Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[CH:23]=3)[C:14]2=[O:29])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:16]1([CH3:20])[C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([O:2][CH3:1])=[O:30])=[CH:8][CH:9]=2)[C:14](=[O:29])[N:15]1[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:23]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)C(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Yield: 68.8 %

Procedure:
To a solution of 1.23 g of 2-{4-[3-(2-chloropyridin-4-ylmethyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-phenyl}-2-methylpropionic acid methyl ester obtained in stage d) below in 40 mL of dioxane are successively added, under argon, 0.4 g of 3-aminopyridine, 0.16 g of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 0.065 g of palladium acetate and 3.65 g of caesium carbonate. The reaction mixture is refluxed for 4 hours and then filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/02 by volume) to give 0.96 g of methyl 2-[4-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)phenyl]-2-methylpropanoate, the characteristics of which are as follows:
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CN(C)[CH:26]=[O:27]>C1COCC1>[CH:26]([C:13]1[CH:14]=[CH:15][S:11][C:12]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1cccs1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sccc1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 35.4 mL, 60.2 mmol, 2.40 equiv) was added to a solution of tert-butyl 2-thienylcarbamate (10-2, 5.00 g, 25.1 mmol, 1 equiv) in THF (75 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. N,N-Dimethylformamide (5.83 mL, 75.3 mmol, 3.00 equiv) was added, and the mixture was then warmed to 0° C. The reaction mixture was partitioned between water (300 mL) and EtOAc (2×200 mL). The combined organic layers were then dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (hexane, initially, grading to 30% hexane in EtOAc) to give tert-butyl 3-formyl-2-thienylcarbamate (10-3) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 9.80 (s, 1H), 7.11 (d, 1H, J=5.7 Hz), 6.68 (d, 1H, J=5.9 Hz), 1.55 (s, 9H).
Reaction SMILES: O.[C:2]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[C:2]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2cccc3ccccc23)cc1

Procedure:
A mixture of 1.5 liters of water, 40 ml of glacial acetic acid and 1.0 mol of 4-(α-naphthoxy)-nitrobenzene was heated to boiling while stirring. After the boiling temperature had been reached, 200 g of iron powder were added in small portions. When the addition was finished, it was refluxed for 6 hours, while stirring.
Reaction SMILES: [BH4-].[Na+].[CH2:3](COC)[O:4]C.[F:9][C:10]1[C:18]([F:19])=[C:17](C(O)=O)[C:16]([F:23])=[C:15]([F:24])[C:11]=1[C:12]([OH:14])=O.Cl>O.C1(C)C=CC=CC=1>[F:24][C:15]1([CH2:3][OH:4])[C:16]([F:23])=[CH:17][C:18]([F:19])=[C:10]([F:9])[CH:11]1[CH2:12][OH:14]
Reactant: COCCOC
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 200 mL flask equipped with a reflux condenser, 2.58 g of sodium borohydride and 25 g of dimethoxyethane were charged. The obtained mixture was adjusted to 50° C. and then, a solution obtained by mixing 6.10 g of 2,3,5,6-tetrafluoroterephthalic acid with 20 g of dimethoxyethane was added dropwise thereto over 1 hour while stirring. The obtained mixture was stirred for 7 hours at 60° C. To the obtained reaction mixture, 20 g of toluene was added followed by cooling to 50° C. Eight point five grams of 35% by weight hydrochloric acid was added dropwise thereto over 1 hour to stir at 60° C. for 6 hours. To the obtained mixture, 30 g of water was added followed by separating to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 30 g of ethyl acetate. The obtained organic layers were mixed and washed with 10 g of a saturated aqueous potassium carbonate solution and then with 10 g of water. The organic layer was concentrated and the obtained solids were recrystallized with toluene and hexane to obtain white powder crystals of 2,3,5,6-tetrafluorobenzenedimethanol. The crystals were analyzed by liquid chromatography absolute calibration curve method to find out that the purity thereof was 95.1%. Yield: 95%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: OC1CCNCC1
Solvent: CCCCO
Solvent: O
Product: OC1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 4,6-dichloro-2-phenyl pyrimidine (1 g. 4.42 mmol) and triethyl mol amine (1.78 g, 17.6 mmol) in n-butanol (10 mL) was added 4-hydroxy piperidine (0.44 g, 4.4 mmol) to temperature in the range of 20-40° C. with stirring. The mixture was then stirred under reflux for 16 hours under nitrogen. The mixture was cooled to room temperature, poured into water (25 mL) and extracted with EtOAc (2×15 mL). Organic layers were collected, combined dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using EtOAc-pet ether to give the desired compound (1.15 g, 91% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[O:22])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: O=C1NCCNC1c1cccs1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1NCCN(C(=O)Nc2cccc(Cl)c2)C1c1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.5 g (0.03 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are dissolved in 60 ml of methylene chloride, 4.6 g (0.03 mol) of 3-chlorophenyl isocyanate, dissolved in 20 ml of methylene chloride, are added dropwise and the mixture is stirred for a further 5 hours at room temperature. The reaction product which has been precipitated is filtered off with suction, washed with methylene chloride and dried.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:25]1[N:26]=[C:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[CH3:35])[O:28][CH:29]=1)[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[O:15][C:16]=1[C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:37][C:34]([F:36])([CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:27]1[O:28][CH:29]=[C:25]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:24])[O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[N:26]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)(F)F)n2)c1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2coc(CCCCC(C)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5,5-difluoro-hexyl)-oxazol-4-yl]-(2-methyl-5-m-tolyl-oxazole-4-carbonyl)-carbamic acid tert-butyl ester (32 mg, 0.06 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.05 mL, 0.65 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a light brown solid. TLC: rf (4:1 hept-EA)=0.21. LC-MS-conditions 02: tR=1.17 min, [M+H]+=404.43.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][N+:8]([O-])=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:14])=O>O1CCOCC1>[Cl:14][C:7]1[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3][S:2][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2ccsc2c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nccc2ccsc12

Procedure:
adb) 671.5 g of thieno[2,3-c]pyridine 6-oxide hydrochloride were suspended in 4000 ml of dioxane under argon and 655 ml of phosphorus oxychloride are added. The mixture was heated on an oil-bath until the exothermic reaction set in. After the exothermic reaction faded away, the mixture was heated to reflux for an additional 10 minutes. The mixture was concentrated in vacuo and the residue was taken up in 2000 ml of toluene. The solution was then treated with 300 ml of water while cooling slowly. The mixture was neutralized by the portionwise addition of sodium carbonate. The organic phase was separated and the aqueous phase was extracted with 1000 ml of toluene. After washing with water, the combined organic solutions were dried over sodium sulfate, filtered and evaporated, whereby crude 7-chloro-thieno[2,3-c]pyridine was obtained as a brown oil.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:32])([F:31])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)=O.O>C1COCC1.CN(C=O)C>[F:32][C:18]([F:17])([F:31])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(F)c([N+](=O)[O-])c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10.9 g (48.5 mmol) of ethyl diethylphosphonoacetate were slowly added dropwise to an ice-cooled suspension of 1.86 g (60% in mineral oil, 46.4 mmol) of sodium hydride in a mixture of 70 ml of THF and 20 ml of DMF. After the addition had ended, the mixture was stirred at 0° C. for another 30 min, and 10.0 g (42.2 mmol) of 2,2,2-trifluoro-1-(4-fluoro-3-nitrophenyl) ethanone were then added. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1 to 10:1), 9.23 g of the target product (71.2% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[C:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[O:4][Si](C)(C)C.[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([CH2:41]OCC)[CH2:37][CH2:36]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.[Cl-].[Mg+2].[Cl-]>[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:9]4([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)[CH2:37][CH2:36]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(O[Si](C)(C)C)=C1CCOCC1
Reactant: CCOCN1CCC(CCOc2noc3cccc(OCc4ccccc4)c23)CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCc5ccccc5)c34)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
[Methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (2.2 g, 10.0 mmol, EXAMPLE 1, step 3) was added to the mixture of 4-(benzyloxy)-3-{2-[1-(ethoxymethyl)piperidin-4-yl]ethoxy}-1,2-benzisoxazole (3.4 g, 8.4 mmol, EXAMPLE 7, step 4) and magnesium chloride (40 mg, 0.42 mmol) in acetonitrile (16.0 mL) at ambient temperature. After being stirred at room temperature for 3 h, the mixture was concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 2:3) to give 3.2 g (75%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1ccccc1-c1nc2nc(N)ncc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nc(NC(C)=O)ncc2c(=O)[nH]1

Procedure:
A stirred mixture of 7-amino-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.59 g)and acetic anhydride (5 ml) was heated under reflux for 1.5 hours Excess acetic anhydride was removed under reduced pressure. The solid residue was washed with water and triturated with hot methanol to yield the title compound, 0.57 g, m.p. 273°-4° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[Na].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[C:21]([C:20]1[C:15]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:22]
Reactant: CN(C)CCCCCCO
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN(C)CCCCCCOc1ncccc1C#N

Procedure:
6-Dimethylaminohexanol is converted into its sodium salt with sodium hydride in toluene, followed by reaction of the sodium salt with 2-chloro-3-cyanopyridine to give 3-cyano-2-(6-dimethylaminohexyloxy)pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][CH2:9][C:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=1)C(O)=O)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:33]([O:32][C:30]([NH:29][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cn1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of 220 mg of (5S)-6-tert-butoxy-2-(tert-butoxycarbonyl)-5-[(tert-butoxycarbonyl)amino]-2-[(5-hydroxypyridin-2-yl)methyl]-6-oxohexanoic acid (0.42 mmol) and 100 mg 4-N,N-dimethylaminopyridine (0.84 mmol) in 1,4-dioxan (10 mL) was heated under reflux for 2 hours. The mixture was evaporated and the residue was purified by column preparative HPLC (method C) to give two batches (107+49 mg; 78% combined yield) of the target compound.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][C:8]=1[CH3:9]>C(O)C>[Cl:2][C:3]1[N:4]=[N:5][C:6]([NH2:1])=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: N
Solvent: CCO
Product: Cc1cc(N)nnc1Cl
Temperature: 100 °C
Reaction time: 70 h
Yield: 57 %

Procedure:
Ammonia (32% solution in water, 54 mL) was added to a solution of 3,6-dichloro-4-methylpyridazine (5.0 g, 30.67 mmol) in ethanol (25 mL) in a sealed tube. The resulting mixture was stirred at 100° C. for 70 hours, cooled down and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (3:2 hexanes/ethyl acetate to 100% ethyl acetate) to yield the title compound (3.8 g, 57%) as a mixture of two isomers which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@H:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@H]1Cc2c(-c3ccon3)ccc3c2[C@@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Yield: 30.9 %

Procedure:
A mixture of (+)(2aS,4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (180 mg, 0.5 mmol) and 1 g of MnO2 in 40 mL of CH2Cl2 was sonicated at 50-55 KHz for 2 hr. The reaction mixture warmed to reflux during the time period. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, ethyl acetate) to provide 50 mg of the isoxazole indole product as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>C(O)C>[CH2:2]([NH:13][CH2:12][CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCCO
Reactant: BrCCc1ccccc1
Solvent: CCO
Product: OCCNCCc1ccccc1
Temperature: 75 °C
Yield: 84.1 %

Procedure:
A mixture of 2-bromoethyl benzene (2.0 g, 10.8 mmol) and ethanolamine (3.96 g, 64.8 mmol) in ethanol (11 mL) was heated at 75° C. for 16.5 hours at which time LC/MS showed the reaction was complete. The reaction mixture was then concentrated to remove ethanol and the resulting residue was diluted with DCM (100 mL). The organic layer was partitioned with water (100 mL) and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a light yellowish oil (1.5 g). (m/z): [M+H]+ calcd for C10H15NO, 166.13; found, 166.2) 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.13-7.29 (m, 5H), 4.4 (br, 1H), 3.42 (t, J=5.7 Hz, 2H), 2.61-2.76 (m, 4H), 2.55-2.59 (t, J=5.7 Hz, 2H), 1.55 (br, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][N:4]=1
Reactant: CNc1ncc([N+](=O)[O-])c(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1ncc(N)c(N)n1
Reaction time: 6 h

Procedure:
N2-methyl-5-nitropyrimidine-2,4-diamine 48 (0.83 g, 4.9 mmol) and 10% palladium on carbon (0.52 g, 0.49 mmol) were combined under nitrogen. Methanol (16 mL) was added, and the atmosphere replaced with hydrogen from a balloon. The reaction was stirred rapidly for 6 h, at which point the atmosphere was replaced with nitrogen and the reaction mixture was filtered through celite, rinsing with methanol. The filtrate was concentrated in vacuo to give N2-methylpyrimidine-2,4,5-triamine 49 as a light pink solid. MS (ES+): 140 (M+H)+; Calc. for C5H9N5=139.16.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=C=O)=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(-c2ccc(N=C=O)cc2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCc1cnc(-c2ccc(N)cc2)nc1
Temperature: 60 °C

Procedure:
8.11 g of crude p-(5-butyl-2-pyrimidinyl)phenyl isocyanate were introduced in small portions into 40 ml of 8N hydrochloric acid heated to 60° C., whereby strong foaming took place. After completion of the addition the mixture was heated to slight boiling for 4 hours and then poured on to ice and an excess of solid sodium carbonate. The aqueous phase was extracted once with 300 ml of diethyl ether and twice with 100 ml of diethyl ether each time. The combined extracts were filtered. The filtrate was washed twice with water, dried over sodium sulphate and concentrated, whereby 5.16 g of yellowish, crystalline p-(5-butyl-2-pyrimidinyl)aniline were obtained; m.p. 154.5°-155.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[N:5]=[C:4]([NH:12][C:13]2[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=C(S)[CH:26]=2)[N:21]=1>C(O)(C)(C)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:11]([S:8][C:6]3[N:5]=[C:4]([NH:12][C:13]4[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=4)[CH:3]=[C:2]([Cl:1])[N:7]=3)[CH:26]=2)[N:21]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: Cc1ccc2cc(S)ccc2n1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc4nc(C)ccc4c3)n2)[nH]n1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (2.02 g, 7.03 mmol) in tert-butanol (20 ml) was added 2-methylquinoline-6-thiol (1.23 g, 7.03 mmol). The mixture was heated to 70° C. for 4 hours, then cooled to ambient and diluted with ethyl acetate/saturated aqueous potassium carbonate. The mixture was filtered to remove unreacted starting material and the organic layer removed form the filtrate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 90 to 100% ethyl acetate/petrol. The title compound was further purified by trituration with dichloromethane. This gave the product as a white solid (514 mg, 19%); MS ES+383.25, ES−381.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 3-chloro-4-hydroxyphenyl-acetic acid (10.0 g, 53 mmol) in ethanol was dropwise added thionyl chloride (3.9 mL. 53.5 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and submitted to flash chromatography (eluent: graduated from 10% ethyl acetate in toluene to toluen) to give 11 g of 3-chloro-4-hydroxyphenyl-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=2[N:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (0.58 g, 1.33 mmol) in THF (30 mL) at RT is treated with NaBH4 (100 mg, 2.65 mmol). The resulting mixture is stirred for 1 h. The reaction is quenched with HCl (1.0 N, 5.0 mL) and extracted with EtOAc (3×50 mL). The organic layer is dried over Na2SO4 and concentrated to afford the title compound (0.58 g, 100%). MS (ES) m/e: 440.3 (M+1), 438.2 (M−1).