Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[NH:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:16]([C:23](O)=[O:24])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:16]([C:23]([NH:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1)=[O:24])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)[C@@H](N)Cc1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 81.2 %

Procedure:
Stir overnight H-(L)-Pal-NH2.2HCl (432 mg, 1.82 mmol), Boc-(L)-Chg-OH (609 mg, 2.37 mmol, 1.3 equivalent), dicyclohexylcarbodiimide (494 mg, 2.4 mmol), hydroxybenzotriazole (324 mg, 2.4 mmol) and diisopropylethylamine (4 mmol) in dimethyl formamide (15 mL). Evaporate dimethyl formamide, add ethyl acetate and store the mixture at room temperature for 1 h. Filter off the diisopropylcarbodiimidecyclohexylurea formed, extract the solution by a saturated solution of sodium bicarbonate (3×), dry over magnesium sulfate, and evaporate. Crystallize by addition of hexanes to give Boc-(L)-Chg-(L)-Pal-NH2 (598 mg, 81%).
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:1][C:2](=[O:20])[C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
(S)-tert-Butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (Example 3, step (i), 3.17 g) and 4-cyanophenylboronic acid (1.19 g) in dioxane (5 mL) were treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.08 g) and the mixture was stirred at room temperature for 15 min under nitrogen. An aqueous solution of potassium carbonate (2M, 8.12 mL) was added and the mixture was stirred for 18 h at 75° C. The reaction mixture was extracted with ethyl acetate, dried and evaporated to afford the sub-titled compound (3.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][O:16][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1cc(CCCO)c2cc(Br)ccc2[nH]1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCc1cc(=O)[nH]c2ccc(Br)cc12)(c1ccccc1)c1ccccc1

Procedure:
6-Bromo-4-(3-hydroxypropyl)quinolin-2(1H)-one (4.7 g, 16.67 mmoles), imidazole (2.84 g, 41.7 mmoles) and tert-butyldiphenylsilyl chloride (5.14 mL, 20 mmoles) were stirred in dimethylformamide (60 mL) overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1cccc(-c2nc(Cl)ncc2C)c1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)c1
Yield: 82 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-(3-(2-chloro-5-methylpyrimidin-4-yl)phenyl)acetamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 82% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.79 (s, 1H), 7.57 (d, 3H, J=8.2 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.35 (d, 1H, J=7.5 Hz), 7.22 (m, 2H), 3.44 (s, 2H), 2.42 (bs, 8H), 2.26 (s, 3H), 2.19 (s, 3H); (ESI): 431.3 [M+H]+, 216.3 [M+2H]2±.
Reaction SMILES: [H-].[Na+].[C:3]1([C:18]([O:20]CC)=O)[C:4](C(OCC)=O)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10]C=C2.C(OCC)(=[O:25])C>>[C:18]1(=[O:20])[C:3]2[C:12](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:11](=[O:25])[CH2:10]1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc2ccccc2c1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: O=C1CC(=O)c2ccccc21
Reaction time: 0.12 h

Procedure:
To a 50% dispersion of sodium hydride in mineral oil (4.55 g) was added to a solution of diethyl naphthalene 1,2-dicarboxylate (18.5 g) in ethyl acetate (22 ml.) and the mixture refluxed for 3.5 hrs. on a steam bath. After cooling the precipitated orange solid was filtered and decarboxylated with hydrochloric acid (35 ml.) in water (350 ml) at 70°C over 7 mins. to yield benze(e) indane-1,3-dione, m.p. (benzene) 178°C (decomp.) (Found: C, 79.21; H, 4.22; C13H8O2 requires: C, 79.58; H, 4.11%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][CH:19]=1
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.83-8.03 (m, 3H), 7.42 (s, 4H), 4.05 (p, J=8.5 Hz, 1H), 3.70 (s, 2H), 2.21-2.44 (m, 4H), 2.02-2.14 (m, 1H), 1.78-1.87 (m, 1H); MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C@@H:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][CH:5]=2.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:20][CH2:19]1)[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: Cc1cc2c(OC[C@@H](O)CNCC3CCN(CCC(F)(F)F)CC3)cccc2[nH]1
Yield: 36 %

Procedure:
Prepared from 2-methyl-4-[(2S)-oxiranylmethoxy]-indole (0.150 g, 0.74 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0. 250 g, 1.2 mmol) of according to the procedure used for Example 2 to give 0.110 g of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:14]=2[CH2:15][N:16]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17]2)=[O:12])/[N:7]([CH2:31][CH2:32][CH2:33][CH3:34])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:37][Si](C)(C)C)=[N-]>CO>[CH2:31]([N:7]1[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:9]/[C:8]/1=[N:10]\[C:11]([C:13]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:14]=1[CH2:15][N:16]1[CH2:19][CH:18]([C:20]([O:22][CH3:37])=[O:21])[CH2:17]1)=[O:12])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCn1nc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1CN1CC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CCCCn1nc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1CN1CC(C(=O)OC)C1
Yield: 83 %

Procedure:
To a solution of Example 21A (200 mg, 0.401 mmol) in MeOH was added (diazomethyl)trimethylsilane (1 mL, 2M in ether). The reaction was concentrated to obtain the title compound (170 mg, 0.332 mmol, 83% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96-1.04 (m, 3H) 1.35-1.47 (m, 2H) 1.43 (s, 9H) 1.85-1.96 (m, 2H) 3.29-3.50 (m, 3H) 3.54-3.67 (m, 2H) 3.71 (s, 3H) 4.26 (s, 2H) 4.41 (t, J=7.12 Hz, 2H) 7.64-7.79 (m, 2H) 8.48 (s, 1H); (ESI) m/z 513 (M+H)−, 511 (M−H)−.
Reaction SMILES: [C:1]([CH:4]([S:28][CH3:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([CH:4]([S:28]([CH3:29])=[O:38])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CC(SC)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: COc1ccc(CC(C(N)=O)S(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To 639 mg of 5-[2-carbamoyl-2-(methylthio)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 70 ml of methylene chloride and 368 mg of mCPBA under cooling with ice, and the mixture was stirred for 3 hours. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=50:1 to 20:1) to obtain 486 mg of aimed product as colorless crystals.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCCCCC.C([Li:25])CCC>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Li:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [Li]CCCC
Reactant: CCCCCCOc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: [Li]c1ccc(OCCCCCC)cc1
Temperature: 25 °C

Procedure:
24.0g (0.093mol) of 4-hexyloxybromobenzene was dissolved in 30ml of benzene and stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50ml of hexane solution including 15% of butyllithium was added drop-wise for 30 minutes and the solution was maintained under stirring for 2 hours. The produced precipitate gathered by filtration in a stream of nitrogen was dried under reduced pressure to yield 11.1g of 4-hexyloxyphenyllithium.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH2:11]([C:14]1(O)[C:19]([Cl:21])([Cl:20])[CH2:18][CH2:17][CH2:16][C:15]1([Cl:23])Cl)[CH:12]=[CH2:13].[OH-].[Na+]>O>[CH2:11]([CH:14]1[C:19]([Cl:21])([Cl:20])[CH2:18][CH2:17][CH:16]2[C:15]1([Cl:23])[O:8]2)[CH:12]=[CH2:13]
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: C=CCC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.12 g (4.03 mmol) of crude alcohol 1l, 5.5 cm3 of distilled water and 0.6 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min followed by ether extraction; the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.89 g of epoxide 2j were obtained, that was a 92% yield (macrobore GC purity>98.6%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:2][CH2:3]1)=[O:26]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 1 h

Procedure:
3.0 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 4.0 ml of tiethylamine were suspended in 20 ml of dichloromethane, and to the suspension was added dropwise 3.5 g of 3,4-dimethoxybenzoylchloride in 20 ml of dichloromethane under ice-cooled condition with stirring. Then the reaction was continued for additional 1 hour at a room temperature. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order and was dried with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue thus obtained was recrystallized from ethanol-chloroform to obtain 4.1 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([NH2:24])=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reactant: N
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(N)=O)[nH]n1
Yield: 29 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of 2-hydroxy-2-methylpropylamine, to the title compound (17 mg, 29%) which was obtained as an off white solid. MS: m/e=316.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:2]([NH:1][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:11]2
Reactant: CCC(=O)Nc1nc2ccc(Cl)cc2nc1N
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)Nc1nc2cc(Cl)ccc2nc1NC(=O)CC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 50 parts of 3-amino-6-chloro-2-propionamidoquinoxaline in 1000 parts of pyridine was cooled to 5° in an ice bath. A solution of 96 parts of hexanoyl chloride in 88 parts of tetrahydrofuran was added as quickly as possible with good cooling to prevent the temperature from rising above 25°. The reaction mixture was stirred for 10 minutes and then poured into 2500 parts of ice water. The yellow gum which separated was removed by filtration and washed with water and then dissolved in 2700 parts of methylene chloride. The methylene chloride solution was washed in succession with 1000 parts each of water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium carbonate, and water. The methylene chloride solution was dried (MgSO4) and evaporated. The residue was recrystallized from 1:4 ethyl acetate-benzene, the solid filtered off, and washed with ether to yield 8 parts of 6-chloro-3-hexanamido-2-propionamidoquinoxaline, m.p. 158°-160°, as a colorless solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[NH:25][CH:29]=[CH:28][N:27]=1
Reactant: O=Cc1ncc[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-imidazolecarboxaldehyde (7.57 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: C=O.O.[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1.[CH3:32]CN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCN(C)CC1
Reaction time: 0.17 h

Procedure:
12.0 M Formaldehyde in water (0.4 mL, 5 mmol) was added to a mixture of N-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-purin-6-amine (200 mg, 0.5 mmol) and DIPEA (0.35 mL, 2.0 mmol) in methylene chloride (5 mL) at 0° C. The reaction was stirred for 10 minutes, and after this time sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. The reaction was stirred at 0° C. for 1 hour. The mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2. found: 415.3. 1H NMR (DMSO-d6, 500 MHz) δ 9.67 (1H, br s), 8.72 (1H, br s), 8.35 (2H, s), 7.51 (1H, s), 5.75 (1H, m), 3.88 (3H, s), 3.49 (2H, m), 3.34 (1H, m), 3.12 (2H, m), 2.81 (1.5H, s), 2.80 (1.5H, s), 2.44-2.31 (2H, m), 2.36 (3H, s), 1.79 (2H, m), 1.49 (3H, d, J=6.5 Hz) ppm.
Reaction SMILES: ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.[Cl:28][C:29]1[CH:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH:32]=[CH:31][C:30]=1[C:44]([C:46]1[CH:51]=[C:50]([C:52]#[C:53][Si](C)(C)C)[CH:49]=[CH:48][C:47]=1[O:58][CH3:59])=[O:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH:32]=[CH:31][C:30]=1[C:44]([C:46]1[CH:51]=[C:50]([C:52]#[CH:53])[CH:49]=[CH:48][C:47]=1[O:58][CH3:59])=[O:45]
Reactant: COc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: C#Cc1ccc(OC)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 407, using compound 426 (0.44 mmol). The crude product was used directly in the next reaction without any further purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:13][C:14]([C:16]1([C:22](OCC)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[CH3:12].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1([CH2:22][OH:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(CO)CCOCC1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.5M diisobutylaluminum hydride (DIBAL-H) (419 mL, 629 mmol) in toluene was added to a 3-L Morton flask equipped with a nitrogen gas inlet, mechanical stirrer, low temperature thermometer, 500 mL pressure equalizing funnel, and containing tetrahydropyran-4,4-dicarboxylic acid diethyl ester (70.78 g, 307.4 mmol) in toluene (600 mL) at -40° C., at a rate to maintain an internal temperature no higher than -25° C. The mixture was stirred an additional 10 minutes and anhydrous ethanol (595 mL) was added dropwise over 20 minutes maintaining an internal temperature no higher than -15° C. Solid sodium borohydride (11.6 g, 307.4 mmol) was added in three portions over a 15 minute period, the cooling bath was removed, the mixture allowed to warm to room temperature over 1 hour, and saturated aqueous sodium sulfate (325 mL) added over 15 minutes. The mixture was cooled to -15° C., ethyl acetate (250 mL) was added, and the flocculent white precipitate filtered over a pad of celite. The celite pad was washed with ethyl acetate (7×450 mL), the filtrate washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in the minimum amount of ethyl acetate, filtered through a sintered glass funnel containing silica gel (40 g), eluting with ethyl acetate, and the filtrate concentrated in vacuo to afford the hydroxyester, 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester, as a pale yellow oil (48.5 g, 84%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15][CH2:14]1>C(Cl)Cl>[O:12]=[C:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:17][CH2:18]1
Reactant: CC(C)C(=O)NC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C(=O)NC1CCC(=O)CC1
Reaction time: 24 h
Yield: 65.9 %

Procedure:
Add pyridinium chlorochromate (561.6 g, 2.61 mol) to N-(4-hydroxycyclohexyl)isobutyramide (321.8 g, 1.74 mol) in CH2Cl2 (8000 mL) and stir mechanically for 24 h under nitrogen. Add silica gel (2000 g), stir, and filter through a silica pad (6000 g). Elute with CH2Cl2 followed by 75-100% EtOAc/hexanes to obtain 210 g of a light brown solid (66%/o). MS (ES): m/z 184 (M+1); 1H NMR(DMSO-d6): δ 5.54 (br s, NH), 4.27 (septet, 1H), 2.20-2.60 (m, 7H), 1.78 (m, 2H), 1.15 (d, 6H).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:14].[NH2:15][C:16]([NH2:18])=[S:17]>CC(C)=O>[NH2:18][C:16]1[S:17][CH:2]2[CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=3[C:3]2([OH:14])[N:15]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC1Br
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: NC1=NC2(O)c3cc([N+](=O)[O-])ccc3CC2S1

Procedure:
1.28 g (5 mmol) of 2-bromo-6-nitroindan-1-one are dissolved in 30 ml of acetone and, while stirring, 530 mg of thiourea in 10 ml of acetone are added. The solution is initially clear but, after a few minutes, the hydrobromide of 2-amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol crystallizes out. It is stirred at room temperature for 1 h, filtered off with suction and washed with a little acetone. The air-dried hydrobromide is dissolved in about 10 ml of methanol and, after addition of 0.7 ml of triethylamine, stirred for 15 min. Then 50 ml of water are added, and the mixture is stirred at room temperature for 1 h. The crystals which have formed are filtered off with suction and washed with a little cold water. 2-Amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point above 250° C.