Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Li+].[Li+].[OH-]>C1COCC1.O>[CH3:6][C:5]([CH3:8])([CH3:7])[C@H:4]([NH:9][C:10]([O:12][C:13]([CH3:19])([CH3:18])[C:14]([F:15])([F:16])[F:17])=[O:11])[C:3]([OH:20])=[O:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NC(=O)OC(C)(C)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-3,3-Dimethyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino)-butyric acid methyl ester (673 mg, 2.249 mmol, from Step 1b) in THF (4 mL) was added to a pre-made solution of lithium hydroxide monohydrate (189 mg, 4.50 mmol) in water (4.00 mL). The cloudy white solution was stirred at rt for 5 hrs. Another 100 mg of LiOH in 1 mL water was added to the mixture and the solution was stirred at rt overnight. The volatiles were removed, and the reaction mixture was diluted with 5% citric acid aqueous solution, and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude material (325 mg, 51%) as white solid was used in the next step reaction without further purification.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[C:11](=O)=[O:12].CC(C)=O.C([Li])CCC.CN(C=O)C>C1COCC1>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:11]=[O:12])=[C:3]([CH3:10])[CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(Cl)cc(C)c1Br
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(C)c1C=O
Reaction time: 2 h

Procedure:
Dissolve 4-bromo-3,5-dimethyl chlorobenzene (6.5 g) in 50 mL anhydrous THF and cool to −78° C. (dry ice/acetone) under N2. Dropwise over 5 minutes add a solution of butyllithium (12.50 mL, 2.5M in hexanes) to the stirring solution of aryl bromide at −78° C. After 2 hours, dropwise add anhydrous DMF (5.0 mL) to the orange/red reaction solution and allow to warn to ambient temperature overnight while stirring under N2. Evaporate the yellow solution down to a yellow oil and partition between H2O (100 mL) and CH2Cl2 (100 mL). Extract the aqueous layer once with CH2Cl2, then pool the organic layers and dry over Na2SO4, filter and evaporate down to 5.0 g of yellow oil. Use without further purification. LCMS=169.6 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[C:8]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:9][CH:10]=[CH:11][CH:12]=1.[NH3:28]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[C:8]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:28])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: N
Reactant: Fc1c(Cl)cccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.23 g, 0.0047 mol), N-[3-(3-chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (2.0 g, 0.0047 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.38 g (20%), m.p. 204°-207 ° C.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:19](#[N:23])[CH2:20][C:21]#[N:22].C(NCC)C.O>CN(C=O)C>[NH2:23][C:19]1[O:1][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[C:20]=1[C:21]#[N:22]
Reactant: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 236 g (974 mmol) 2-hydroxy-1-(4-methoxyphenyl)-2-phenylethanone and 83.66 g (1266 mmol) malononitrile in 470 ml DMF and, with cooling on an ice bath, add 86.6 ml (836.7 mmol) diethylamine. After 1 h, heat the mixture to RT and continue stirring for 4 h at RT, before adding 2.5 liter water and a few seed crystals. After 30 min, decant the supernatant water and replace with 1.25 liter of fresh water. Stir the suspension thoroughly and again decant the supernatant water. Take up the sticky crystalline residue in ethyl acetate and then concentrate under vacuum almost completely. Stir the residue with 730 ml diisopropyl ether and leave the suspension to stand overnight at RT. Then filter off the solid matter with suction and dry under vacuum. 211.5 g (57.6% of theor.) of the title compound is obtained.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:30][CH3:31])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C.CO>[CH2:30]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1)[CH3:31]
Reactant: CCN(CC)CCC1CCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 13 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(diethylamino)ethyl]pyrrolidine in a yield of 13% of theory. Colourless crystals, m.p. 137°-138° C. (from ethyl acetate/methanol 98/2 v/v).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.[Li]CCCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>C1COCC1>[CH:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[N:3]=1)([CH3:11])[CH3:10]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)Oc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
Sodium pieces (200 mg) was added portion wise to 2-propanol (0.521 g, 6.35 mmol) and the reaction was stirred for 12 h at RT. To the above thick solution, 2,6-dibromo pyridine (1 g, 4.23 mmol, Aldrich) was added and the reaction was heated to 90° C. for 2 h. The mixture was cooled to RT and the solvent was removed. The crude residue was treated with ice water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (Eluent: 0.5% EtOAc in petroleum ether) to give 2-bromo-6-isopropoxypyridine (600 mg, 66.5%) as a colorless liquid. MS (ESI, pos. ion) m/z: 216.0 (M+1); 1H-NMR (400 MHz, CDCl3): δ 7.38-7.34 (m, 1H), 6.99 (dd, J=7.2 Hz, J=4 Hz 1H), 6.60 (dd, J=8.0 Hz, J=4 Hz 1H). 5.28-5.25 (m, 1H), 1.32 (d, J=4.4 Hz, 6H). A solution of 2-bromo-6-isopropoxypyridine (1 g, 4.67 mmol) in dry THF (10 mL) was treated with n-BuLi (1.6M in hexane) (3.2 mL, 5.14 mmol) dropwise at −78° C. and the reaction was stirred at the same temperature for 30 min. Tributyl tin chloride (1.8 mL, 5.60 mmol, Aldrich) was added to the reaction at −78° C. and the reaction was stirred at the same temperature for 30 min. The mixture was treated with saturated NH4Cl solution (10 mL) and extracted with EtOAc (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified with silica gel column chromatography using (eluent: 100% petroleum ether) to give 2-isopropoxy-6-(tributylstannyl)pyridine (1 g, 50%) as a colorless liquid. 1H-NMR (300 MHz, CDCl3): δ 7.40-7.35 (m, 1H), 6.99 (dd, J=5.4, 4.5 Hz, 1H), 6.65 (dd, J=7.2, 0.6 Hz, 1H). 5.32-5.24 (m, 1H), 1.34-1.32 (m, 10H), 1.31-1.25 (m, 13H), 0.87-0.84 (m, 10H).
Reaction SMILES: NN.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C@@H:15]([N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C@@H:15]([NH2:17])[CH3:16])=[N:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: C[C@@H](c1ncc(-c2ccc(Cl)cc2)o1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@H](N)c1ncc(-c2ccc(Cl)cc2)o1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
Hydrazine (0.55 ml, 6.09 mmol) was added to a solution of (S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione (430 mg, 1.219 mmol) in ethanol (15 ml) and heated at 80° C. for 13 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded the desired product (200 mg, yellow oil). 1H NMR (400 MHz, CDCl3) δ 7.67-7.51 (m, 9H), 7.47-7.35 (m, 8H), 7.31-7.21 (m, 1H), 4.25 (q, J=6.8 Hz, 4H), 1.97-1.66 (m, 15H), 1.63-1.48 (m, 2H). HRMS(B) tR=1.49 min; MS m/z 222.0560
Reaction SMILES: ClCCCCCC(=O)C(OCC)=O.CC1(C)C[C@@H]1C(N)=O.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[C:28](\[NH:34][C:35]([C@H:37]1[CH2:39][C:38]1([CH3:41])[CH3:40])=[O:36])/[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[C:28](/[NH:34][C:35]([C@H:37]1[CH2:39][C:38]1([CH3:40])[CH3:41])=[O:36])\[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)/C(=C/CCCCCl)NC(=O)[C@H]1CC1(C)C
Agent: CC1(C)C[C@@H]1C(N)=O
Agent: CCOC(=O)C(=O)CCCCCCl
Product: CCOC(=O)/C(=C\CCCCCl)NC(=O)[C@H]1CC1(C)C
Yield: 10.5 %

Procedure:
As described in European Patent No. 48301, 250 g of ethyl 7-chloro-2-oxoheptanoate and 141 g of (S)-2,2-dimethyl cyclopropanecarboxamid were reacted and concentrated. In result, 372.4 g of ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-hepnoate (2) containing, by gas chromatography assay, 10.5% of ethyl (E)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (3) was obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1([CH2:47][CH2:48][CH2:49][NH2:50])[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCn1ccnc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCn2ccnc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.029 mL (0.25 mmole) of 3-imidazol-1-yl-propylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-imidazol-1-yl-propyl)-3-methoxy-benzamide (I-61) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19](S(C(F)(F)F)(=O)=O)[N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)c(F)cc3c(OC(C)C)n2)nn1S(=O)(=O)C(F)(F)F
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)c(F)cc3c(OC(C)C)n2)n[nH]1
Temperature: 200 °C

Procedure:
Trifluoro-methanesulfonic acid 7-fluoro-1-isopropoxy-3-(5-methyl-1-trifluoromethanesulfonyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester (100 mg) and morpholine (100 ul) was added to NMP (1 ml). The mixture was heated at 200° C. for 1 hour under microwave irradiation. It was purified by preparative LC-MS to give (7-Fluoro-1-isopropoxy-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (26 mg). LC-MS: m/e 386 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH:15]([Mg]Br)=[CH2:16].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:16]=[CH:15][NH:12][C:5]2=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ncccc12
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2cc[nH]c2c2cccnc12
Reaction time: 0.67 h
Yield: 20.6 %

Procedure:
To a stirred solution of 8-chloro-5-nitroquinoline (5.0 g, 24 mmol) in tetrahydrofuran (70 mL) at −78° C. under Ar was added a solution of vinylmagnesium bromide (1.0 M in tetrahydrofuran, 72 mL, 72 mmol) over 5 min. The mixture was stirred for 40 minutes, poured into aqueous ammonium chloride solution (200 mL) and extracted with ether (3×100 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give 5-chloro-1H-pyrrolo[2,3-f]quinoline as an orange solid (1.0 g, 21%): mp 248-250° C.; IR νmax (Nujol)/cm−1 3198, 2924, 2854, 1500, 1465, 1377, 1364, 1290, 1162, 1126, 1085, 949, 887, 810, 780, 744, 706, 633, 599 and 512; NMR δH (400 Mz, CDCl3) 6.64 (1H, d, J 3 Hz) 7.56 (1H, t, J 4 Hz) 7.65 (1H, dd, J2.5, 8.5 Hz) 8.14 (1H, s) 8.83 (1H, d, J 8.5 Hz) 8.88 (1H, d, J 2.5 Hz) 12.37 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)[CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C1CCc2cc(N3CCN(C(=O)c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Yield: 57 %

Procedure:
6-[4-(4-Nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (400 mg) was added to 20 ml of methanol and reduced at room temperature at atmospheric pressure using 50 mg of 10% palladium-carbon as a catalyst. After completion of absorption of hydrogen gas the catalyst was removed by filtration. The filtrate was subjected to distillation under reduced pressure and the residue was purified through silica gel column chromatography. Recrystallization from ethanol gave 210 mg of 6-[4-(4-aminobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 244°-246° C., pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[Cl:27].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CS(C)=O.C(O)C.C(OCC)(=O)C.O1CCCC1.O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[N:10]=3)[CH:7]=2)=[C:19]([Cl:27])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.921 mmol) and 4-fluoro-3-chloro-1-nitrobenzene (193 mg, 1.11 mmol) in dimethyl sulfoxide (2 mL) was added cesium carbonate (450 mg, 1.38 mmol), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. A mixed solution of the obtained residue, reduced iron (271 mg, 4.61 mmol) and ammonium chloride (493 mg, 9.21 mmol) in ethanol (2 mL)/tetrahydrofuran (2 mL)/water (1 mL) was stirred at 80° C. for 7 hr. The reaction mixture was diluted with ethyl acetate and tetrahydrofuran, and filtered through celite. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1→ethyl acetate alone) to give the title compound (177.5 mg, 56%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a round bottom flask contained (R)-4-benzyl-2-oxazolidinone (800 mg, 4.51 mmol) in THF (10 mL), n-BuLi (2.83 mL, 1.6M, 4.52 mmol) was added at −78° C., dropwise. The solution was stirred at −78° C. for 10 min. A solution of 2-(4-bromophenyl)acetyl chloride (1.0 g, 4.28 mmol) in 10 mL THF was added. The solution was stirred −78° C. for 30 min, and rt for 3 h, and then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76A (1.29 g, 80%). MS (ESI) m/z 374.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(Cl)Cl>O1CCOCC1.CCOC(C)=O.CCCCCC.O>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(-c2ccccc2Cl)cc(N)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine (8.90 g, 43.7 mmol, prepared as described in the previous step) in 1,4-dioxane (200 mL) and water (100 mL) was treated with Cs2CO3 (35.6 g, 109 mmol) and 2-chlorophenylboronic acid (10.2 g, 65.5 mmol) under Ar. To the resulting mixture was added Cl2Pd(dppf).DCM (3.50 g, 4.30 mmol) and the mixture was then heated to 90° C. for 15 h. The cooled mixture was diluted with EtOAc (500 mL) and washed with water (500 mL). The aqueous layer was extracted twice with EtOAc (3×300 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (0:100-50:50 EtOAc/hexanes) to yield a yellowish white solid. The solid was dissolved in EtOAc (200 mL) with heating and hexane (150 mL) was added. The resulting solution was concentrated until the solution became turbid and heated to yield a clear solution which was left overnight at room temperature. The crystals formed were collected by suction filtration. This recrystallization procedure was repeated twice to yield 6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.59-7.66 (m, 1H), 7.43-7.51 (m, 1H), 7.31-7.39 (m, 2H), 6.69 (s, 1H), 6.11 (br. s., 2H), 4.07 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calculated for C12H10N3O3Cl: 280.0 (M+H), Measured: 280.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:41][N:42]([CH3:46])[C:43]([N:24]1[CH2:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([NH:17][C:15]3[N:16]=[C:9]4[C:8]([C:6]5[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:13][CH:12]=[CH:11][N:10]4[N:14]=3)=[CH:19][C:20]=2[CH2:26][CH2:25]1)=[O:44]
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.054 g, 0.110 mmol) in dichloromethane (4 mL) under an atmosphere of nitrogen was added triethylamine (0.0349 g, 0.345 mmol), N,N-dimethylcarbamoyl chloride (0.0159 mL, 0.172 mmol), followed by 4-dimethylaminopyridine (0.0014 g, 0.012 mmol) and was stirred at r.t. for 3 h and concentrated. The reaction was partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give 7-{8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid dimethylamide (0.030 g, 48%). MP=98-99° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.58 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.48 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.38 (m, 2H), 3.28 (m, 4H), 2.84 (m, 4H), 2.74 (s, 6H). MS=541 (MH)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-[4-(cyclopropylmethyl)-1-piperazinyl]benzenamine (3.7 g, 16 mmol) (from Step B above) in N,N-dimethylformamide (50 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (2.87 g, 16.1 mmol) (Aldrich) in N,N-dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water (1000 mL) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum. (4 g, 91%).