Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](CO)CC1
Reaction time: 8 h

Procedure:
To a mixture of 1.0 g of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid, 20 mL of N,N-dimethylformamide, 1.32 g of potassium carbonate, and 0.24 g of tetrabutylammonium iodide was added dropwise 0.83 mL of benzyl bromide at room temperature, followed by stirring overnight. The reaction liquid was filtered and then the filtrate was concentrated. To the residue were added ethyl acetate and water, and the aqueous layer was separated. The organic layer was washed with water, a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 1.70 g of benzyl trans-4-(hydroxymethyl)cyclohexane carboxylate.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:62][C@H:63]([C:67]([OH:69])=[O:68])[CH:64]([CH3:66])[CH3:65].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:62][C@H:63]([C:67]([OH:69])=[O:68])[CH:64]([CH3:66])[CH3:65])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Yield: 62.6 %

Procedure:
3-Hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation A-2 (5) and N-hydroxysuccinimide (2.3 g) was dissolved in dioxane (60 ml). N,N'-Dicyclohexylcarbodiimide (4.2 g) was added thereto under ice cooling. The mixture was stirred at ambient temperature over-night. The crystallized N,N'-dicyclohexylurea was filtered off and the filtrate was concentrated to give a residue. The residue was dissolved in N,N-dimethylformamide (70 ml). To this solution was added a solution of L-valine (5.85 g) and triethylamine (6.95 ml) in water (50 ml) at 0° C. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was crystallized from petroleum ether to give crystals of N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (8 g).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([Br:26])[N:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:1]([NH:9][C:10]([NH:27][C:21]1[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:25][C:24]([Br:26])=[CH:23][N:22]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)nc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)nc1OCc1ccccc1)c1ccccc1
Yield: 65.6 %

Procedure:
Following the method of Example 1, Step B, benzoyl isothiocyanate (1.47 g, 8.99 mmol) and 3-(benzyloxy)-5-bromopyrazin-2-amine (2.29 g, 8.18 mmol) were reacted in THF (30 mL) to provide 1-benzoyl-3-(3-(benzyloxy)-5-bromopyrazin-2-yl)thiourea (2.38 g, 66%) as a yellow powder. 1H NMR (CDCl3) δ 8.15 (bs, 1H), 7.91 (d, 2H), 7.66 (t, 1H), 7.53-7.57 (m, 4H), 7.36-7.44 (m, 3H), 5.55 (s, 2H). Mass spectrum (apci) m/z=202 (100), 443 (45), 445 (43) (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:30][C:31](OC)=[O:32])=[O:27])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO.O>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH:29]([NH:28][C:26]([C:11]2([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:27])[CH2:30][CH2:31][OH:32])=[CH:40][CH:39]=1
Reactant: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 70 h
Yield: 30 %

Procedure:
Sodium borohydride (1.019 g, 26.93 mmol) was added in one portion to a stirred suspension of methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 35) (1.0 g, 1.80 mmol) dissolved in EtOH (400 mL) under argon. The resulting suspension was stirred at 20° C. for 70 hours. A few drops of water were added to quench the excess of hydride and the mixture stirred for 1 hour. The mixture was evaporated to dryness and the residue was partitioned between CH2Cl2 and water saturated with NaCl. The organic phase was dried and concentrated to provide crude product as white crystals. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (286 mg, 30.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14].[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1.Cl>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14]
Reactant: C=C(C(=O)OC)c1ccc(Cl)c(F)c1
Reactant: CC(C)[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(CC(C)(C)[N+](=O)[O-])c1ccc(Cl)c(F)c1
Yield: 106.7 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)acrylate (1.00 g, 4.66 mmol) and 2-nitropropane (502 uL, 5.59 mmol) were dissolved in MeCN (16 mL) and treated with DBU (835 uL, 5.59 mmol) at room temperature. The mixture was allowed to stir over the weekend to completion. The mixture was poured into 1M HCl solution and extracted with ethyl acetate (2×). The combined organic portions were washed with water (1×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to yield methyl 2-(4-chloro-3-fluorophenyl)-4-methyl-4-nitropentanoate (1.51 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:35]([C:10](=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:36])[CH3:34]
Reactant: C=C=O
Reactant: CC(CSc1ccccc1)C(=CC(=O)OCc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(NCc1ccccc1)C(C)CSc1ccccc1

Procedure:
p-Nitrobenzyl 3-benzylamino-4-methyl-5-phenylthio-2-pentenoate (505 mg; 1 mmole) was dissolved in toluene (5 ml), and gaseous ketene was introduced therein at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give p-nitrobenzyl 2-acetyl-3-benzylamino-4-methyl-5-phenylthio-2-pentenoate.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=1)[N:7]=3.Cl.[NH2:27][C@@H:28]([CH2:32][O:33][CH3:34])[C:29]([OH:31])=[O:30]>>[CH3:34][O:33][CH2:32][C@H:28]([NH:27][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=1)[N:7]=3)[C:29]([OH:31])=[O:30]
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COC[C@H](N)C(=O)O
Agent: Cl
Product: COC[C@H](Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)O

Procedure:
8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and (S)-2-amino-3-methoxypropanoic acid hydrochloride were reacted to form (S)-3-Methoxy-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionic acid. LCMS: RT=2.89 min, [M+H]+=453
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.CCN(CC)CC.Cl[CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:41]([CH:40]=[CH2:39])(=[O:43])=[O:42])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.14 mL (1.0 mmol) of Et3N in 4 mL of THF was added 0.063 mL (0.6 mmol) of 2-chloroethanesulfonyl chloride. The solution was stirred 1 h, warming to ambient temperature. The solution was poured into 10% aq. citric acid and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO4), and concentrated under reduced pressure. The crude product was chromatographed (elution with 1:1 EtOAc-hexanes) to afford 221 mg (80%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. 1H NMR (300 MHz, DMSO) δ 12.47(br. s, 1H); 9.92(br. s, 1H); 7.97(s, 2H); 7.17(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 6.69(dd, 1H, J=16.5, 9.9 Hz); 6.04(d, 1H, J=16.5 Hz); 5.96(d, 1H, J=9.9 Hz); 3.78(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C>[C:19]([NH:22][NH:23][C:13]([C@:12]1([CH3:16])[CH2:11][O:10][C:9]([CH3:18])([CH3:17])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C(=O)O
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)[C@]1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
To a mixture of 1.00 g of (4S)-3-(tert-butoxycarbonyl)-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid, 400 mg of acetohydrazide, 850 mg of 1-hydroxybenzotriazole, 2.0 ml of diisopropylethylamine, and 20 ml of DMF was added 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.11 g of tert-butyl (4S)-4-[(2-acetylhydrazino)carbonyl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[C:9]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[Br:24]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][Br:24])=[C:9]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Temperature: 60 °C
Yield: 73.2 %

Procedure:
A suspension of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (1.62 g, 0.0052 mol) in carbon tetrachloride (10 ml) containing benzoyl peroxide (20 mg) was heated to 60° C. N-bromosuccinimide (0.92 g, 0.0052 mol) was added and the mixture heated at reflux for seventeen hours. The cooled solution was treated with dichloromethane and aqueous ferrous sulfate solution, the organic phase was separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (92.5/7.5). The product was washed with diethyl ether/pentane to give 1.49 g of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 221° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:6]2[C:10]=1[S:9][CH:8]=[N:7]2
Reactant: O=S(=O)(O)Cl
Reactant: Fc1cccc2ncsc12
Product: O=S(=O)(Cl)c1ccc(F)c2scnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
7-fluorobenzo[d]thiazole 25D (500 mg, 3.26 mmol) was added dropwise to chlorosulfonic acid (2.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.44 (s, 1H), 8.32 (dd, J=8.6, 4.6 Hz, 1H), 7.38 (t, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([Br:26])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2cccnc2N)cc1C
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-(2-aminopyridin-3-yl)-2-methylbenzoate (4.2 g, 17.34 mmol) in acetonitrile (173 mL) was added NBS (3.15 g, 17.68 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction completed. After quenched with sat. Na2SO3 and NaHCO3, the reaction mixture was stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times, washed by sat NaHCO3, water and brine. The organics was dried over Na2SO4, filtered and concentrated. The crude material was triturated with ether and taken to the next step without further purification. LCMS (m/z): 323.1 (MH+), 0.68 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:27])[NH:15][CH2:16][C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]5)[CH2:18]3)[CH2:24]4)[N:9]2[CH:28]=1)C.[Li+].[BH4-]>C1COCC1>[C:17]12([CH2:16][NH:15][C:14]([C:10]3[N:9]4[CH:28]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=[C:8]4[CH:13]=[CH:12][CH:11]=3)=[O:27])[CH2:24][CH:23]3[CH2:25][CH:19]([CH2:20][CH:21]([CH2:22]3)[CH2:26]1)[CH2:18]2
Reactant: CCOC(=O)Cc1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2nc(CCO)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {5-[(adamantan-1-ylmethyl)-carbamoyl]-imidazo[1,2-a]pyridin-2-yl}-acetic acid ethyl ester (65 mg, 0.16 mmol) in THF (5 mL) at RT, is added portion-wise LiBH4 (10 mg, 0.46 mmol). The resulting mixture is stirred at RT for 16 h. The reaction is quenched by the slow addition of water, followed by the addition of EtOAc. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by PTLC (10% MeOH in DCM) the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C@H:16]1[O:17][C@@H:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1
Yield: 98.7 %

Procedure:
1-Fluoro-4-nitrobenzene (4.9 g, 34.75 mmol) was added to a stirred mixture of cis-2,6-dimethylmorpholine (44.4 g, 38.26 mmol) and anhydrous potassium carbonate (2.5 g, 18.12 mmol) in acetonitrile (50 mL). The mixture was heated under reflux for 19 h, cooled, filtered and the solid washed with acetonitrile. The filtrate was concentrated by evaporation to give the title compound (8.1 g, 99%) as a solid; 1H NMR δ (CDCl3): 8.13 (2H, d), 6.82 (2H, d), 3.76 (2H, m), 3.66 (2H, dt), 2.61 (2H, t), 1.28 (6H, d); MS m/e MH+: 237.
Reaction SMILES: C([Li])(C)(C)C.BrC1C=C(O)C=CC=1.[CH2:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCOCC1C=CC=CC=1.C([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:58])[CH:55]=[CH:56][CH:57]=1)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:58])[CH:55]=[CH:56][CH:57]=1.[CH2:20]([O:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1cccc(CCCCCOCc2ccccc2)c1
Agent: [Pd]
Agent: BrCCCCCOCc1ccccc1
Agent: Oc1cccc(Br)c1
Solvent: CCCCCOCCCCC
Solvent: CCO
Solvent: C1CCOC1
Product: OCCCCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At a temperature of -78° C., 19.4 ml of t-butyl lithium (1.7M) is added to 4.0 gm of the above 3-bromo-phenol, n-pentyl ether in 50 mls tetrahydrofuran; and to this is added 3.3 ml of a freshly prepared solution of Li2CuCl3 (0.10M/THF). The mixture is stirred for 10 minutes, and then 4.35 grams of the 1-bromo-5-benzyloxy pentane are added. The reaction is allowed to warm slowly to ambient temperature over 12 hours and is then stirred an additional 24 hours before being quenched with silica gel. After removing the solvent, the mixture is chromatographed over silica gel (1:1 hexane:ether) to yield a crude mixture containing 3-(benzyloxypentyl)-phenol, n-pentyl ether. A solution of 6.0 gm of this crude mixture in ethanol is hydrogenated over 5% Pd on carbon for 5 hours. After filtering through celite and concentrating, pure 3-(5-hydroxypentyl)-phenol, n-pentyl ether is obtained as a clear oil by HPLC chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].C1C(=O)N([Br:32])C(=O)C1>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:32])=[O:4]
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (121 g, 296 mmol), NBS (63 g, 354 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (14.4 g, 59 mmol) in 1,2-dichloroethane (1.2 L) was heated under reflux for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as a white solid (130 g, 90%). 1H NMR (400 MHz, CDCl3): 8.47-8.46 (m, 4H), 7.64-7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[NH2:17])=[C:14]([CH3:18])[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:29]=[O:31])=[C:14]([CH3:18])[C:13]([C:19]([F:21])([F:20])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1

Procedure:
To a solution of 3-amino-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1E (1.74 g, 4.39 mmol) in anhydrous toluene (50 mL) was added triphosgene (0.44 g, 1.48 mmol) and triethylamine (0.89 g, 8.81 mmol). The reaction mixture was heated at reflux for 3 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F which was used in the next step without further purification.