Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(C(F)(F)F)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH2:37][CH2:36][CH:35]([CH3:48])[CH3:34])=[CH:44][CH:43]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC(C)CCCc1ccc(B(O)O)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(CCCC(C)C)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (500 mg, 0.91 mmol) was coupled with 4-(4-methylpentyl)phenyl boronic acid according to general procedure G to give (4-{4-(2,4-dichloro-phenyl)-2-[4′-(4-methyl-pentyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenylamino)-acetic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)C1
Temperature: 25 °C

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (0.5 g, 0.002 mol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (0.975 g, 0.00523 mol), methanol (15 mL, 0.37 mol), and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature. LC-MS showed that the starting material was completely consumed. Volatiles were removed and the resulting oil was purified by silica-gel twice in a methanol:methylene chloride (0-10%) gradient and in a EtoAc:Hexane(30-80%). A light yellow solid was obtained (0.56 g). m/z=360.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:15](=[O:16])[NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][N:13]([C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: COCCOC(=O)Cl
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)OCCOC)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-methoxyethyl chloroformate were reacted according to General Method 5. Yield: 73 mg (89% of theory)
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=O)[C:6](=[O:14])[C:5]2[CH:15]=[CH:16][S:17][C:4]1=2)[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:9]([C:7]2[C:6](=[O:14])[C:5]3[CH:15]=[CH:16][S:17][C:4]=3[N:3]([CH2:1][CH3:2])[CH:8]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(CC)c2sccc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccsc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of ethyl 7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.447 g) and 4-chlorobenzylamine (2.42 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene. The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield a pale yellow solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.312 g (45%) of the title compound as a white solid.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[P:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]=[N:31][NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCSP(=O)(OCC)Oc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCCSP(=O)(OCC)Oc1ccc(C=NNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl O-(4-formylphenyl) thiophosphate (5.44 grams; 0.019 mole), ethanol (150 ml) and benzoylhydrazine (2.57 grams; 0.019 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then stripped of ethanol under reduced pressure having a viscous oil as the residue. The residue was then dissolved in diethyl ether resulting in the formation of a precipitate. The ether solution was decanted from the precipitate and was stripped of solvent under vacuum leaving an orange-brown oil. This oil was chromatographed on a silica gel column using methylene chloride and methylene chloride-acetone mixtures as the eluant. Fourteen fractions were recovered and fractions 3 plus 4, 7, 8 and 9 were analyzed by infra red spectroscopy revealing that fraction 8 was the desired product. This fraction was stripped of solvent to yield the desired product O-ethyl S-propyl O-[4-(benzoylhydrazonomethyl)phenyl] thiophosphate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(OC)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NC1N=C(c2ccccn2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (3.42 g, 7.82 mmol) in CH2Cl2 (90 mL) was cooled in an ice bath and treated with TFA (13.2 mL, 172 mmol). The cold bath was removed and the solution stirred at room temperature for four hours. The reaction mixture was washed with 1 M aq. K2CO3 and the aqueous back-extracted with CH2Cl2. The combined extracts were washed with H2O, dried (MgSO4) and concentrated to obtain 1.75 g (66% yield) of the title compound as an off-white foam. MS (IS+) 338 (m/e).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:8]3([OH:29])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[C:13](\[CH3:19])/[C:14](OCC)=[O:15])[CH2:3]1>O1CCCC1.[AlH](CC(C)C)CC(C)C.CCCCCC>[OH:15][CH2:14]/[C:13](/[CH3:19])=[CH:12]/[C@@H:11]1[C@:20]2([CH3:28])[C@@:8]([OH:29])([C@H:7]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CCOC(=O)/C(C)=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C(=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 9.60 g of ethyl (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxylate (Boutagy J. and Thomas R., Aust. J. Pharm, Chem., 1972, NS1, 67) in 370 ml of dry tetrahydrofuran, 104 ml of 1M i-Bu2AlH in hexane were added dropwise under nitrogen at -78° C. After 2 hrs the reaction was quenched with a solution of 46.0 g of sodium sulfate in 350 ml of water and stirred at room temperature for 2 hours. The mixture was then filtered through Celite and washed with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness to give 8.30 g of (E)-21-hydroxymethyl-21-methyl-5β-pregn-20-ene-3β,14β-diol as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([S:21](=[O:25])(=[O:24])[NH:22][CH3:23])[CH:12]=2)[N:8]=[C:7]([C:26]#[N:27])[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:23][NH:22][S:21]([C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH2:4][CH2:3][CH:2]=[O:1])[N:6]=[C:7]([C:26]#[N:27])[N:8]=2)[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=1)(=[O:25])=[O:24]
Reactant: CNS(=O)(=O)c1cc(-c2cc(CCCO)nc(C#N)n2)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(-c2cc(CCC=O)nc(C#N)n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.3 %

Procedure:
A suspension of 4-(3-hydroxy-propyl)-6-(3-methylsulfamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (235 mg) and Dess Martin reagent (299 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 h. The reaction mixture was purified by flash silica chromatography to afford 4-(3-methylsulfamoyl-5-tri-fluoromethyl-phenyl)-6-(3-oxo-propyl)-pyrimidine-2-carbonitrile as a pink oil (300 mg). MS m/z 399.0 (M+1), 100%.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][C:9]=2[CH:16]=1)[OH:4].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10][C:9]=2[CH:16]=1)[O:4][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc2O1
Reaction time: 18 h

Procedure:
To the product of step (d) (10 g, 34.8 mmol) and imidazole (4.7 g, 69.7 mmol) dissolved in 100 mL DMF was added tert-butyldimethylsilyl chloride (5.78 g, 38.3 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was then partitioned between 200 mL of saturated sodium chloride and 200 mL of diethyl ether. The aqueous layer was extracted with 200 mL of diethyl ether. The organic layers were then combined, washed with saturated sodium chloride (3×100 mL), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography, eluting with hexanes followed by 5% ethyl acetate in hexanes. The desired fractions were combined and concentrated to give the title compound as an oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:19]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([CH2:37][O:38][CH3:39])[O:17]2)=[C:9]([NH:40][CH2:41][CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:8]=1)(=O)=O.[C-:55]#[N:56].[K+]>CN(C)C=O>[Si:22]([O:21][C@@H:20]1[C@H:19]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C@@H:18]([CH2:37][O:38][CH3:39])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([CH2:6][C:55]#[N:56])=[N:8][C:9]=2[NH:40][CH2:41][CH:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: [C-]#N
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 67.5 °C
Yield: 80.3 %

Procedure:
A stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (3.0 g, 3.76 mmol) (preparation 16) in anhydrous N,N-dimethylformamide (20 ml) was treated with potassium cyanide (0.37 g, 5.69 mmol) and heated to 65-70° C. for 3 hr. The mixture was cooled to room temperature and partitioned between diethyl ether and water. The organic phase was separated and the aqueous phase extracted again with diethyl ether. The combined organic solutions were then washed with brine, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of diethyl ether:pentane (1:1) to afford the title compound as a foam (2.2 g). MS: 751 (MNa+).
Reaction SMILES: [H-].[Na+].[Si]([O:20][CH2:21][CH2:22][OH:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[CH:32][N:33]=2)[N:30]=1>CN(C)C=O>[N:33]1[CH:32]=[N:31][N:29]2[C:28]=1[CH:27]=[CH:26][C:25]([O:20][CH2:21][CH2:22][OH:23])=[N:30]2
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2ncnn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
60% Oily sodium hydride (510 mg) was suspended in N,N-dimethylformamide (70 ml), followed by addition of 2-(t-butyldiphenylsilyloxy)ethanol (3.83 g). The mixture was stirred at room temperature for 1 hour, followed by addition of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (1.98 g). The mixture was stirred at room temperature for 5 hours and poured into ice-water, followed by extraction with ethyl ether. The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml), followed by addition of tetra-n-butylammoniumfluoride trihydrate (2.02 g). The mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the objective compound were collected and concentrated to yield the title compound (0.875 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH2:14]Br.[CH3:17][NH2:18]>C1COCC1>[F:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:14][N:18]([CH3:17])[C:3]2=[O:2]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CBr
Reactant: CN
Solvent: C1CCOC1
Product: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
At room temperature, a solution of 2-bromomethyl-3-fluoro-6-nitro-benzoic acid methyl ester (4.48 g, 15.3 mmol) in THF (100 mL) is treated with 2M solution of methylamine in THF (23 mL, 46 mmol), and the mixture is stirred for 48 h at the room temperature. The reaction mixture is filtrated through a glass filter and the precipitates are collected and washed with ethyl acetate. The filtrate is washed with sat. aqueous solution of NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (1.6 g, 7.61 mmol 50%) as yellow solids. 1H-NMR (400 MHz, δ, ppm) CDCl3: 3.22 (s, 3H), 4.47 (s, 2H), 7.32 (dd, 1H), 7.84 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:22])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])C(OC)=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([C:9](=[O:22])[CH2:10][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)c1ncc(Cl)cc1Cl)c1ccccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccccc1F)c1ncc(Cl)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of 4.50 g (13.2 mmol) of methyl 3-(3,5-dichloropyridin-2-yl)-2-(2-fluorophenyl)-3-oxopropanoate from example 1A, 845 mg (14.5 mmol) of sodium chloride, 474 mg (26.3 mmol) of water and 13.5 ml of DMSO is heated in a microwave at 150° C. for 10 min and then stirred into water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane) to result in a yellow oil which gradually crystallizes and affords 3.18 g (85% of theory) of the title compound.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:17][S:18][CH2:19][C@H:20]([NH2:39])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCO.[Pd]>[NH2:39][C@@H:20]([CH2:19][S:18][CH2:17][C@H:16]([O:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:22]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCC(=O)O)OC(=O)CCCCCCCCCCC
Reaction time: 8 h

Procedure:
To a solution of (R)-3-((R)-2-amino-3-(6-(benzyloxy)-6-oxohexylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate in EtOH (0.1 M) was added palladium black (2 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the product as an off-white solid. 1H NMR (CDCl3): δ 7.33 (t, 1H), 5.06-5.15 (m, 1H), 4.30 (dd, 1H), 4.08 (dd, 1H), 3.43 (dd, 1H), 3.20-3.31 (m, 1H), 3.09-3.19 (m, 1H), 3.04 (dd, 1H), 2.61-2.74 (m, 3H), 2.21-2.31 (m, 6H), 1.84-2.06 (m, 3H), 1.40-1.63 (m, 8H), 1.28-1.37 (m, 2H), 1.12-1.28 (m, 32H), 0.81 (t, 6H). LRMS [M+H]=673.5.
Reaction SMILES: [N:1]1([C@H:10]2[CH2:13][C@H:12]([NH2:14])[CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.Cl[C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>CN(C)C1C=CN=CC=1.CS(C)=O>[N:1]1([C@H:10]2[CH2:11][C@H:12]([NH:14][C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH2:13]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: N[C@H]1C[C@H](n2ccc3cccnc32)C1
Reactant: Clc1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2c(c1)ccn2[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C

Procedure:
trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutanamine (78 mg, 0.42 mmol), 4-dimethylaminopyridine (3.56 mg, 0.029 mmol), N,N-diisopropylethylamine (159 μl, 0.916 mmol) and 2-chlorobenzothiazole (81 μl, 0.625 mmol) were added in a round bottomed flask, followed by dry DMSO (833 μl). The mixture was sealed and heated at 110° C. for 16 h. The reaction mixture was partitioned between water, saturated ammonium chloride and ethyl acetate. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using ISCO (0-60% EtOAc in hexane), gave N-(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (23 mg, 0.072 mmol, 17% yield) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 2.77 (ddd, J=14.04, 8.46, 3.72 Hz, 2 H) 2.96-3.14 (m, 2 H) 4.56 (dt, J=7.43, 3.72 Hz, 1 H) 5.59-5.76 (m, 1 H) 6.54 (d, J=3.52 Hz, 1 H) 7.04-7.17 (m, 2 H) 7.28-7.36 (m, 1 H) 7.45 (d, J=3.72 Hz, 1 H) 7.60 (t, J=8.51 Hz, 2 H) 7.92 (dd, J=7.82, 1.37 Hz, 1 H) 8.32 (dd, J=4.69, 1.37 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4′-hydroxyacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (78%, colourless oil). HPLC-MS: m/z=270.1 (M+1); Rt: 3.62 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(OCc3ccccc3)nccc2c1
Temperature: 25 °C

Procedure:
To a solution of 3.93 g (17.5 mmol) 6-Bromo-2H-isoquinolin-1-one (6) in 150 ml Toluene were added 12.13 g (44.0 mmol) silver carbonate and 3.60 g (21.1 mmol) of benzyl bromide. The reaction mixture was refluxed for 1.5 h and then cooled to room temperature. The solution was filtered. The filtrate was washed with water and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. Final purification was achieved by preparative HPLC. Rt=2.47 min (Method B). Detected mass: 314.1/316.5 (M+H+).