature. The reaction mixture was filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give N-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (10 mg, 43%) as white solid. LCMS: m/e 600.47 (M+H)+, ret time 2.67 min (method 4). 1H NMR (500 MHz, DMSO-D6) δ ppm 1.22 (s, 9H) 3.23-3.29 (m, 2H) 3.39-3.49 (m, 4H) 3.68-3.74 (m, 2H) 3.99 (s, 3H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.88 (s, 1H) 8.13-8.18 (m, 1H) 8.21 (s, 1H) 8.23 (d, J=3.66 Hz, 1H) 8.64-8.69 (m, 1H) 11.36 (s, 1H) 12.59 (d, J=3.36 Hz, 1H)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([O:12][CH2:13][C:14]2([CH3:19])[CH2:18][CH2:17][NH:16][CH2:15]2)[C:7]([C:10]#[N:11])=[N:8][CH:9]=1.[F:20][C:21]([F:32])([F:31])[C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([O:12][CH2:13][C:14]2([CH3:19])[CH2:18][CH2:17][N:16]([C:28]([C@H:25]3[CH2:24][CH2:23][C@H:22]([C:21]([F:20])([F:31])[F:32])[CH2:27][CH2:26]3)=[O:29])[CH2:15]2)[C:7]([C:10]#[N:11])=[N:8][CH:9]=1
Reactant: CC1(COc2cc(Cl)cnc2C#N)CCNC1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CC1(COc2cc(Cl)cnc2C#N)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using 5-chloro-3-((3-methylpyrrolidin-3-yl)methoxy)picolinonitrile dihydrochloride (EXAMPLE 84, Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].O=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>C1COCC1>[CH2:13]([O:12][C:10](=[O:11])[CH:9]=[C:18]1[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]1)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To an ice-cold solution of ethyl 2-diethoxyphosphorylacetate (25.9 g, 116 mmol) in THF (200 mL) was added carefully NaH (60% dispersion in mineral oil, 4.62 g, 116 mmol) over 25 min. The cold bath was removed and after 30 min, tert-butyl 3-oxoazetidine-1-carboxylate (9.88 g, 57.7 mmol) in THF (40 mL) was added over 5 min. After 30 min, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by column chromatography (6/1 Pet ether/ethyl acetate) gave the ester (8.59 g, 62%) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: Cc1cccc(CBr)c1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1cccc(C)c1)OC

Procedure:
Following the procedure of Compound 11, 3-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:46]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:43]#[N:44])([CH3:42])[CH3:41])[CH:35]=4)[CH:28]=[CH:29][C:30]=3[CH3:31])=[CH:23][N:18]2[N:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:43]([C:40]([C:36]1[CH:35]=[C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[O:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([NH:15][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:8])[N:46]=3)[CH:23]=2)=[O:45])[CH:39]=[CH:38][CH:37]=1)([CH3:42])[CH3:41])#[N:44]
Reactant: O=C(O)c1cocn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cocn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 1,3-oxazole-4-carboxylic acid (107 mg, 946 μmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (123 μL, 1.42 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (202 mg, 473 μmol) were dissolved in pyridine (5 mL), and the mixture was stirred at room temperature for 15 hr. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→98/2), and fractions containing the desired product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (196 mg, 79%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Temperature: 40 °C
Yield: 94.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.02 g (6.58 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4 and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 1.71 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate as a white crystalline product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][N:11]1[C@H:15]2[C:16]([C:19]([O:21]C)=O)=[CH:17][CH2:18][C@@H:12]1[CH2:13][CH2:14]2>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]([C@H:16]2[C@@H:17]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=3)[CH2:18][C@H:12]3[N:11]([CH3:10])[C@@H:15]2[CH2:14][CH2:13]3)=[O:21])=[CH:3][CH:4]=1.[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]([C@@H:16]2[C@@H:17]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=3)[CH2:18][C@H:12]3[N:11]([CH3:10])[C@@H:15]2[CH2:14][CH2:13]3)=[O:21])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: [Mg]
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)c1ccc(F)cc1)[C@@H](c1ccc(F)cc1)C2
Product: CN1[C@H]2CC[C@@H]1[C@H](C(=O)c1ccc(F)cc1)[C@@H](c1ccc(F)cc1)C2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Grignard reagent was made in a three necked reaction flask equipped with mechanical stirring, an intensive condenser and a pressure equilibrated funnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesium turnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. The solution of grignard reagent was cooled to -20° C. and a solution of (-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolute diethyl ether was added over 1/2 hour. The reaction was first stirred one hour at -20° C. and then 16 hours at room temperature and was finally quenched by addition of water (50 ml). The mixture was acidified by addition of hydrochloric acid (4M, 50 ml) and the aqueous phase was washed twice with diethyl ether. To the aqueous phase was added ammonium hydroxide (25%) to basic reaction and the resulting mixture was finally extracted three times with diethyl ether. After drying and concentration of the combined organic phase in vacuo, the crude product was subjected to column chromatography using diethyl ether+triethyl amine (5%) as eluent, yielding (1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 178°-180° C. and (1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, white crystals m.p. 124°-140° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:17])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>>[C:5]([Cl:3])(=[O:17])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCCCCCC(=O)O
Product: C=CCCCCCCC=CC(=O)Cl
Yield: 88 %

Procedure:
Thionyl chloride (25.6 ml, 0.36 mole) was added to undec-10-enoic acid (62.6 grams, 0.34 mole) over a period of 45 minutes, while stirring and the resulting mixture was thereafter refluxed for 2 hours. The acyl chloride was then removed under reduced pressure (102° C./2 mm Hg), to give Compound 55 (see, Scheme 30 below) in 88% yield.