Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:37]3[C:38]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.30 mg, 66.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H) 7.72 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.5 (m, 2H), 7.45–7.30 (m, 6H), 7.25 (m, 3H), 7.17 (apparent dd, 1H, J=2.6, 9.0 Hz), 7.01 (apparent d, 1H, J=2.6 Hz), 6.97 (apparent d, 1H, J=7.9 Hz), 5.46 (apparent dd, 1H, J=4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30–2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3 Hz, overlapped); ESMS m/e: 507.2 (M+H)+.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[O:13]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[O:13]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[N:22]=[C:1]=[S:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: S=C=Nc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.96 g (0.011 mol) of thiocarbonyl diimidazole were added to a solution of 1.85 g (0.01 mol) of 2-phenoxyaniline in 50 ml of THF and the mixture was stirred at room temperature for 4 hours, giving, after removal of the solvent by distillation, the compound as a brown amorphous product.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28]C)=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3]>CO>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([OH:28])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Solvent: CO
Product: COc1c(O)cc2c(c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reaction time: 1 h
Yield: 51 %

Procedure:
Using the same procedure as for colchicine, after evaporating the solvents 10 ml of a 10% methanolic K2CO3 solution was added and the mixture stirred for 1 h. The MeOH was evaporated and cold 2N HCl was added until pH 6-7. Extraction with CHCl3, washing with brine, drying and evaporating gave a brown residue which was purified by flash chromatography (CHCl3 /MeOH 100:7) and crystallized from CHCl3 : 2 as a light yellow solid, (51% yield), mp 246°-248° C., [α]D25 0° (c 0.12, MeOH).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:13][CH:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-ylamine (0.50 g, 2.84 mmol) (from Example 123) and 4-cyanobenzaldehyde (0.74 g, 5.64 mmol) were dissolved in anhydrous methanol (10 mL) and acetic acid (0.97 mL, 17 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium cyanoborohydride (0.267 g, 4.25 mmol) was added, then the reaction mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between sat. NaHCO3 (aq) (50 mL) and dichloromethane (25 mL), and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane--30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:35]>C(OCC)(=O)C.CO>[ClH:35].[ClH:35].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1
Reactant: CN(Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cc(Nc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
tert-Butyl methyl{[1-phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methyl}carbamate (90 mg) was dissolved in ethyl acetate (2 mL) and methanol (1 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 62 mg, yield 75%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:3]1=2.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl>C(C(C)=O)C.C(OCC)(=O)C>[ClH:17].[O:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:13][CH2:12]3)[C:3]1=2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)c2occc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(CCCN1CCN(c2cccc3ccoc23)CC1)c1ccc(F)cc1

Procedure:
7.5 Mmol (1.79 g) of 1-benzo[b]furan-7-yl-piperazine HCl, together with 9.1 mmol (1.82 g) of 1-chloro-3-(4-fluorobenzoyl)-propane, 20 mmol (2.80 g) of potassium carbonate and a catalytic quantity (approximately 100 mg) of sodium iodide as a suspension in 50 ml of methyl ethyl ketone, was heated with thorough stirring so that the solvent refluxes. After stirring for 16 hours, 9.1 mmol of 1-chloro-3-(4-fluorobenzoyl)propane and 20 mmol of potassium carbonate were added again. After stirring for another 16 hours at reflux temperature, cooling, filtering and evaporating to dryness in vacuo were carried out. The residue was chromatographed on silica gel with ethyl acetate as an eluent. After evaporating the fractions which comprised the desired product, material was obtained which was converted into the title compound via treatment with 1 equivalent of a HCl solution in ethyl acetate.
Reaction SMILES: [C:1]([C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:7]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:25])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]([Cl:25])[C:7]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Nc1ccc(OC)c(OC)c1C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1c(Cl)cc(OC)c(OC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The chloroform solution of ethyl 2-carboethoxy-3,4-dimethoxybenzenecarbamate prepared in A above was treated with sulfuryl chloride (30.2 g, 0.22 mole) and optionally with sodium bicarbonate (33.3 g, 0.40 mole) and the mixture was stirred at room temperature for 4 hours. An additional charge of sodium bicarbonate (3.3 g, 0.04 mole) and sulfuryl chloride (3.0 g, 0.02 mole) was added and stirring was continued for 16 hours. Filtration and concentration of the filtrate provided crude product as an oil which was crystallized from aqueous methanol. The resultant solid was dissolved in chloroform and the solution was dried, filtered and concentrated to give an oil which was crystallized from hexanes; 37.3 g (85%), mp 111°-113° C.
Reaction SMILES: C=CCCCC.B1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:8]1[CH2:9][CH2:10][CH2:11]2.C1COCC1.ClC1C=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1C1C=CC=C(C)C=1>[CH2:11]([C:10]1[CH:9]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:8]
Reactant: COc1ccc(Cl)cc1
Reactant: B1C2CCCC1CCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cccc(-c2cc(C)ccc2C)c1
Solvent: C1CCOC1
Solvent: C=CCCCC
Product: CCCCCCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
An oven-dried resealable Schlenk tube was capped with a rubber septum, cooled under an argon purge, charged with 1-hexene (0.19 mL, 1.5 mmol), and cooled to 0° C. A solution of 9-BBN in THF (3 mL, 1.5 mmol, 0.5 M) was added, the flask was stirred at 0° C. for 15 min, then warmed to room temperature and stirred for 5 h. 4-Chloroanisole (0.12 mL, 1.0 mmol) was added, the septum was removed, and palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 (11.9 mg, 0.03 mmol, 3 mol %), and cesium fluoride (456 mg, 3.0 mmol) were added under a stream of argon. The septum was replaced and the flask was purged with argon for 30 s. Dioxane (2 mL) was added, the septum was removed, the tube was sealed with a teflon screw cap, and the mixture was stirred at rt for 2 min. The reaction mixture was then heated to 50° C. with stirring for 22 h, at which time GC analysis showed the aryl chloride had been completely consumed. The mixture was cooled to room temperature, diluted with ether (20 mL), and poured into a separatory funnel. The mixture was washed with 1 M aqueous NaOH (20 mL), the layers were separated, and the aqueous phase was extracted with ether (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography to afford 170 mg (89%) of a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.09 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.6 Hz), 3.78 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.54-1.60 (m, 2H), 1.28-1.35 (m, 6H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 157.6, 135.0, 129.2, 113.6, 55.2, 35.0, 31.73, 31.70, 28.9, 22.6, 14.1; IR (neat, cm−1) 2926, 1513, 1243, 1038, 822. Anal Calcd for C13H20O: C, 81.20; 11, 10.48. Found: C, 81.19; H, 10.62.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:23][C:24]([F:31])([F:30])[C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][C@@H:25]3[C:24]([F:31])([F:30])[F:23])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: FC(F)(F)[C@H]1CCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 130 °C
Reaction time: 168 h

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (270 mg, 0.85 mmol) in DMSO (1 mL) was added (R)-2-(trifluoromethyl)pyrrolidine (275 mg, 1.99 mmol). The resulting solution was stirred 7 days at 130° C. and then evaporated in vacuo. The residue was diluted with petroleum ether (15 mL) and filtered. The filtrate was concentrated and purified by a silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether to afford (R)-methyl 2-(4-fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (35 mg, crude).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N+:19]=[N-:20].Cl>O.C(O)C>[N:18]([C:21](=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:8]=1[O:7][CH3:6])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N+:19]=[N-:20]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1cccc(C=O)c1OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc(OC)c1OC)N=[N+]=[N-]
Temperature: -30 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A sodium ethoxide solution, prepared using 80 ml of absolute ethanol and 2.76 g of sodium, is cooled to −30° C., under nitrogen. 4.99 g of 2,3-dimethoxybenzaldehyde and 15.5 g of ethyl azidoacetate are added and the mixture is then left stirring between −20° C. and −10° C. for 2 hours. The reaction medium is poured into 250 ml of water containing 25 ml of concentrated HCl. The precipitate formed is filtered off, washed with water and then dissolved in ether. This solution is dried over Na2SO4 and concentrated to give 5.86 g of the expected compound: m.p.<50° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[CH2:28]([N:30](CC)CC)[CH3:29].C(N)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:28]([NH:30][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:29]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]-pyrimidine (27.4 mg) was dissolved in THF (1 mL), and triethylamine (53 μL) was added. A solution of 2.0M ethylamine in THF (76 μL) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.9 mg) and 4-dimethylaminopyridine (˜1 mg). Stirred at room temperature for 2 h then another portion of 2.0M ethylamine in THF (76 μL) was added along with more 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.4 mg). 1.5 h later the mixture was concentrated under reduced pressure then purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 18.2 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.48 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.90 (m, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.64 (m, 1H); 7.58 (d, J=5.8 Hz, 1H); 7.44 (t, J=7.7 Hz, 1H); 7.34 (m, 3H); 6.79 (d, J=5.5 Hz, 1H); 6.11 (br s, 1H); 5.81 (br s, 1H); 5.25 (br s, 1H); 3.49 (m, 2H); 1.65 (d, J=6.9 Hz, 3H); 1.25 (t, J=7.3 Hz, 3H). Mass Spectrum (ESI): m/e 387.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([N:22]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>CCO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:20])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)C(N)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of product of step 7 (0.4 mmol) in 10 mL of EtOH, was added hydrazine (4 mmol) at 0° C. The mixture was stirred at 80° C. overnight. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with 10% NaOH, H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (20% EtOAc:hexane) to yield 52 mg of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17](C4CCCCO4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[CH2:30][C:29]3([CH3:43])[CH3:42])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[CH3:20][C:19]1[C:14]2[C:15](=[N:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)=[CH:12][C:13]=2[CH2:27][N:28]2[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH2:30][C:29]2([CH3:43])[CH3:42])[NH:17][N:18]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)N(Cc4cccnc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)N(Cc4cccnc4)CC3(C)C)c12
Reaction time: 0.17 h
Yield: 128.1 %

Procedure:
65 mg of 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5-trimethyl-4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine were dissolved in 1.5 ml of 1,4-dioxane and treated with 1.5 ml of hydrochloric acid (4 M in dry dioxane). After standing at rt for 10 min the volatiles were removed in vacuo. The residue purified by HPLC and 65 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])(O)[CH:17]=[CH2:18])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4].C(O)=[O:24].O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][CH2:18][OH:24])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4]
Reactant: O=CO
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C)=CCO
Reaction time: 0.75 h

Procedure:
47.8 g of 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-1-yl]-3-methyl-penta-1,4-dien-3-ol are dissolved in 720 ml of methylene chloride. After the addition of 200 ml of formic acid, the solution is stirred at room temperture for 45 minutes, then introduced into water and extracted with diethyl ether. The ether extract is evaporated. The residue is taken up in 500 ml of methanol, treated with 100 g of potassium carbonate 250 ml of water, stirred for 1 hour, then introduced into water and extracted with ethyl acetate. The 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-yl]-3-methyl-penta-2,4-dien-1-ol isolated from the extract is processed further as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](OC(OCC)OCC)C>>[N:1]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[O:5][CH:11]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccccc1C(=O)O
Product: O=c1ocnc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-aminobenzoic acid (1 g, 7.29 mmol) and triethylorthoformate (3 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and triturated with 10 mL of hexane. The resulting solid was filtered and further washed with hexane to yield 1.1 g of the expected benzo[d][1,3]oxazin-4-one.
Reaction SMILES: C[N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[N:25]2[C:16](=[O:18])[CH2:15][C:3]1[NH:2][C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 29.2 %

Procedure:
The product is prepared by following the procedure described in example 29c using 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c), 0.11 g of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c], and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 120 μl of pyridine and 3.0 ml of N,N-dimethylformamide. 79 mg of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6](Cl)[N:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-Amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile (1.35 g) was dissolved in dioxane (135 ml). To the solution were added phenylboronic acid (1.89 g) and Pd(PPh3)4 (179 mg) and Na2CO3 (2.19 g) in water (27 ml) at 25° C. The reaction mixture was heated at 80° C. for 2 hours, then at ambient temperature for 3 hours. The above mixture was portioned to EtOAc and water. The organic layer was separated and washed with aq. Na2CO3 and brine, and dried over MgSO4. Evaporation of solvent in vacuo gave oily residue, which was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile as yellow crystal which was crystallized from EtOAc (1.15 g).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[S:15][C:14]2[C:16]3([O:29][CH2:30][CH2:31][C:13]=2[CH:12]=1)[CH2:21][CH2:20][N:19]([CH2:22][C:23]1[C:24]([CH3:28])=[N:25][NH:26][CH:27]=1)[CH2:18][CH2:17]3>>[F:10][C:11]1[S:15][C:14]2[C:16]3([O:29][CH2:30][CH2:31][C:13]=2[CH:12]=1)[CH2:21][CH2:20][N:19]([CH2:22][C:23]1[C:24]([CH3:28])=[N:25][N:26]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[CH2:18][CH2:17]3
Reactant: O=Cc1cccnc1Br
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Product: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Yield: 83 %

Procedure:
The compound of Preparation 13 is essentially prepared as described in Preparation 12 by using 2-bromopyridine-3-carbaldehyde and 2-fluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]. Residue is purified by normal phase Isco chromatography to yield 83% of the title compound. MS (m/z): 427 (M+1).