Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:4]=2[CH2:3]1.C(OC([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)C>C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:4]2[CH2:3][CH:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:8]3[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:16]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)c1ccc2c(c1)C(Cl)Cc1ccc(F)cc1S2
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCNCC1)Cc1ccc(F)cc1S2

Procedure:
A mixture of 20 g of 10-chloro-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin, 21 g of 1-(ethoxycarbonyl)piperazine and 30 ml of chloroform is refluxed for 5 hours. After cooling, it is diluted with chloroform, the solution thoroughly washed with water, dried with potassium carbonate and after filtration evaporated under reduced pressure. The residue (27 g, 96%) is a crude glassy 10-(ethoxycarbonylpiperazino)-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin which is used for hydrolysis in this state without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:37][C:36]4[C:28]([F:27])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][CH:31]=[CH:30]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (190 mg, 0.50 mmol), (prepared as described for the starting material in Example 4), 4-fluoro-5-hydroxyindole (83 mg, 0.55 mmol), (WO 00/47212, Example 242), and potassium carbonate (76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85° C. for 3 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[3-(4-acetylpiperzin-1-yl)propoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-6-methoxyquinazoline (75 mg, 30%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].COC1C=C(OC)C=CC=1C[NH2:27]>C(O)C>[NH2:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O

Procedure:
To the yellow solution of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (500 mg, 1.57 mmol) in ethanol (0.5 ml) is added 2,4-dimethoxybenzylamine (4.72 ml, 31.4 mmol) under argon. The solution is heated at 150° in a closed vial in a microwave reactor for 4 minutes. After removal of the solvent and 2,4-dimethoxybenzylamine by high-vacuum rotavapor evaporation the remaining deep purple oil is treated with diethyl ether to obtain a suspension, which is filtered and dried to yield the crude title compound as a deep purple solid, m.p. 232-237° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: c1nc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide (5 g, 19.3 mmol) in DMF (50 ml) were added 1,2,4-triazole (3.3 g, 48.25 mmol, 2.5 eq.), copper(I) oxide (0.56 g, 3.86 mmol, 0.2 eq.) and cesium carbonate (12.5 g, 38.6 mmol, 2 eq.) and the mixture was heated at 90° C. for 48 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 86% yield (4.1 g). LC-MS (ESI): Calculated mass: 247.21; Observed mass: 248.0 [M+H]+ (rt: 0.257 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]2)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)c(F)c2)CC1

Procedure:
A Grignard reagent was prepared from commercially available 2-fluoro-4-bromobiphenyl, and the resulting Grignard reagent was reacted with 4-pentylcyclohexanone in the same manner as in (1-b) and (1-c) to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)biphenyl. The product was brominated in the same manner as in (29-a) to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)-4'-bromobiphenyl. A Grignard reagent was prepared therefrom and reacted with 4-pentylcyclohexanone-2,2,6,6-d4 in the same manner as in Example 4 to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)-4'-(trans-4-pentylcyclohexyl-2,2,6-d3)biphenyl. The phase transition temperatures of this compound are shown in Table 3.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(NCCN(C)C)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Temperature: 80 °C

Procedure:
3-benzyl-2-(1-bromopropyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-3, 0.080 g, 0.23 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.05 mL, 0.46 mmol). The reaction was heated to 80° C. for 24 hours. The reaction was diluted with EtOAc (10 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-4). MS 355.1 found 354.5 required.
Reaction SMILES: O1CCCC1.B.[O:7]=[C:8]([CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[OH:7][C@H:8]([CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCCC(C)=O
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCCC[C@@H](C)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
(S)-methyloxazaborolidine (8.77 g, 31.63 mmol) dissolved in 30 mL of toluene. The solution was cooled to 0° C. and the borane tetrahydrofuran complex (31.6 mL of 1.0M solution in THF, 31.6 mmol) was added. After 30 min the ketone 24 (5.0 g, 31.63 mmol) was added. The reaction solution was stirred for 4 h and was then quenched by slow addition of saturated aqueous ammonium chloride. The resultant mixture was extracted with EtOAc (2×). The combined organic portions were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 3:1 hex/EtOAc) afforded 2.58 g (51%) of the alcohol 25 (see scheme 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccc(Br)c1

Procedure:
To CHCl3 is added 3-bromobenzoic acid (100 g) and thionyl chloride (109 ml) and refluxed overnight. The remaining thionyl chloride is evaporated off to afford 3-bromobenzoic acid chloride.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=O)([CH3:4])[CH3:3].Cl.[NH2:15]O.CCOCC>C(O)(=O)C>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[C:8]#[N:15])([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)c1cc(C#N)ccc1O
Temperature: 0 °C

Procedure:
3-(1,1-dimethylethyl)-4-hydroxybenzaldehyde (Intermediate 108, 550 mg) and hydroxylamine hydrochloride (322 mg, 4.63 mmol) were stirred in 8.0 mL of acetic acid at reflux for 1 h. After cooling down to 0° C., the mixture was poured into Et2O and washed once with water and once with NaOH (5% aqueous solution). The collected aqueous phases were extracted with Et2O (two times) and the combined organic phases were dried over Na2SO4, filtered, evaporated and triturated with pentane affording 540 mg of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:18][C@H:19]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[O:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.[H][H]>[Pd].CCO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:19]([O:20][CH3:21])[CH2:18][C@H:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([O:16][CH3:17])=[O:15])=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](OC)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H](CCCCO)C[C@@H](OC)c1ccc(F)cc1

Procedure:
(S)-methyl 6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)hex-4-enoate (494 mg, 1.2 mmol) was dissolved into 5 mL EtOH and to it added 10% Pd/C (450 mg). The solution was saturated with H2 (stream of H2 bubbled through solution) and then stirred for 3 h at room temperature under one atmosphere of hydrogen (balloon). The mixture was filtered through a bed of Celite and rinsed with ethyl acetate. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[C:20]4[N:27]3[CH2:32]CN(C)C[CH2:28]3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C=C2C(=CC=1)N(C)N=C2N(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[C:20]4[N:27]([CH3:32])[CH3:28])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3ccc4c(c3)c(N3CCN(C)CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CN(C)c1nn(C)c2ccc(Br)cc12
Product: Cc1cc2nc(-c3ccc4c(c3)c(N(C)C)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetic acid, except using 5-bromo-N,N,1-trimethyl-1H-indazol-3-amine instead of 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole. LCMS-ESI+: calc'd for C30H31ClN4O3S: 563.2, 565.2 (M+H+); Found: 563.2, 565.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.96 (dd, J=8.9, 1.5 Hz, 1H), 7.78 (s, 1H), 7.74-7.64 (m, 1H), 7.62-7.52 (m, 3H), 7.41 (d, J=8.9 Hz, 1H), 5.25 (s, 1H), 3.86 (s, 3H), 3.16 (s, 6H), 2.60 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: COC1[C:8]2[C@H:9]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.N1C=CC=CC=1.[C:31]([O:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])(OC(C)(C)C)=O>O>[C:42]([O:41][C:39]([O:38][C:31]1[C:8]2[C@H:9]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cccc2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CCO2
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Oc1cccc2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Example 272E (2.0 g, 6.3 mmol) and pyridine-HBr (8.0 g, 50 mmol) was heated at 135° C. for 72 hours. The mixture was cooled to room temperature, water was added, and saturated NaHCO3(aqueous) was added to adjust the pH value to 7. Di-tert-butyl dicarbonate (3.0 g, 13.8 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate, dried, and concentrated. The mixture was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to give a mixture of Example 374A and tert-butyl trans-10-[(tert-butoxycarbonyl)oxy]-1,3,3a,4,5,10b-hexahydro-2H-[1]benzoxepino[4,5-c]pyrrole-2-carboxylate side product. The mixture was dissolved in methanol (10 mL) and sodium methoxide (25%, 1.5 mL) was added. The mixture was heated at 50° C. for 1 hour, 1 N HCl(aq) was added to adjust pH value to 2, and the mixture was extracted with ethyl acetate. The crude material was triturated in acetone, precipitates were collected to afford the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1

Procedure:
12 mg of the target compound (0.03 mmol, 4.03%) was obtained using 1-(4-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: C[N:2]([CH3:8])/[CH:3]=[CH:4]/[C:5](=O)[CH3:6].[NH:9]([C:11]1[CH:16]=[CH:15][CH:14]=CN=1)[NH2:10]>C(O)C>[CH3:14][C:15]1[CH:16]=[CH:11][N:9]([C:8]2[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=2)[N:10]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)/C=C/N(C)C
Solvent: CCO
Product: Cc1ccn(-c2ccccn2)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(3E)-4-(dimethylamino)but-3-en-2-one (255 mg, 2.25 mmol) and 2-hydrazinopyridine (369 mg, 3.38 mmol) were added to ethanol (3 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave reactor. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel, (ethyl acetate/isohexane gradient) to afford 2-(3-methyl-1H-pyrazol-1-yl)pyridine (faster eluting isomer) and 2-(5-methyl-1H-pyrazol-1-yl)pyridine (slower eluting isomer).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1(O)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:7][C:16]1([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2cnccn2)CN2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: FC1(c2cnccn2)CN2CCC1C2
Reaction time: 24 h
Yield: 14.8 %

Procedure:
Diethylaminosulphur trifluoride (0.42 g, 2.62 mmol) was added to a stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (0.5 g, 2.62 mmol) in dichloromethane (30 ml), at -65° C. After 24 h, water (20 ml) was added, basified with potassium carbonate, and extracted into dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4), evaporated, and the residue chromatographed through silica-gel, eluting with dichloromethane-methanol (90:10) to give 3-fluoro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane (75 mg). The compound was further purified as the hydrogen chloride salt, m.p. 245° C. (dec.) (isopropylalcohol); (Found: C, 52.33; H, 5.79; N, 17.97. C10H12F.HCl requires C, 52.29; H, 5.66; N, 18.30%) m/e 193 (M+ for free base); δ(360 MHz, CDCl3) 1.06-1.13 (1H, m, CH of CH2 --N); 1.44-1.55 (1H, m, CH of CH2 --N); 2.58 (1H, dd, J=3.1 and 9.7 Hz, CH of CH2 --N); 2.65-2.72 (1H, m, CH of CH2 --N); 2.83-2.91 (2H, m, CH-bridgehead and CH of CH2 --N); 3.09-3.24 (2H, m, 2 of CH of CH2 --N); 3.59 (1H, ddd, J=3.1, 13.6 and 20.8 Hz, CH of CH2 --N); 8.50-8.53 (2H, m, 2 of pyrazine-H); 8.91 (1H, d, J=1.2 Hz, pyrazine-H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1)([OH:20])=[O:19]>O>[F:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Solvent: O
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(C(F)(F)F)nc2c1
Yield: 19 %

Procedure:
Followed the coupling procedure described in Step 1 of Compound VIII-2 (Example 65), where the starting materials were 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and 4-carboxy-2-fluorobezeneboronic acid After H2O quench, the aqueous layer was acidified with 0.1M HCl to pH=1, followed by EtOAc/aqueous workup and column purification to give 3-fluoro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (50 mg, yield 19%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:26])[C:15](=O)[CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:1]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=2)[N:2]=1)=[O:26])[CH3:12]
Reactant: COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(OC)cn2)n1

Procedure:
The above-obtained 2-hydrazino-5-methoxypyridine (705 mg) and the 2,4-dioxo-4-phenylbutyric acid ethyl ester (1.12 g) prepared in Referential Example 123-1) in ethanol (25 mL) was refluxed under heat for 19 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (hexane-ethyl acetate), to thereby give 1-(5-methoxy-2-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester as an amorphous product (705 mg, 43%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([CH2:28][CH:29]=O)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([BH3-])#N.[Na+]>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][N:8]2[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH:3]2[C:2]([F:1])([F:16])[F:17])=[CH:27][C:20]=1[O:19][CH3:18])#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1
Reactant: COc1cc(CC=O)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (72 mg, 0.28 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (50 mg, 0.28 mmol) in methanol (2.5 mL) at 0° C. was added sodium cyanoborohydride (25 mg, 0.40 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by column chromatography (4->30% ethyl acetate:hexanes) to provide tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 414.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:42])[CH:38]=[CH:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:42])/[CH:38]=[CH:39]/[CH2:40][CH3:41]
Reactant: CCC=CC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C=C/C(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 100 mg (1 mmole) of n-pentenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 95 mg (Yield: 23%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
58 g of 3-[4-chloro-2,6-difluorophenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione were dissolved in 400 ml of concentrated sulfuric acid and, at 0° C., admixed dropwise with a mixture of 10.7 g of 98% strength nitric acid and 10 ml of concentrated sulfuric acid. The mixture was stirred at 0° C. for 30 minutes and then at 20° C. for 18 hours. Another 10.7 g of the acid mixture were then added dropwise at 0° C. The mixture was stirred at 20° C. for two hours and then poured into ice-water, and the resulting precipitate was filtered off with suction and washed with water until neutral. The solid was dried in a vacuum drying cabinet. Yield: 58.0 g;