Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[CH3:19].[OH-].[Na+].CN([CH:25]=[O:26])C>O>[CH3:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:25]=[O:26])[C:9](=[O:18])[N:8]1[CH3:19]
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccccc2)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(-c2ccccc2)c(C=O)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
N,N-Dimethylformamide (3.4 mL, 43.6 mmol) was added to a flask under nitrogen atmosphere. After cooling to 0° C., phosphorus oxychloride (1.4 mL, 15.2 mmol) was added. The resulting reaction mixture was stirred at room temperature for 50 minutes. The resulting reaction mixture was transferred to a reaction flask containing a solution of 1,2-dimethyl-5-phenyl-1H-pyrazol-3(2H)-one (820 mg, 4.36 mmol) in DMF (4.9 mL). The reaction flask was immersed in a preheated oil bath (120° C.) and, after stirring for 12 minutes, cooled to room temperature. 5 N NaOH (15 mL) was added to the cooled reaction mixture. After diluting with icy water, the mixture was extracted with chloroform. The organic layer was dried with sodium sulfate and then filtered. The filtrate was concentrated. After diluting DMF remaining in the resulting residue again with chloroform and then washing with water, the aqueous layer was extracted again with chloroform. The organic layer was collected, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The concentrated residue was subjected to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:29](Br)[C:30]#[CH:31]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH2:31][C:30]#[CH:29])[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: C#CCBr
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCON(C(=O)Cc1c(C)cc(C)cc1C)C1(C(=O)OC)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (500 mg, 1.37 mmol) in tetrahydrofuran (3 ml) at 0° C. was added sodium hydride (66 mg, 55% w/w dispersion in mineral oil, 1.51 mmol) in 2 portions. The reaction mixture was stirred at 0° C. for one hour, treated with propargyl bromide (202 mg, 1.65 mmol) dropwise, and further stirred at room temperature overnight. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed twice with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2). Yield: 321 mg of 1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.4) as a colorless gum.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]([OH:33])(=[O:32])[C:26]([CH2:28][C:29](O)=[O:30])=[CH2:27]>>[CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:27][CH:26]([C:25]([OH:33])=[O:32])[CH2:28][C:29]2=[O:30])=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(N2CC(C(=O)O)CC2=O)cc1

Procedure:
The title compound was prepared from trans-N-(1-methyldecyl)-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized from acetic acid to give a 21% yield of material having a melting point of 226°-228° C. The infrared spectrum (KBr disc) showed absorptions at 3280, 2900, 1695 and 1625 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12](Cl)([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:24][Al](C)C>C1CCCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([CH3:24])([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Al](C)C
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(Cl)C(F)(F)C3
Solvent: C1CCCCC1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(C)C(F)(F)C3
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
Into a glass vial the product from step (b) (214 mg, 0.623 mmol) dissolved in cyclohexane (3 ml) was added. To this solution, AlMe3 (2M in hexanes, 1.2 ml, 2.49 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature and was quenched by the addition of 2M HCl (20 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 20% EtOAc in hexanes) gave the sub-title compound as an orange oil (20 mg). NMR (300 MHz, CDCl3) δ 6.99 (s, 2H); 4.15 (q, J=7.2 Hz, 2H); 3.62-3.59 (m, 4H); 3.29 (t, J=14.1 Hz, 2H); 3.01-2.91 (m, 2H); 1.39 (s, 6H); 1.26 (t, J=7.2 Hz, 3H); MS: ESI (positive): 324 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(I)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 8-Iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0016 mol) in N-methyl 2-pyrolidone (5 mL) was added powdered potassium hydroxide (0.9 g, 0.016 mol) and allowed to stir for 10 min at RT. 2-Methyl-5-vinyl-pyridine (0.969 g, 0.0048 mol) was added and stirred for further 24 hours at 100° C., after completion (TLC), reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (6% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), then further purified by preparative HPLC to get the desired compound as brown solid (0.105 g, 15.2% yield). 8-Iodo-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.095 g, 0.00022 mol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.0277 g, 0.00022 mol) in THF (2.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.09 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=O)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[N:31][OH:32])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C=NO)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-methyl-4-(-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.6 g), hydroxylamine hydrochloride (495 mg) and sodium acetate (691 mg) in acetic acid (20 ml) was stirred at room temperature for an hour to form diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (2.18 ml) and the mixture was heated at 110° C. for 3.5 hours with stirring. Acetic acid was distilled off under reduced presssure from the reaction mixture and the resultant residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The resultant oil (2.88 g) was chromatographed on a column of silica-gel (72 g), and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give an oil (1.6 g), which was triturated with diisopropyl ether (3 ml) to give crystalline powder (1.3 g). Recrystallization from a mixture (20 ml) of diisopropyl ether and ethanol (15:1, v/v) gave pure crystals of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.03 g), mp 120° to 127° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:31])[F:32])=[CH:25][CH:26]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(C)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.135 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 210 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:12]=[C:11]([C:13]([O:15]CC)=[CH2:14])[N:10]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.O.Cl>O1CCOCC1>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[N:8]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:10]=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=2)[CH2:3][CH2:2]1
Reactant: C=C(OCC)c1cc(COCC2CC2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC3CC3)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 4-((cyclopropylmethoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (98 mg, 0.23 mmol) in dioxane (15 mL) were added water (1 mL) and hydrochloric acid (conc., 0.056 mL, 0.68 mmol). The mixture was stirred at 50° C. for 20 min. The solvents were evaporated. Sodium bicarbonate (aq, 50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and the solvents were evaporated to give the title compound 90 mg (98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[N:28][S@@:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NCCC(=N[S@](=O)C(C)(C)C)c1ccc(F)cc1)c1ccc(Br)cc1
Yield: 73.3 %

Procedure:
A mixture of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propan-1-one (14.5 g, 0.04 mol), (R)-2-methylpropane-2-sulfinamide (5.5 g, 0.046 mol), and Ti(OEt)4 (18 g, 0.08 mmol) in THF (150 mL) was heated to reflux overnight. The mixture was treated with brine, and the precipitate was filtered. The filtrate was concentrated to give (R)—N-(3-((1S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propylidene)-2-methylpropane-2-sulfinamide (13.3 g, 59%), which was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=2[N:6]=1.Cl.[Cl:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]2[NH:6][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:3][C:4]=2[CH:10]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl
Agent: Cl
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4Cl)CC3)nc2cc1Cl

Procedure:
2,5-Dichloro-6-(trifluoromethyl)benzoimidazole (255 mg, 1.0 mmol, Example 84c) reacted with 1-(3-chloropyridin-2-yl)piperazine hydrochloride (233 mg, 1.0 mmol, Example 3b) under the conditions of Example 3c to give the title compound as a white solid. M.p. 208.9-211.0° C. MS (ESI, pos. ion) m/z: 416.3, 420.1 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 46 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminomorpholine, to the title compound (50 mg, 46%), which was obtained as a white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([Cl:14])=[CH:11][C:12](Cl)=[C:7]2[C:6]([CH3:15])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.C(OCC)(=O)C>CS(C)=O>[Cl:14][C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([CH3:15])[C:7]2=[C:12]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH2:22])=[CH:24][C:25]=2[F:30])[CH:11]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: CC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of 1-acetyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (from example XL) and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through CELITE (diatomaceous earth) and the filtercake is washed with ethyl acetate. The filtrate is extracted three times with sat. sodium bicarbonate solution and with sat. sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:methanol=50:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][C:10]([CH3:17])([CH3:16])/[CH:11]=[CH:12]/B(O)O>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[CH:12]=[CH:11]/[C:10]([CH3:17])([OH:9])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(C)(O)/C=C/B(O)O
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)/C=C/c1ccc(Cl)nn1
Temperature: 85 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and [(1E)-3-hydroxy-3-methylbut-1-en-1-yl]boronic acid (218 mg, 1.68 mmol) in THF (5 mL) and 2.0 M NaHCO3 (1.70 mL) was added palladium tetrakis triphenylphosphine (97 mg, 0.084 mmol). The solution was degassed with nitrogen and heated to 85° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:25])([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(N(CC)CC)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:25])([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:29])=[O:28]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCO)cc1)Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-methyl-2-phenoxypropionate (1.10 g), which is the product of Reference example 8(d), triethylamine (0.49 ml) and methanesulfonyl chloride (0.25 ml) and the reaction mixture was treated to afford the desired compound (1.42 g) as a syrup.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]#[N:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39](=[N:2][OH:3])[NH2:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: NO
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 1.49 g (20.6 mmol) of hydroxylamine hydrochloride in DMSO (10 mL) was added 2.88 mL (20.6 mmol) of triethylamine. The slurry was stirred for 5 min and then filtered twice through cotton, rinsing with THF, to remove the solids. The filtrate was partially concentrated under reduced pressure to remove THF, and then was added to a flask containing 915 mg (2.06 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetonitrile (Example 82, Step B). The resulting yellow solution was heated at 75° C. for 22 h, and then was partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[C:22]3[CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]cc(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in dioxane (5 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (395 mg, 1.54 mmol), K2CO3 (106 g, 0.77 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 5 h at 90° C., and then poured into water (100 mL), extracted with DCM (4×50 mL), dried over anhydrous sodium sulfate and then concentrated under vacuum to give a residue. The residue was purified via silica gel chromatography (25% ethyl acetate in petroleum ether) to afford methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a yellow solid (80 mg, 45%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: CN(C)CCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN(C)CCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 3-dimethylamino-propylamine comparable as in Example A. A colorless, crystalline product with a melting point of 107° to 108° C. was obtained.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)-ethylamino]ethylene (see Example 31 (ii) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [Br-].[CH3:2][CH:3]([O:7][C:8]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4](=O)[CH3:5].[Na].[CH2:36](OCC)C.O>C(O)C>[I:34][C:31]1[CH:32]=[CH:33][C:8]2[O:7][C:3]([CH3:2])([CH3:36])[C:4]([CH3:5])=[CH:10][C:9]=2[CH:30]=1
Reactant: CCOCC
Reactant: CC(=O)C(C)Oc1ccc(I)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1=Cc2cc(I)ccc2OC1(C)C
Yield: 85 %

Procedure:
To a suspension of 2-(1-methyl-2-oxo-propyloxy)-5-iodobenzyltriphenylphosphonium bromide (0.71 g, 0.00108 mol) in absolute ethanol (3 ml) was added dropwise at room temperature a solution of sodium (0.025 g) in absolute ethanol (1 ml). After twelve hours at room temperature, diethyl ether and water were added. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel, eluting with a mixture of dichloromethane/heptane (50/50) to give 0.29 g (85%) of 6-iodo-2,2,3-trimethyl-1(2H)-benzopyran, as an oil, 1NMR (CDCl3): δ1.4 (s, 6H), 1.8 (s, 3H), 6.0 (s, 1H), 6.55 (d, 1H), 7.2 (d, 1H), 7.35 (d, 1H).