Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[C:15]([C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5])#[N:16]
Reactant: CNC(=O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 77 %

Procedure:
Prepared as in Example 197c from 3-hydroxy-N,2,2-trimethylpropanamide (Example 202d) and 2,6-dinitrobenzonitrile in 77% yield as a pale yellow solid. MS 378 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[F:12][CH2:13][CH2:14]I.O>CN(C=O)C>[F:12][CH2:13][CH2:14][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc[nH]1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1CCF
Reaction time: 0.5 h

Procedure:
Methyl 1H-pyrrole-2-carboxylate (3.0 g, 23.3 mmol) was solved in DMF (40 ml). Sodium hydride (1.40 g, 34.9 mmol, 60% in oil) was added and the mixture was stirred for 30 minutes at room-temperature. 1-Fluoro-2-iodoethane (4.1 g, 23.2 mmol) was added and the mixture was stirred for 15 h at 50° C. Water was added and the mixture was extracted with diethylether. The mixture was washed with saturated aqueous ammonium chloride. The product was purified chromatographically, using a mixture of petroleum and ethylacetate as eluent. Yield 1.1 g (28%).
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](F)[C:6]([F:13])=[C:5]([F:14])[C:4]=1[F:15]>C(OCC)C>[N+:9]([C:8]1[C:3]([F:2])=[C:4]([F:15])[C:5]([F:14])=[C:6]([F:13])[C:7]=1[NH2:1])([O-:11])=[O:10]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Product: Nc1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
2-Nitro-3,4,5,6-tetrafluoroaniline was prepared using an adaptation of the method of Brooke et al., J. Chem. Soc. 802 (1961). Ammonia gas was bubbled through a solution of pentafluoronitrobenzene (3.00 g, 114.1 mmol) in 200 mL anhydrous diethyl ether for 4 h. During this time the color changed from clear white to a deep yellow and a white precipitate formed. The precipitate (ammonium fluoride) was separated by vacuum filtration and washed with ether (30 mL). The filtrate was rotary evaporated and the resulting orange crystals gave 3 spots on TLC (alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, activity II) on a 1.5"×20" column. The first band was collected and concentrated to yield a yellow solid 1.88 g (63.0%), mp 44.5-45 (lit. 42.5°-43.5° C.). 19F NMR (C6F6 external standard, δ -162.9) δ -149.9(m), -1.56.6(m), -162.0 (m), -178.3(m).
Reaction SMILES: [Cl:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[S:8])[N:3]1[CH3:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].[I-].[Na+]>CC(C)=O>[Cl-:1].[Cl:1][C:2]1[N:3]([CH3:9])[CH:4]([S:8][CH2:11][C:12](=[O:14])[CH3:13])[NH+:5]([CH3:7])[CH:6]=1
Reactant: CN1CC(Cl)N(C)C1=S
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)CSC1N(C)C(Cl)=C[NH+]1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 gram (0.0062 mol) of 4-chloro-1,3-dimethyl-imidazoline-2-thione in 180 mL of acetone was added 0.569 g (0.0062 mol) of chloroacetone and a small crystal of sodium iodide. The mixture was stirred overnight at room temperature whereupon a product precipitated. The latter was recovered by filtration and recrystallized from isopropyl alcohol-hexane to obtain purified 4-chloro-1,3-dimethyl-2[-(2-oxopropyl)thio]-1H-imidazolium chloride, m.p. 134°-136° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8].[CH2:11]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.O>C(OCC)(=O)C>[CH2:11]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[C:7](=[O:8])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)CCC(=O)O
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(=O)OC
Reaction time: 1 h

Procedure:
A solution of 5.1 g (34 mmol) of succinic acid monomethyl ester monochloride in 20 ml of ethyl acetate is added dropwise, while cooling with ice, to a solution of 6.0 g (22.7 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 13 ml of Hunig base in 100 ml of ethyl acetate. The reaction mixture is stirred at from 0° to 5° for 1 hour and then 30 ml of water are added. The organic phase is washed in succession with 30 ml of 2N hydrochloric acid, water and saturated potassium hydrogen carbonate solution and is dried. Evaporation of the solvent yields crude 3-methoxycarbonylpropanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide in the form of an oil that has an Rf value of 0.32 [toluene/methanol (19:1)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]2([CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35][CH:34]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])[C:9]1=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Yield: 64.2 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2.6 mmol) prepared in example 24a was reacted with 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.3 g, 14.1 mmol) prepared in example 17a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.92 g, 65%).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2].II.[Cl:15][C:16]1[C:17]([NH:26][NH2:27])=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.O.OO>O.C(O)(=O)C.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:26]=[N:27][C:9]2[CH:10]=[CH:11][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=2[OH:12])=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)c1cccc(O)c1
Agent: II
Agent: OO
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(N=Nc2ncc(C(F)(F)F)cc2Cl)c(O)c1

Procedure:
Next, a reaction flask was loaded with 3-(N,N-diethlyamino)phenol (1.3 g), dimethylformamide (9 ml), acetic acid (3 ml) and iodine (0.14 g), and they were mixed, followed by addition of 3-chloro-2-hydrazino-5-trifluoromethylpyridine (1.0 g) to the flask with stirring. Then, to this mixture, a 30 % hydrogen peroxide water (1.4 g) was dropwise added in one hour and the mixture was stirred overnight. Water was added to this reaction mixture, followed by extraction with ether. The organic layer was condensed to precipitate crystals. The crystals were filtrated for collection and dried to give intended crystals (0.5 g).
Reaction SMILES: [CH2:1]([N:3]([N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[Li+].CCC[CH2-].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:12]1[N:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=1
Reactant: CCN(C(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)n1cc(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
A vacuum dried 25 mL round bottomed flask equipped with a magnetic stir bar and containing tert-butyl ethyl(4-(pyridin-3-yl)-1H-imidazol-1-yl)carbamate (77 mg, 0.267 mmol) was charged with anhydrous tetrahydrofuran (THF, 3 mL) and cooled to −78° C. N-butyllithium (0.25 mL 0.675 mmol, 2.5 M in hexanes) was added and the mixture was stirred for 15 minutes. Hexachloroethane (189 mg, 0.80 mmol) dissolved in anhydrous THF (1 mL) was added dropwise to the reaction mixture while maintaining a temperature of −78° C. After stirring for 1 hour, the reaction was allowed to warm to room temperature. The reaction mixture was loaded directly on a silica gel column and the THF was removed in a vacuum oven. The crude product was purified using silica gel chromatography (0-25% methanol/dichloromethane) to afford the title compound (3 mg, 0.009 mmol, 3.5%) as a yellow oil: 1H NMR (600 MHz, CDCl3) δ 8.92 (d, J=1.6 Hz, 1H), 8.50 (dd, J=4.8, 1.5 Hz, 1H), 8.06 (dt, J=7.9, 2.0 Hz, 1H), 7.33-7.27 (m, 2H), 3.89 (dq, J=14.5, 7.3 Hz, 1H), 3.68 (dq, J=14.3, 7.2 Hz, 1H), 1.44 (s, 9H), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 152.90, 148.47, 146.02, 136.07, 134.08, 131.81, 128.79, 123.36, 117.66, 83.23, 45.32, 28.04, 13.03; ESIMS m/z 323 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3OC)[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)([O-])[O-])=CC=3[Cl:93])N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CC3(CO)COC3)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[Cl:93])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)([O-])[O-])cc2Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: CC1(C)OB(c2cnn(CC3(CO)COC3)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(Cl)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1

Procedure:
Prepared analogously to Compound 44A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-chlorobenzyl)phosphonate (Compound 58B, 200 mg, 0.321 mmol) and (3-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 44B, 99.0 mg, 0.337 mmol) to afford 160 mg of the title compound as a racemic mixture (56%). MS (ESI): m/z=899.74/901.72 [M+H]+. UPLC: tR=1.64 min (UPLC-TOF: polar—2 min).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][C:16](=[O:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:25][C:21]1[CH:20]=[C:19]([N:15]2[CH2:14][C@H:13]([CH2:12][N:26]=[N+:27]=[N-:28])[O:17][C:16]2=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(c3cccc(F)c3)C(=O)O2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl 4-methylbenzenesulfonate (PREPARATION 15, 2.340 g, 6.40 mmol) in dry DMF (60 ml) is treated with solid sodium azide (3.331 g, 51.23 mmmol) at 20-25°. The resultant slurry is warmed to 65° for 4.5 hr and then cooled to 20-25° and left overnight. The reaction mixture is then diluted with ethyl acetate and water, transferred to a separatory funnel, and extracted with ethyl acetate. The combined ethyl acetate extracts are washed thoroughly with water, and then dried (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound, mp 81-82°; [α]25D -136.5° (c 0.9, CHCl3); IR (mineral oil mull): 2115, 1736, 1614, 1591, 1586, 1497, 1422, 1233, 1199, 1081, 1049 cm-1 ; NMR (CDCl3, 300 MHz) δ 7.45, 7.34, 7.23, 6.86, 4.81, 4.09, 3.86, 3.72 and 3.60; MS (m/z) 236 (59.0, M+), 179, 136, 122, 109, 95, 75; HRMS (m/z) 236.0708 (calc'd for C10H9FN4O2 : 236.0709).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:26][CH2:25][CH2:24][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:20]1[C:19]2([CH2:24][CH2:25][CH2:26][C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:27])=[O:2])=[CH:14][CH:13]=3)=[CH:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@H](CC(=O)O)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
To a solution of (R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (23.5 g) obtained in Step 4 in a mixed solvent of tetrahydrofuran (94 mL)-methanol (94 mL) was added 2N aqueous sodium hydroxide solution (48 mL), followed by stirring the mixture at room temperature overnight. To the reaction mixture was added 2N aqueous hydrochloric acid solution (48 mL), followed by extraction with n-hexane twice. The organic layers were combined, washed with saturated brine, dried and concentrated to give (R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (26 g).
Reaction SMILES: [OH:1][CH:2]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:3]([O:5]CC)=[O:4].O[Li:22].O.[OH-].[Na+]>>[Li+:22].[OH:1][CH:2]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:3]([O-:5])=[O:4]
Reactant: CCOC(=O)C(O)C1CN(c2ccc(C)cc2)CCO1
Reactant: [Li]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N2CCOC(C(O)C(=O)[O-])C2)cc1
Product: [Li+]
Yield: 98.9 %

Procedure:
According to the Step 1-2 in synthetic method for EXAMPLE 1, compound 117-1 (45 mg) and LiOH—H2O (6.8 mg) were used instead of 1-1 (LP) and NaOH to obtain compound 117-2 (41 mg) as a pale yellow amorphous solid.
Reaction SMILES: C([Sn]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:23]1[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Clc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cccs2)nn1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of tri-n-butylstannylthiophene (6.26 g, 16.78 mmol), 3,6-dichloropyridazine (5.00 g, 33.56 mmol), tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and few crystals of 1,2-ditert-butyl of 2,6-di-tert-butyl-4-methylphenolo in dry DMF (50 mL) was deareated twice with nitrogen. The reaction mixture was heated at 80° C. for 6 hours and, after cooling, poured onto water (100 mL). A white precipitate was collected, washed several times with water and dried under vacuum. This solid was taken up with ether (25 mL) and filtered to afford 3.01 g of almost pure product. Finally, this solid was crystallized from MeOH—H2O to give the pure target compound as white crystals (1.56 g, 7.90 mmol, 47.3% yield). Mp 155° C.; 1H NMR (CDCl3) δ 7.75 (1H, d, 2J=11.0), 7.68 (1H, d, 2J=3.6), 7.54 (1H, d, 2J=5.0), 7.51 (1H, d), 7.18 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[Li+].[OH-].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NN
Reactant: O=C(Cl)c1ccco1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(4-chloro-2-methylphenyl)hydrazine as the hydrochloride salt (96 mg, 0.5 mmol) in Et2O (10 mL) was added a 2 N solution of LiOH (3 mL), and the resulting mixture was stirred for 15 minutes. After the system became homogenous, furan-2-carbonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The crude material of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide obtained after the removal of the solvent was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([Cl:22])[CH2:7]1)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[ClH:22].[ClH:22].[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(Cl)C1
Reactant: C1COCCN1
Product: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(N2CCOCC2)C1
Product: Cl
Yield: 51 %

Procedure:
5-Morpholino-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester dihydrochloride was prepared from 5-chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and morpholine analogous to Example 173, but at atmospheric pressure.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (99 mg, 91%), MS (ISP) m/z=435.3 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].CCN=C=NCCC[N:21]([CH3:23])C.Cl.C(N(CC)CC)C.N[O:33][CH3:34].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([N:21]([O:33][CH3:34])[CH3:23])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CON
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A mixture of 2-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (20 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].O1CCCC1>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH:21][S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A mixture of ethyl 4-methyl-2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (0.42 g), 8N aqueous sodium hydroxide solution (0.4 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.17 g, yield 44%) as yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point>253° C. (decomposition).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=1[CH3:21])=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:59]=[N+:60]=[N-:61])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[CH3:21])[N:61]=[N:60][N:59]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a solution of 2-{[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 46, 710 mg, 2.37 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (1.24 g, 4.73 mmol), DIAD (0.920 mL, 4.73 mmol) and trimethylsilylazide (0.628 mL, 4.73 mmol). The reaction was stirred at room temperature for 18 hours. Solvent was removed under vacuum and residue was purified by silica chromatography (Biotage SP4, eluting 0% ethyl acetate in iso-hexane (2 column volumes), then a gradient from 0-50% ethyl acetate in iso-hexane (over 10 column volumes)). Pure fractions were combined and the solvent removed to yield the titled compound as a white solid (330 mg).