Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])=[N+:2]=[N-:3].[C:12](O)(=[O:15])[C:13]#[CH:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:1]=[N+:2]=[N-:3])(=[O:15])[C:13]#[CH:14]
Reactant: C#CC(=O)O
Reactant: [N-]=[N+]=Nc1ccccc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 2-azidobenzyl alcohol (15.66 g, 105.1 mol) in 200 mL of methylene chloride was added propiolic acid (7.1 mL, 115.6 immol), dicyclohexylcarbodiimide (20.0 g, 110.3 mnmol) and 4-dimethylaminopyridine (1.93 g, 15.8 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The mixture was filtered, concentrated and the residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 10.7 g (51%) of the title compound. 1H NMR (CDCl3) δ7.40 (m, 2H), 7.17 (m, 2H), 5.20 (s, 2H), 2.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:14]([Cl:13])[CH:15]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1F)Nc1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (144 mg, 0.617 mmol), 3,4-dichloroaniline (100 mg, 0.617 mmol) and HATU (704 mg, 1.852 mmol) in DCM (20 mL) was added Et3N (0.258 mL, 1.852 mmol) dropwise. Then the mixture was stirred at 20° C. under a N2 atmosphere for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give the crude product which was purified by silica column chromatography (PE/EA=100/1 to 8/1) to afford pure product 2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (190 mg, 0.419 mmol, 67.8% yield): 1H NMR: (400 MHz, CD3OD) δ 10.25 (br. s, 1H), 7.89 (s, 1H), 7.44 (s, 2H), 7.28-7.37 (m, 3H), 3.74 (s, 2H); ES-LCMS: m/z 377.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([O:26]C)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylate (150 mg, 0.35 mmol) in 7.5 mL of 1,4-dioxane and 7.5 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was suspended in 50 mL of H2O, then treated by 1N HCl until pH=5. The white solid was appeared and then filtered the solid was dried to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (130 mg, 90%) as a yellow solid
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([C:22]2([C:28](=[O:30])[CH3:29])C=CC=CC2)CCCC[CH:17]=1>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:28]([OH:30])([CH:22]=[C:16]=[CH2:17])[CH3:29]
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)C1(C2=CCCCC2)C=CC=CC1
Product: C=C=CC(C)(O)c1ccccc1-c1ccccc1

Procedure:
When Example 1 is repeated using p-phenyl-acetophenone and 1'-cyclohexenyl acetophenone in place of the p-tert butylbenzaldehyde, there is obtained 2-(p-biphenylyl)-3,4-pentadien-2-ol m.p. 65° to 66°, and 2-(p-1'-cyclohexenylphenyl)-3,4-pentadien-2-ol, respectively.
Reaction SMILES: N1C=CC=CC=1.Cl.[C:8]1(/[CH:14]=[CH:15]/[C:16]([NH:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34]([Cl:37])(=[O:36])[CH3:35]>O>[ClH:37].[C:8]1(/[CH:14]=[CH:15]/[C:16]([N:18]([C:34](=[O:36])[CH3:35])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1

Procedure:
A pyridine solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide. hydrochloride (0.25 g) and acetyl chloride (0.3 ml) was stirred at 60° C. for 2 hours. Water was added to the reaction mixture after being left standing for cooling; the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off. The oily residue was subjected to silica gel column chromatography (developing solvent : ethyl acetate). The solvent of the solution containing the object compound was distilled off. To the residue was added an ethanol solution of 3N hydrogen chloride. The solvent was then distilled off to obtain hydroscopic amorphous powder (0.16 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(O)(=O)C.[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([CH3:26])[C@@H:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=O)=[O:18])=[CH:15][C:14]=1[CH3:29].[Na].[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([C@@H:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH3:26])=[O:18])=[CH:15][C:14]=1[CH3:29]
Reactant: OC1CCNCC1
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(O)CC2)C(C)C)ccc1F
Reaction time: 3 h
Yield: 21.5 %

Procedure:
Piperidin-4-ol (0.048 g, 0.48 mmol) and acetic acid (0.032 mL, 0.56 mmol) was added to (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.1 g, 0.40 mmol) in DCM (3 mL). The resultant mixture was stirred at rt for 30 min before sodium triacetoxyhydroborate (0.101 g, 0.48 mmol) was added. The stirring was continued at rt for 3 h. NaOH (1 N aq.) was added to the mixture. The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak AD 5 μm 20×250 mm column and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title compound (29 mg, 22%). Enantiomeric excess: 99.9%. Mixture of rotamers: (600 MHz, CD3OD) δ 0.82-1.08, 1.43-1.63, 1.71-2.06, 2.12-2.51, 2.54-2.81, 2.89, 2.97-3.09, 3.27-3.46, 3.51-3.65, 4.40-4.59, 7.06-7.14, 7.22-7.37. Total no of protons: 28. HRMS (M+H)+: calculated 337.2291. found 337.2268.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:24])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:25]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[C:1]12([O:11][CH2:12][C:13]3[NH:17][N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(Br)c(COC23CC4CC(CC(C4)C2)C3)[nH]n1C1CCCCC1
Yield: 48.1 %

Procedure:
A CCl4 solution (10 mL) of 5-(adamantan-1-yloxymethyl)-2-cyclohexyl-2H-pyrazol-3-ol (0.11 g, 0.33 mmol), azobisisobutyronitrile (2 mg) and N-bromosuccinimide (70 mg, 0.4 mmol) was irradiated by a 100 W light source for 0.3 h at rt. After filtration to the filtrate was concentrated in vacuo to afford a crude product as a purple solid, which was purified by chromatography with EtOAc-DCM (1:4) as eluant. The product was obtained as a white glassy solid (65 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH3:15]>>[CH2:14]([C:15]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:13]
Reactant: Nc1cnc2ccccc2c1S
Reactant: CCC(=O)O
Product: CCc1nc2cnc3ccccc3c2s1

Procedure:
Propionyl anhydride (20 mL) was added to a suspension of 3-amino-quinoline-4-thiol (15 g) in propionic acid (100 mL). The reaction mixture was heated at reflux overnight and then filtered to remove a precipitate. The filtrate was concentrated under vacuum. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate then with water, and then dried over magnesium sulfate. The solution was filtered through a layer of silica gel eluting first with 1:1 ethyl acetate:hexane and then with ethyl acetate. The filtrate was evaporated to provide 2.6 g of 2-ethylthiazolo[4,5-c]quinoline as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: Cc1ccc2c(c1)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc2c(c1)OCC(=O)N2CCCCl
Yield: 78.6 %

Procedure:
7-Methyl-4H-benzo[1,4]oxazin-3-one (81MF2246a) (1.42 g, 8.7 mmol), Cs2CO3 (4.24 g, 13.0 mmol) and 3-chloro-1-iodopropane (1.95 g, 9.5 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2246b) (1.64 g, 79%). 1H NMR (CDCl3) δ 6.98-6.81 (m, 3H), 4.59 (s, 2H), 4.06-4.03 (m, 2H), 3.63-3.60 (m, 2H), 2.26 (s, 2H), 2.20-2.15 (m, 2H); 13C NMR (CDCl3) δ 164.8, 145.8, 134.3, 123.9, 118.1, 114.9, 68.0, 42.8, 39.4, 30.5, 21.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:17][CH:16]=1)[N:8]=[CH:7]2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1cc(Br)c2nc(Cl)ncc2c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(F)cc(Br)c3n2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a 0.4M suspension of 8-bromo-2-chloro-6-fluoroquinazoline in isopropanol was added 4-aminobenzensulfonamide (1 eq). The reaction mixture was heated to 120° C. in an oil bath for 2 days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O>[Cl:26][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)[CH:19]=[CH:18][C:17]=2[N:16]2[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]=12
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)c(Cl)c2n3[C@H](C)CNC2=O)CC1
Reaction time: 18 h
Yield: 0 %

Procedure:
To the solution of 0.20 g (0.58 mmol) (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8) in 3 mL N,N-dimethylformamide, 86 μg (0.64 mmol) N-chlorosuccinimide were added and the solution was stirred for 18 hours. The reaction mixture was poured on 1M aqueous sodium hydroxide solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 81 μg (37%) of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.[C:45](=[O:48])([O-])[O-:46].[K+].[K+]>CN1C(=O)CCC1>[C:31]1([O:46][C:45](=[O:48])[NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[N:15]=[C:14]4[C:10]([N:11]=[CH:12][N:13]4[C@@H:16]4[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]4[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[N:8]=3)[CH2:3]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)Oc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture comprising N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 step 4) (50 mg, 83 μmol) and potassium carbonate (46 mg, 332 μmol) in NMP (1 ml) is treated with phenylchlorofomate and stirred at room temperature for 90 minutes. This mixture was used in the next step without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+]>O>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[NH:21][C:20]1=[O:19]
Reactant: COC(=O)c1ccccc1NCCO
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred mixture of 10 parts of methyl 2-[(2-hydroxyethyl)amino]benzoate and 100 parts of acetic acid is added dropwise a solution of 4.5 parts of potassium cyanate in 25 parts of water. Upon completion, stirring at room temperature is continued overnight. The reaction mixture is evaporated. The solid residue is stirred with water. The product is filtered off, washed with water and ethanol, and dried, yielding 5 parts (48%) of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione; mp. 273.6° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15). Light brown foam (21%). MS (ESI): m/z=569.077 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1cc(-c2nccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (0.2890 g, 0.967 mmol), 2-methylpyridin-4-ylboronic acid (0.1684 g, 1.20 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (0.0355 g, 0.0484 mmol) in DME. An aqueous solution of cesium carbonate (0.213 ml, 2.61 mmol) was added and the temperature was brought to 80° C. to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 356.1. IC50 (uM)=0.033.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:25][CH2:24]2)[CH:18]=1)=[O:15]
Reactant: ClCCCSc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.48 (s, 1H), 7.33 (m, 3H), 7.27 (t, 2H, J=7.5 Hz), 7.20 (t, 1H, J=7.9 Hz), 7.15 (tt, 1H, J=7.2, 1.4 Hz), 6.95 (d, 1H, J=7.6 Hz), 2.97 (t, 4H, J=7.3 Hz), 2.46 (m, 4H), 1.99 (dt, 2H, J=11.4, 3.0 Hz), 1.84 (qt, 2H, J=7.3 Hz), 1.77 (m, 4H), 1.21 (d, 6H, J=6.8 Hz); ESMS m/e: 396.8 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[CH:28](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:28]=[N:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
20 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are heated to reflux for 6 hours in 200 ml of triethyl orthoformate. The mixture is then concentrated under vacuum and the residue is taken up with ether. The crystals obtained are drained and washed with ether to give 18.8 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[4,3-c]pyrimidine in the form of crystals of melting point 153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[BH3-]C#N.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:29]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2CCN(C(=O)Cc3ccc(Cl)c(Cl)c3)C3C(N4CCCC4)CCCC32)cc1
Reaction time: 8 h

Procedure:
Anisaldehyde (361 mg, 2.6 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (170 mg, 2.6 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (105 mg, 0.26 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was washed three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). The fractions containing the product were evaporated, the residue was taken up in CH2Cl2 and the solution was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A yellowish resin was isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)cc(N)c1
Reaction time: 1 h
Yield: 63 %

Procedure:
3,5-Dinitroanisole (20 gm.) is suspended in methanol (250 ml.) and 5% palladium on charcoal (2.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour. The solution is filtered with suction and the catalyst washed with a few cc of methanol. Removal of the methanol gives a clear brown glass which crystallized on standing. Extraction with boiling benzene (250 ml.) and treatment with Darco® gives white needles (8.7 gm., m.p. 79°-80°, 63% yield).