Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>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>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): S=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+—C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12].Cl.[C:16](=N)(OCC)[CH3:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:16]([CH3:17])=[N:14][N:13]=1
Reactant: Cc1cccc(C)c1NCC(=O)NN
Reactant: CCOC(C)=N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nnc(CNc2c(C)cccc2C)o1
Yield: 34.1 %

Procedure:
A solution of 19.3 g (0.1 mol) alpha-(2,6-dimethylphenyl-amino)acethydrazide and 14 g (0.11 mol) ethyl actimidate hydrochloride (Aldrich Chemical Co.) in 150 ml pyridine was heated under reflux for 9 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give an oil. The oil was placed on 400 g silica gel in a chromatography column and eluted the following solvent systems: (1) petroleum ether, (2) petroleum ether/ethyl ether, (3) ethyl ether, and (4) ethyl ether/methanol. The crude product (11.5 g) was eluted from the column with the ethyl ether/methanol solvent system. Crystallization of the crude product from dichloromethane/ethyl ether gave 7.4 g of crystalline product, m.p. 134°-135° C. The product is tabulated in Table I as Compound No. 1-A.
Reaction SMILES: [O-]CCCC.[K+].C1COCC1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:34]=1[C:43](Cl)=[O:44]>O>[F:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[C:14]=1[C:20]1[CH:24]=[CH:23][N:22]([C:25](=[C:43]([C:34]2[C:35]([C:39]([F:42])([F:41])[F:40])=[N:36][N:37]([CH3:38])[C:33]=2[Cl:32])[OH:44])[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:21]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1Cl
Reactant: C=CCOC(=O)Cn1ccc(-c2c(F)cccc2F)n1
Agent: CCCC[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=C(O)c1c(C(F)(F)F)nn(C)c1Cl)n1ccc(-c2c(F)cccc2F)n1
Reaction time: 0.08 h

Procedure:
Potassium butoxide (0.5 g) was added to a THF (10 mL) solution of allyl 2-(3-(2,6-difluorophenyl)pyrazol-1-yl)acetate (0.5 g) and 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride (0.44 g) at 0° C. and stirred for 5 minutes. Water (5 ml) was added thereto, and then extracted with diluted hydrochloric acid and ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, and then concentrated, and the resulting concentrate was purified through silica gel column chromatography (chloroform) to obtain the intended product, Compound No. I-133 (0.89 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH:37]C(OC(C)(C)C)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[O:18][N:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH2:37])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[O:18][N:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1ncno1)N(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1ncno1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-((2-tertbutoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,2,4-oxadiazol-5-yl)ethylamide (440 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The mixture was stirred at room temperature for 1 hour and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (370 mg, 99%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (102 mg, 0.33 mmol) in anhydrous MeCN (8 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (95.3 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.8 μL, 0.33 mmol). The resultant solution was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:99–1:49 EtOAc:cyclohexane afforded the title compound as a colourless oil (110 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(F)ccc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: COc1cc(F)ccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 62 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 4-fluoro-2-methoxybenzoyl chloride, the title compound (yield 62%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: C#CC
Reactant: Nc1ncc(Br)cc1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(Br)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Propyne (28 g, 700 mmol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (150 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-bromo-3-iodo-pyridin-2-ylamine (139 g, 465 mmol), bis(triphenylphosphine)dichloropalladium(0) (16.3 g, 23.2 mmol), copper (I) iodide (5.3 g, 27.9 mmol) and triethylamine (141 g, 194 mL, 1.4 mol) in THF (1.25 L). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a buff solid (91 g, 93%). 1H NMR (400 MHz, CDCl3): 8.01 (d, J=2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 4.96 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][NH:32]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[CH:36][C:31](=[O:30])[NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reactant: O=c1ccc(B(O)O)c[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.37 min, m/z=474(M+1); 1H NMR (CDCl3) 7.97, (dd, 1H), 7.73 (s, 1H), 7.33 (m, 2H), 7.20 (d, 2H), 7.17 (t, 2H), 6.98 (m, 3H), 5.67 (q, 1H), 3.00 (dt, 1H), 2.49 (m, 2H), 2.30 (m, 1H), 2.13 (s, 2H), 1.55 (d, 3H), 1.45 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=[N:30][OH:31])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2)NO
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(/C=C/c1ccc2c(c1)C(=NO)CC1(CCCN(C3CCCC3)C1)O2)NO
Temperature: 80 °C
Yield: 12.6 %

Procedure:
A mixture of (E)-3-(1′-cyclopentyl-4-oxospiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide hydrochloride (80 mg, 0.197 mmol), hydroxylamine hydrochloride (27.3 mg, 0.393 mmol) and pyridine (0.032 ml, 0.393 mmol) in ethanol (2 ml) was heated at 80° C. The solvent was removed in vacuo and the crude was purified by preparative LC-MS to give the title compound (9.56 mg) as trifluoroacetate
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][CH:11]3[CH:16]([N:17]=2)[CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C1=CC2N=C(N3CCCCCC3)C(=O)NC2C=C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (150.0 mg, 0.50 mmol) in dichloromethane (50 mL) was added pyridine (210 mg, 2.64 mmol) and Tf2O (375 mg, 1.32 mmol) with stirring overnight under atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated in vacuo to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude), which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:25]([C:28]1[O:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:32][C:31]4[O:34][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=4)=[CH:7][CH:6]=3)=[CH:16][C:15](=[O:17])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N=Cc3ccc([N+](=O)[O-])o3)cc2)cc1=O
Temperature: 25 °C
Yield: 31.4 %

Procedure:
In 10 ml of ethanol were suspended 0.3 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid and 0.15 g of 5-nitrofurfural, and the suspension was subjected to reaction at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. Then, 10 ml of diethyl ether was added to the residue, and the insolubles were collected by filtration to obtain 0.13 g of 1-(4-fluorophenyl)-6-[4-{(5-nitrofurfurylidene)amino}-phenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:19][NH2:20])=[CH:4][CH:3]=1.[CH:21](OCC)(OCC)OCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]3[CH:21]=[N:20][N:19]=[C:9]23)=[CH:4][CH:3]=1
Reactant: NNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)n2cnnc2n1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-3,4-dihydro-2-hydrazino-6-trifluoromethylpyrimidin-4-one (0.7 g), triethyl orthoformate (1.0 g) and acetic acid (10 ml) was heated for one hour at 120° C. The solvent was distilled off under reduced pressure and the residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=4/6) to give the compound of interest (0.45 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:1]=[C:2]2[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COc1ccc(C(=O)c2c(N)sc(C)c2C)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of 2-amino-3-(3,4-dimethoxybenzoyl)-4,5-dimethylthiophene (3.6 g), ethyl 4-chloroacetoacetate (2.1 g), concentrated sulfuric acid (0.5 ml) and acetic acid (50 ml) was stirred for two hours at temperature ranging from 90° to 100° C. The reaction mixture was concentrated under reduced pressure. The concentrate was poured into water, which was neutralized with potassium carbonate, followed by extraction with chloroform. The chloroform layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fractions eluted with chloroform-hexane (4:1, v/v), ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (3.5 g, 67%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.162°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Oc4cccc(OC(F)(F)F)c4)C3)CC2)cc1
Yield: 99.3 %

Procedure:
The title compound (D189) (39 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-fluoro-2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)nicotinic acid (D134) (27 mg, 0.072 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (16.5 mg, 0.072 mmol).
Reaction SMILES: CS[C:3](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.[Hg](Cl)Cl>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]1[C:3]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:26][N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=Nc1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 456 h
Yield: 84.7 %

Procedure:
Part C: To a solution of tert-butyl 4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00 g, 36.0 mmol) in DMF (200 mL) at 25° C. was added sodium azide (11.60 g, 178 mmol), followed by mercury(II)chloride (10.90 g, 40.0 mmol), and the resulting mixture was stirred at 25° C. for 19 d. The mixture then was filtered, and the solids were washed with DMF. The combined filtrate was concentrated under vacuum, and the residue was diluted with ethyl acetate. The resulting mixture was filtered again. The filtrate was washed with water (×3) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% diethyl ether/methylene chloride) to afford tert-butyl 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (10.10 g) as an off-white solid, following crystallization from a mixture of 1-chlorobutane/hexane; Mass Spec.: m/e: 332.11 (M+H)+ [calc'd: 332.17]; 1HNMR (300 MHz, CDCl3) δ 8.57 (m, 1H), 7.94 (m, 1H), 7.79 (d, 1H, J=8 Hz), 7.40 (m, 1H), 3.52 (m, 4H), 3.34 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:19][CH2:18]1.[Br:32]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:32])[C:26]=2[F:31])[CH2:19][CH2:18]1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN1CCC(NCc2ccccc2F)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Br)c2F)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Add n-butyl lithium (1.6 M in hexanes, 4.3 mL) into a solution of 2,2,6,6-tetramethyl-piperidine (0.97 g) in THF (10 mL) at −78° C. and stir for 30 minutes. Add a solution of 1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23, 1.02 g) in THF (10 mL) portion wise and stir for 10 minutes. Add 1,2-dibromo-1,1,2,2-tetrachloroethane (1.50 g) in THF (10 mL) dropwise and stir for 1 hr. Remove the cooling bath and stir for 30 minutes. Partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.49 g of the title intermediate.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:9])=[CH:6][N:5]=[C:4]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])=[CH:6][N:5]=[C:4]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cnc(-n2cccn2)nc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1cnc(-n2cccn2)nc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl N-{[4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl]carbonyl}glycinate (140 mg, 0.44 mmol, prepared in similar fashion to that of the preceding examples) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction was stirred at rt for 4 h, concentrated and partially dissolved in EtOAc and hexane was added to precipitate the desired compound. The product was isolated affording the title compound. HPLC/MS: 264.0 (M+1); Rt=0.65 min.