Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:3])[CH3:2].O[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>>[CH2:6]([N:7]([CH2:2][CH2:1][OH:3])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:5]
Reactant: Cc1ccc(NCCO)cc1
Reactant: CC=O
Product: CCN(CCO)c1ccc(C)cc1

Procedure:
N-ethyl-N-(2-hydroxyethyl)-p-toluidine (EHPT) was prepared substantially as described above in Example 1, except that acetaldehyde was added to ethylate N-(2-hydroxyethyl)-p-toluidine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=1[CH2:8]C.[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:18]([C:19]1[CH:27]=[CH:26][C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=2[CH3:8])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1nc(CCl)c(CC)o1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
A mixture of ethyl (2E)-3-(4-chloromethyl-5-ethyl-1,3-oxazol-2-yl)-2-propenoate (11.62 g), vanillin (7.70 g), potassium carbonate (6.99 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of ethyl (2E)-3-{4[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (12.15 g, yield 70%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Brc1ccccc1I
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 1.0 g, 2.392 mmol), 1-bromo-2-iodobenzene (1.0 g, 3.588 mmol, Aldrich), Pd2(dba3)2 (138 mg, 0.239 mmol), Xantphos (437 mg, 0.478 mmol) and sodium-tert-butoxide (459 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to get 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow coloured solid (1.2 g, 88.2%). m/z (ESI) 571.9 (M+H)+.
Reaction SMILES: C([Mg]Cl)C.Br[C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28].[CH2:29]([O:31][C:32](C#N)=[O:33])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]([C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28])=[O:33])[CH3:30]
Reactant: CCOC(=O)C#N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Ethylmagnesium chloride (10.9 ml, 2M in THF) is added over 30 minutes to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (10.0 g, Example 2, step D) in THF (15 ml) at 0° C. After 1 hour at room temperature, a solution of ethylcyanoformate (2.81 g) in THF (15 ml) is added to the reaction mixture. After 40 minutes, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is extracted three times with MTBE. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (5.6 g) as a yellowish oil.
Reaction SMILES: C1(C)C=CC=CC=1.O[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[CH2:11][CH2:10]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[C:12]12([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]1)[C:13]1[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:10][CH2:11]2
Reactant: O=C1NC(=O)C2(CCC(O)c3ccccc32)N1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(CC=Cc3ccccc32)N1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a refluxing solution of 100 ml. of toluene containing 4.5 g. (0.019 mole) of 3',4'-dihydro-4'-hydroxyspiro [imidazolidine-4,1'(2'H)-naphthalene]2,-5-dione was added a trace of -toluenesulfonic acid and the refluxing continued for 2 hours. The reaction was cooled, stripped to dryness and the residue dissolved in 100 ml. of ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to dryness. The residue was triturated with diethyl ether, 2.7 g. (65% yield).
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[CH3:26][C@@H:19]([O:18][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:27])=[O:8])=[CH:15][CH:14]=1)=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [H][H]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)O)cc1
Yield: 99.6 %

Procedure:
Then, 0.12 g of 5% palladium/carbon and 30 ml of a tetrahydrofuran solution containing 1.21 g of 4-((R)-1-methylheptyloxycarbonyl)benzoic acid benzyl ester were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.91 g of 4-((R)-1-methylheptyloxycarbonyl) benzoic acid as a colorless liquid (gradually crystallized) (isolated yield: 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6](=O)[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.500 g, 1.49 mmol), 2,6-lutidine (0.69 mL), and POCl3 (0.555 mL) in CHCl3 (10 mL) for 5 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (MgSO4) and concentrate under reduced pressure. Purified the crude by flash column chromatography on a silica gel (EtOAc eluent) and concentrate under reduced pressure to give 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.C(O)=[O:20]>[Ni]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1cccc(CCOc2ccc(C#N)cc2)n1
Agent: [Ni]
Product: Cc1cccc(CCOc2ccc(C=O)cc2)n1

Procedure:
A mixture of 4-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile (9.62 g), Raney nickel alloy (10.0 g) and 75% formic acid (150 ml) was heated under reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water, alkalinized with 4N-KOH, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was recrystallized from ethyl etherhexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][C:21]=1[O:24][CH3:25])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:10]1[CH:5]=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=1
Reactant: Cc1cccc(O)n1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(COc2cccc(C)n2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (1.5 g), 2-hydroxy-6-methylpyridine (0.4 g), potassium carbonate (0.511 g) and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 2 hours. Then the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off. The residual oil was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate, ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)- 2-[(2-methyl-6-pyridyl)oxymethyl]quinoline-3-carboxylate (0.79 g, 46%) was obtained and recrystallized from chloroform/hexane.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([C:33]([NH2:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH3:32]>>[CH2:31]([C:33]([NH:42][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH3:32]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CCC(N)(CC)c1ccccc1
Product: CCC(CC)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-ethyl-1-phenylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 79%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH2:27][C@@H:28]([NH2:30])[CH3:29].CN1CCOCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH:28]([CH2:27][CH3:26])[CH3:29])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC[C@H](C)N
Solvent: c1ccccc1
Solvent: CN1CCOCC1
Product: CCC(C)NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), S-(+)-sec-butylamine (0.235 g, 3.21 mmol), N-methylmorpholine (0.270 g, 2.67 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(sec-butyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.300 9, 27.8% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([Cl:14])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: NCc1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2cc(Cl)nc(NCc3ccncc3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.87 mmol) and (pyridin-4-yl)methanamine (188 mg, 1.74 mmol), DIEA (302 μL, 1.74 mmol) were dissolved in dioxane (5 mL). The reaction mixture was stirred at 90° C. overnight and then cooled to room temperature. The solvent was removed under vacuum and the crude product was purified by silica column chromatography using hexane/ethyl acetate/7N NH3 in methanol (60:33:7) to obtain the yellow 5-((pyridin-4-yl)methylamino)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 1H NMR (DMSO-d6) δ 9.45 (t, J=6 Hz, 1H), 8.49 (m, 3H), 7.32 (d, J=6H, 2H), 6.68 (s, 1H), 4.73 (d, J=6 Hz, 2H), 3.46 (s, 3H); ESI-MS m/z 302.1 (MH+).
Reaction SMILES: [C:1](#N)C.C1OCCOCCOCCOCCOCCOC1.CI.[OH:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:41])([CH3:40])[O:30]2>[Na]>[CH3:1][O:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:40])([CH3:41])[O:30]2
Reactant: CCC(C)Oc1cc(O)c2c(c1)OC(C)(C)CC2=O
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: CI
Product: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Reaction time: 3 h
Yield: 92 %

Procedure:
In 100 ml of acetonitrile 5.6 g (20 millimoles) of the sodium salt of 5-hydroxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved and stirred in the presence of 0.5 g (2 millimoles) 18-Crown-6 for 30 minutes. Thereafter 4.25 g (1.9 ml, 30 millimoles) of methyl iodide are added and the reaction mixture is stirred for another 3 hours. The inorganic salt is filtered off, the solvent removed and the residue suspended in carbon tetrachloride, extracted twice with 30 ml of water each, the organic phase is dried over sodium sulfate and evaporated. Thus 5.1 g of the desired compound are obtained in the form of a light yellow oil, yield 92%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:31][CH2:32][OH:33])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[F:34][C:35]([F:43])(S(F)(=O)=O)C(O)=O>C(#N)C.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:31][CH2:32][O:33][CH:35]([F:43])[F:34])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: OCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: [Cu]I
Solvent: CC#N
Product: FC(F)OCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A mixture of 2-((6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol (58B, 500 mg, 0.987 mmol) and copper(I) iodide (282 mg, 1.480 mmol) in acetonitrile (2861 μl) were degassed (evacuated and back filled w/Argon). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (153 μl, 1.480 mmol) was added, degassed, and heated at 80° C. for 30 min. Reaction was quenched with water (1 mL), diluted with EtOAc and filtered through a celite pug. The solution was concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-20%) affording 6-chloro-3-(2-(difluoromethoxy)ethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (59B, 277 mg, 0.547 mmol, 55.5% yield) as a white crystalline solid. MS: [M+H]+ m/z 506.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][C:14]1([C:20]([O:22]CC)=O)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[H-].[Na+]>>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)[CH2:15]2)[C:20]1=[O:22]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1(CCNc2cnccc2C)CCCNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylate trihydrochloride (42.8 mg, 0.000107 mol), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) and N,N-diisopropylethylamine (0.056 mL, 0.00032 mol) in N-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwaves to 180° C. for 20 min. Sodium hydride (30.0 mg) was then added to the above solution and the mixture was stirred overnight. The product was purified by prep-HPLC. LC-MS: 391.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:21][OH:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([O:22][CH2:21][C:11]1[N:10]([CH2:9][C:8]2[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)(=[O:27])[CH3:26]
Reactant: COc1ccc2c(c1)cc(CO)n2Cc1ccc(C(C)(C)C)cc1
Reactant: CC(=O)Cl
Product: COc1ccc2c(c1)cc(COC(C)=O)n2Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from [1-(4-tert-butylbenzyl)-5-methoxy-1H-indol-2-yl]methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a white solid. Mass spectrum (ESI, [M+H]+) m/z 366. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (s, 1H), 7.28 (d, 2H, J=8.10 Hz), 7.07 (d, 1H, J=2.45 Hz), 7.86 (d, 2H, J=8.24 Hz), 7.76 (dd, 1H, J=8.86 and 2.29 Hz), 6.54 (s, 1H), 5.36 (s, 2H), 5.18 (s, 2H), 3.74 (s, 3H), 1.77 (s, 3H), and 1.20 ppm (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:21]([O:23]C)=O)=[N:4][C:5]([CH2:9][C:10]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[OH:8].CO.[NH3:27]>>[OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:12][CH2:13][CH2:14]2)=[N:4][C:3]=1[C:21]([NH2:27])=[O:23]
Reactant: N
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Solvent: CO
Product: NC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Yield: 49 %

Procedure:
A solution of methyl 5,6-dihydroxy-2-((1-phenylcyclopentyl)methyl)pyrimidine-4-carboxylate (0.020 g, 60.9 μmol) in ammonia in MeOH (435 μl, 3.05 mmol) was heated at 100° C. for 20 min. The cooled solution was evaporated to dryness. The residue was diluted with MeOH and heated in the presence of Amberlyst resin (H+) until in solution. The material was filtered to remove the resin and evaporated to dryness. Trituration with MeOH followed by washing with Et2O provided the desired product as a white solid (0.011 g; 49%). LCMS: m/z=314 (MH+).
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][C:30]=1[CH3:43]>C1(C)C=CC=CC=1.C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]([OH:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][C:30]=1[CH3:43]
Reactant: COC(=O)CCC(=O)c1ccc(F)c(C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of BH3.THF (1M, 1.2 mL, 1.2 mmol) was added to 10 mL anhydrous THF followed by the dropwise addition of (S)-2-methyl-CBS-oxazaborolidine (1M, 109 μL, 0.1 mmol) in toluene at 25° C. After stirring for 5 min, methyl 4-(4-fluoro-3-methylphenyl)-4-oxobutanoate (229 mg, 1.0 mmol) was slowly added as a solution in 5 mL THF. The mixture was stirred for 30 min at room temperature and then the reaction was quenched by the careful addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL) before being dried over Na2SO4. The solvents were removed under reduced pressure and the product isolated by silica gel chromatography to afford the title compound 181 mg, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: O=C1Nc2c(cc(Cl)cc2[N+](=O)[O-])C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.17 %

Procedure:
To a slurry of 5-chloro-7-nitro-1H-indole-2,3-dione (3.2 g, 14.15 mmol) in aqueous 5N NaOH solution (30 mL) added an aq. solution of 33% hydrogen peroxide solution (3 mL) slowly at 0° C. After the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with an aq. solution of 2N HCl and the resulting precipitated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).