Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O1CCOCC1>[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][N:36]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1c1ccc(C#N)cn1
Yield: 42.2 %

Procedure:
Solid Na2CO3 (50 mg, 0.47 mmol, 1.5 eq) is added to a solution of 6-chloronicotinonitrile (50 mg, 0.36 mmol, 1.2 eq), 1-benzyl-4-((R)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) in DMF (1 mL) and dioxane (2 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 180° C. (high absorption setting) for 30 minutes. The reaction mixture is concentrated, dichloromethane is added and is washed with water then brine. The organic fraction is dried over sodium sulfate, and is evaporated under reduced pressure, then purified by flash chromatography (50%-90% EtOAc/Hexane) to afford the title compound as a white solid (55 mg, 42% yield).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]([N+:21]([O-])=O)[CH:11]=1.O1CCCC1>O.C(O)C>[NH2:21][C:12]1[CH:11]=[C:10]([Cl:9])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-n1cccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1-n1cccc1

Procedure:
10 g of sodium hydrosulfite are added portionwise to a stirred solution of 10.0 g (0.045 mole) of 1-(4-chloro-2-nitrophenyl)pyrrole, 200 ml. of tetrahydrofuran and 100 ml. of water, and the solution is heated on a steam bath for 5 minutes. An additional 10 g of sodium hydrosulfite are added and the solution is again heated on a steam bath for 5 minutes. Then 23 g more of sodium hydrosulfite and a solution of 200 ml. of ethanol in 250 ml. of water are added and heated for 5 minutes on a steam bath. The organic solvents are distilled, leaving a suspension of a tan solid. The solid is filtered, washed with water, dried, and recrystallized from hexane to give yellow needles, m.p. 89°-90°C. of 1-(2-amino-4-chlorophenyl)pyrrole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[CH3:8]>[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([O:23][CH3:24])[CH:16]=1)[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Agent: [Fe]
Product: COc1cc(N)cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Yield: 76.6 %

Procedure:
Using the method described in Example 196, 0.2 g of 4-(3-hydroxy-4-methyl-phenylamino)-8-methoxy-6-nitro-quinoline-3-carbonitrile and 0.1 g of iron was converted to 0.14 g of the title compound: :MP=227° C. (dec)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:16]=1)[C:9](=[O:35])[NH:8][C:7]2=[O:36])([O-])=O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)[CH2:27][CH2:28]3)=[O:22])[CH:16]=1)[C:9](=[O:35])[NH:8][C:7]2=[O:36]
Reactant: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cc([N+](=O)[O-])ccc32)c1)N1CCN(c2ncccn2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(c1)c(=O)[nH]c(=O)n2Cc1cccc(C(=O)N2CCN(c3ncccn3)CC2)c1
Yield: 23.6 %

Procedure:
A mixture of 6-nitro-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-quinazoline-2,4(1H,3H)-dione (50 mg, 0.10 mmol) in EtOH (10 mL) with Fe powder (33.5 mg, 0.60 mmol) and sat. NH4Cl solution (0.2 mL) were refluxed under N2 overnight. The mixture was filtered to remove the solid. The solution was concentrated and purified by flash chromatography (DCM:MeOH=50:3) to give the title compound (10.79 mg, 23.6% yield) as yellow solid. 1H NMR (DMSO-d6): 11.46 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 7.42-7.31 (m, 4H), 7.20 (d, J=2.7 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.89 (dd, J=8.7 and 2.7 Hz, 1H), 6.67 (t, J=4.8 Hz, 1H), 5.26 (s, 4H), 3.81-3.68 (m, 8H). MS: m/z 458.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].Cl.Cl.[CH2:15]1[C@@H:20]2[CH2:21][NH:22][CH2:23][CH2:24][N:19]2[CH2:18][CH2:17][O:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:22]2[CH2:23][CH2:24][N:19]3[C@H:20]([CH2:15][O:16][CH2:17][CH2:18]3)[CH2:21]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CN2CCOC[C@@H]2CN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1[N+](=O)[O-]
Yield: 75 %

Procedure:
5-Fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.318 g, 1.86 mmol), (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (Example 87, step G) (0.190 g, 0.880 mmol) and K2CO3 (0.614 g, 4.44 mmol) were stirred in DMSO (4 mL) at rt overnight. The reaction was diluted with EtOAc, washed with H2O (3×), dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.196 g, 0.660 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12-2.24 (m, 3H), 2.68 (d, J=11.4 Hz, 1H), 2.78-2.84 (m, 1H), 2.96 (td, J=12.3, 3.3 Hz, 1H), 3.10-3.18 (m, 1H), 3.52 (td, J=11.5, 2.4 Hz, 1H), 3.75 (dd, J=11.0, 2.9 Hz, 3H), 3.82-3.88 (m, 1H), 3.89 (s, 3H), 3.97 (d, J=13.9 Hz, 1H), 6.52 (d, J=2.6 Hz, 1H), 6.59 (dd, J=9.2, 2.6 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:7][CH2:6]2)[O:4]CC1.O>C(O)(=O)C>[C:5]1(=[O:4])[CH2:6][CH2:7][CH:8]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:9][CH2:10]1
Reactant: FC(F)(F)c1cccc(COCc2ccccc2)c1C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2c(COCc3ccccc3)cccc2C(F)(F)F)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 20.3 grams (0.050 mole) of phenylmethyl [(1,4-dioxaspiro-[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether and 35 mL of water in 125 mL of acetic acid, yielding phenylmethyl [(cyclohexanon-4-yl)(3-trifluoromethylphenyl)]methyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Oc1cccc(Cl)c1
Product: COc1ccc2c(Oc3cccc(Cl)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-chloro-phenol to give [1-(3-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: CC1(C)N(CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=[O:17])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O.[CH3:44][C:45]1([CH3:81])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][S:55][CH2:56][CH2:57][CH2:58][C:59]([F:65])([F:64])[C:60]([F:63])([F:62])[F:61])[C:48](=[O:66])[N:47]([C:67]2[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[C:69]([C:76]([F:79])([F:78])[F:77])[CH:68]=2)[C:46]1=[O:80]>>[CH3:44][C:45]1([CH3:81])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][S:55]([CH2:56][CH2:57][CH2:58][C:59]([F:64])([F:65])[C:60]([F:63])([F:62])[F:61])=[O:17])[C:48](=[O:66])[N:47]([C:67]2[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[C:69]([C:76]([F:79])([F:78])[F:77])[CH:68]=2)[C:46]1=[O:80]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCS(=O)CCCC(F)(F)C(F)(F)F

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 4 replacing the compound of Example 1. 136 mg of a white solid is obtained (73%). Melting point: 95-96° C.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=2)[CH2:8][C:7](C(OC)=O)=[C:6]([OH:13])[CH2:5][CH2:4]1)#[N:2].[Na+].[Cl-].O>CS(C)=O>[CH3:20][C:17]1[N:16]=[CH:15][C:14]([C:3]2([C:1]#[N:2])[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8]2)=[CH:19][N:18]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2cnc(C)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncc(C2(C#N)CCC(=O)CC2)cn1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A solution of methyl 5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate (6.2 g, 0.023 mol), NaCl (1.46 g, 0.025 mol) and H2O (1.24 mL, 0.069 mol) in DMSO (50 mL) was heated to 160° C. for 3 h. After cooling to room temperature, the reaction was added water and extracted with EtOAc (6×100 mL). The organic layer was washed with brine, dried over Na2SO4 and concentracted. The crude product was purified by flash chromatography(EtOAc: Petroluem ether=1:3˜3:2) to give 1-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile (2 g, yield: 41%). 1H NMR (CDCl3 400 MHz): δ8.80 (s, 2H), 3.00-2.90 (m, 2H), 2.77 (s, 3H), 2.70-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.40-2.25 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C1([C@@H](C)COS(C2C=CC(C)=CC=2)(=O)=O)C=CC=CC=1>>[F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H](C)c2ccccc2)cc1
Product: C[C@@H](CF)c1ccccc1

Procedure:
The title compound was prepared as described above for the synthesis of ((S)-2-fluoro-1-methyl-ethyl)-benzene, but using toluene-4-sulfonic acid (R)-2-phenyl-propyl ester instead of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:16]N(C=O)C>>[CH3:16][S:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CSc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (containing by 60%, 6.15 g) was suspended in DMF (120 mL) and 2-mercapto-6-nitrobenzothiazole (20 g) was added thereto under ice-cooling. After completion of bubbling, methyl iodide (26.4 mL) was added thereto. The mixture was stirred at room temperature for 18 hr. Water (800 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give 2-methylthio-6-nitrobenzothiazole (21.2 g) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=O)[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2].[NH2:14][NH2:15]>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[N:14][NH2:15])[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=O)[nH]c1C
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1cc(C=NN)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6.30 g, 0.034 mol) in EtOH (6.3 mL) was added a solution of hydrazine (1.69 mL, 0.034 mol). The reaction mixture was stirred at RT overnight. The resulting precipitate was filtered and dried in vacuo to give the titled compound, 6.79 g as a light yellow solid. This material was used without further purification.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:26]=3)=[CH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1.[I:40]CI>C1COCC1.[Cu]I>[I:40][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:26]=3)=[CH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(N)c4)nc3)cn2)CC1
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(I)c4)nc3)cn2)CC1
Yield: 78.4 %

Procedure:
Isopentyl nitrite (192 μl; 1.43 mmol; 3.0 eq.) was added to a solution of tert-butyl 4-4-[2-(3-aminophenyl)pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5, step 1, 200 mg; 0.48 mmol; 1.0 eq.), Copper(I) iodide (91 mg; 0.48 mmol; 1.0 eq.) and diiodomethane (193 μl; 2.38 mmol; 5.0 eq.) in dry THF (8.0 mL) and the reaction mixture was refluxed for 2 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness. Purification by flash chromatography (EtOAc:heptane, gradient from 20:80 to 50:50) afforded the title compound as a white solid (200 mg; 67%). 1H NMR (300 Mz, DMSO-d6) δ 9.17 (s, 2H), 8.71 (t, J=1.7 Hz, 1H), 8.56 (s, 1H), 8.40-8.37 (m, 1H), 8.15 (s, 1H), 7.90-7.86 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 4.48-4.38 (m, 1H), 4.08-4.03 (m, 2H), 2.95 (m, 2H), 2.08-2.05 (m, 2H), 1.87-1.73 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.47 min (purity 91.0%). MS (ESI+): 532.4
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.13) (0.31 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.08 g, 26%). MS (ISP) 397.3 [(M+H)+]; mp 230-232° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[O:5]1[CH2:26][CH:6]1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:25])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]2)=[CH:11][CH:10]=1>C(O)C>[OH:5][CH:6]([CH2:26][NH:4][CH2:1][CH2:2][CH3:3])[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:25])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: CCCN
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Solvent: CCO
Product: CCCNCC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Yield: 56.9 %

Procedure:
To 10.35 liters (125.9 mol) of n-propylamine were added 530 g (1.8 mol) of 7-(2,3-epoxypropoxy)flavone and 5.4 liters of abs ethanol. The mixture was heated at 50° to 55° for 1.5 hr, with stirring. The reaction mixture was cooled and clarified by filtration, and the filtrate concentrated in a rotary evaporator to a volume of 4.0 liters. The resulting solid product was filtered and washed with 1 liter abs ethanol; yield 383 g (60%) of a bright yellow solid, m.p. 144°-146°. The bright yellow solid was suspended in a mixture of 3.41 liters of water and 1.14 liters of 95% ethanol and then treated with 537 ml of 2.5N hydrochloric acid to obtain a solution of pH 1 to 2. The resulting aqueous solution was extracted twice with 537 ml of methylene chloride and then four times with 268 ml of CH2Cl2. The aqueous solution was clarified by filtration. Water (1.14 liters) was added to the filtrate, followed by the slow addition of 537 ml of 2.5N NaOH until the mixture tested for a pH of 10 to 11 to give a solid precipitate. The mixture was stirred for 1/2 hr. The product was filtered, washed with 2.68 liters water and air dried; yield, 362 g (57%) of the title compound as a pale yellow powder, m.p. 145°-147°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH:26]([C:30]([NH:32][C:33]4[CH:34]=[C:35]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=4)[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[CH:15][N:14]=1.O>C(Cl)Cl>[CH:12]([C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH:26]([C:30]([NH:32][C:33]4[CH:34]=[C:35]([CH:45]=[C:46]([C:48]([F:51])([F:49])[F:50])[CH:47]=4)[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(CO)c4)cc3C2)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C=O)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of oxalyl chloride (0.086 mL, 1.02 mmol) in DCM (4 mL) at −78° C., was added a solution of DMSO (0.109 mL, 1.53 mmol) in DCM (1 mL) dropwise. The reaction mixture was allowed to stir at −78° C. for 30 min, and then a solution of tert-butyl [3-{[(7-{[2-(hydroxymethyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (292 mg, 0.51 mmol) in DCM (1 mL) was added dropwise. After 45 min. the reaction was incomplete. In a separate flask, oxalyl chloride (0.086 mL, 1.02 mmol) and DCM (4 mL) were cooled to −78° C., and a solution of DMSO (0.109 mL, 1.53 mmol) in DCM (1.00 mL) was added dropwise. The solution was stirred at −78° C. for 15 min, and then transferred via cannula to the reaction mixture and allowed to stir for 1 h. TEA (0.712 mL, 5.11 mmol) was added and the mixture was allowed to warm to rt. Water was added and the layers were separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl [3-[({7-[(2-formylpyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (285 mg, 97.9%). LCMS: (FA) ES+ 570.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](O)[N:6]=1)=[O:4].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(O)n1
Product: COC(=O)c1cccc(Cl)n1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To 6-hydroxy-pyridine-2-carboxylic acid methyl ester (10.0 g, 71.9 mmol) was added phosphorus oxychloride (138 mL). The mixture was heated in an oil bath at 110° C. for 14 h and the excess phosphorus oxychloride was removed in vacuo. The resulting residue was cooled in an ice bath and anhydrous methanol (146 mL) was slowly added. After 15 min, half of the methanol was removed in vacuo and water (208 mL) was added. The solution was cooled in an ice bath and the precipitate was collected. The solid was dissolved in ethyl acetate and this organic phase was washed with water and then a saturated sodium bicarbonate solution. The combined aqueous layers were extracted with ethyl acetate and diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo generating 7.47 g (61% yield, 43.5 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][CH2:10][CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1.[CH:13]1([C:16]([OH:18])=O)[CH2:15][CH2:14]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:10][CH3:11])[C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:18])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1
Reactant: O=C(O)C1CC1
Reactant: CCNCc1cc(C)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C)cnc1Cl)C(=O)C1CC1
Temperature: 25 °C

Procedure:
(2-Chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amine (0.126 g, 0.69 mmol), cyclopropanecarboxylic acid (0.08 mL, 1.03 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.197 g, 1.03 mmol), 1-hydroxybenzotriazole hydrate (0.139 g, 1.03 mmol), and triethylamine (0.29 mL, 2.05 mmol) were combined in CH2Cl2 and stirred at room temperature over the weekend. The mixture was concentrated and purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:19]=[N+]=[N-])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N=[N+]=[N-])c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(N)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Triphenylphosphinie (20.5 g) was added in small portions to a solution of α-(4-methoxyphenyl)-3-nitrobenzyl azide (18.5 g) [prepared as described in step (a) above] in anhydrous tetrahydrofuran (100 ml). When the triphenylphosphine was dissolved and the evolution of nitrogen had ceased, water (20 ml) was added to the reaction mixture and this mixture was heated under reflux for 6 hours. At the end of this time, the tetrahydrofuran of the reaction mixture was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford a colorless oil. This oil was dissolved in a solution of hydrogen chloride in ethyl acetate (4N). The ethyl acetate was evaporated to dryness. The residue was suspended in diisopropyl ether and filtered to afford the title compound (13.8 g) as a white solid.
Reaction SMILES: [C-]#N.[K+].CN([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)C.[CH3:18][N:19](C=O)C>O.C1(C)C=CC=CC=1>[F:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH2:7][C:18]#[N:19])=[CH:9][NH:10]2)=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: CN(C)Cc1c[nH]c2cc(F)ccc12
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine KCN (50.8 g, 0.78 mol), 3-(N,N-dimethylaminomethyl)-6-fluoroindole (100 g, 0.52 mol), DMF (400 mL) and water (200 mL). Heat to reflux. Evolution of gas begins at about 70° C. Maintain the reflux for 4 hours. Cool the reaction mixture to room temperature, dilute with water and toluene and stir for 10 minutes. Decant the organic layer and wash successively with of saturated aqueous sodium bicarbonate and of 2M aqueous hydrochloric acid. Concentrate to dryness the organic layer to give 2-(6-fluoro-1H-indol-3-yl)acetonitrile.