Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CN1CCCC1=O.[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:22]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][CH2:18][CH2:19][CH2:20]1)=[O:33]
Reactant: CN(C)CCCO
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CCCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
3-Dimethylamino-propan-1-ol (346 uL, 2.92 mmol) was dissolved in N-methylpyrrolidinone (25.0 mL, 259 mmol) and sodium hydride 60% dispersion in mineral oil (93.5 mg) was added. The reaction was stirred for 5 minutes and then 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one (500 mg, 1.95 mmol) was added. The reaction was stirred at room temperature for 4 hours and then partitioned between ethyl ether (100 mL) and water (50 mL). The layers were separated and the organic layer was washed twice with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester as a yellow oil (437 mg, 69%). LCMS (m/e) 324 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.80 (m, 2H), 7.53-7.36 (m, 1H), 4.29-4.17 (m, 4H), 3.89-3.77 (m, 2H), 2.39-2.08 (m, 4H), 2.19 (s, 6H), 1.88-1.73 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C(=O)N([I:50])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:50])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38B) (2.2 g, 3.53 mmol) in DCM (30 mL) was added NIS (0.795 g, 3.53 mmol). The mixture was stirred at r.t. overnight. The mixture was then diluted with EtOAc (300 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 2.6 g of the desired product. LC/MS (APCI): m/z 749.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.O.[Br:17]Br>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:17])([O-:3])=[O:2]
Reactant: BrBr
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1CBr
Yield: 45 %

Procedure:
Even the side-chain brominations of o-nitrotoluene in a carbon tetrachloride/water mixture using elementary bromine and under UV-irradiation, which have been described recently in German Democratic Republic patent specifications Nos. 74279 and 82463, provide only o-nitrobenzyl bromide in a yield of 45 to 55%. The process described in German Democratic Republic patent specification 118609 affords a somewhat better yield when o-nitrotoluene is brominated in carbon tetrachloride under irradiation with visible or ultra-violet light or using peroxide as catalyst; but in this process too it was not possible to obtain either o-nitrobenzal bromide or a complete sidechain bromination of o-nitrotoluene to yield o-nitrobenzyl bromide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=2)=[C:7]([O:20][CH3:21])[CH:6]=1.[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:33])[F:32])[C:29]=1[CH3:30])#[N:24]>C(O)C.C1COCC1>[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:32])[F:33])[C:29]=1[CH:30]=[CH:18][C:16]1[S:17][C:13]([CH:12]=[CH:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH3:22])=[CH:6][C:7]=2[O:20][CH3:21])=[CH:14][CH:15]=1)#[N:24]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=O)s1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of ethanol (15 ml) and THF (5 ml) were dissolved 5-(2-{4-[(2-hydroxyethyl) methylamino]-2-methoxyphenyl}vinyl)thiophene-2-carbaldehyde (0.5 g, 1.58 mmol) and 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-5H-furan-2-ylidene)malononitrile (0.50 g, 1.58 mmol). The mixture was stirred at room temperature for 18 hours and further at 50° C. for 3 hours. The mixture was cooled and the solid was collected. The solid was washed with cold ethanol (40 ml) 3 times to give a reddish brown crystal (yield: 0.91 g (93.8%)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][OH:1]
Reactant: OCCc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: OCCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of 2-(2-hydroxy-ethyl)-naphthalene (58.5 g, 0.34 mol) in anhydrous acetonitrile (500 mL) was treated with N-bromo-succinimide (66.5 g, 0.37 mol). The resulting solution was stirred at room temperature under a nitrogen atmosphere and protected from light for 30 minutes, then heated in an oil bath at 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was evaporated under vacuum to a viscous oil. The oil in diethyl ether (350 mL) was washed with water (350 mL), dilute aqueous sodium thiosulfate (300 mL), water (300 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to an oil (89.5 g) that solidified on standing. The crude product was chromatographed on a column of EM silica gel 60, eluting with methylene chloride, to afford a yellow solid (78.2 g). Recrystallization of this material from carbon tetrachloride provided the title compound (46.5 g) as a pale yellow solid.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[C:37]([CH:38]=[CH:39][CH:40]=2)[C:35]#[N:36])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C#N)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and 3-cyanophenylboronic acid (52 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9]1[O:11][C@H:10]1[CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C@H:10]([OH:11])[CH2:12][OH:13])[CH:8]=1)([O-:3])=[O:2]
Reactant: OC[C@H]1CO1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(C[C@H](O)CO)c1
Yield: 18.1 %

Procedure:
3-Nitro-1-H-pyrazole (27) (600 mg, 5.3 mmol), (S)-glycidol (702 μL, 10.6 mmol) and K2CO3 (1.1 g, 8.0 mmol) in acetonitrile (7 mL) were heated in the microwave at 100° C. for 1 h. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer further extracted with ethyl acetate (10×20 mL). The organics were combined, dried over MgSO4, filtered and evaporated to give a crude oil. This was purified by flash chromatography on silica eluting with a gradient of 70% ethyl acetate/isohexane to ethyl acetate, to give the desired compound as a white solid (180 mg, 18%); LCMS, Rt=0.98 min (MeOH-FA method), m/z 188 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:11][CH:12]1[O:17][C:16]2[CH:18]=[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=[CH:21][C:15]=2[CH2:14][O:13]1)CC)[C:2]1C=CC=CC=1>[Pd].CCO>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:15]2[CH2:14][O:13][CH:12]([CH2:11][NH:8][CH2:1][CH3:2])[O:17][C:16]=2[CH:18]=1)(=[O:23])=[O:24]
Reactant: CCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 76.5 %

Procedure:
(−)-N-benzyl-N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}ethanamine (0.47 g, 1.30 mmol), palladium on carbon (10%, 30 mg) and EtOH (15 ml) was hydrogenated at 50 psi for 13 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness (0.34 g). Purification by flash chromatography (EtOAc/MeOH 4:1) afforded the pure title compound (0.27 g, 77%, >95% e.e.). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p 219° C. [α]DMeoH=−79°. 1H-NMR (400 MHz, CDCl3): δ 7.49 (1H, dd, J1 8.0 Hz, J 2 2.0 Hz), δ 7.45 (1H, d, J 2.0 Hz), δ 7.17 (1H, d, J 8.0 Hz), δ 5.19 (1H, t, 4.8 Hz), δ 5.0 (2H, dd, J1 49 Hz, J2 15 Hz), δ 3.03 (3H, s), δ 2.76 (2H, q, J 7.2 Hz), δ 1.46 (1H, s), δ 1.16 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.ClC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([CH2:31][OH:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CO)c12
Yield: 55 %

Procedure:
At 0° C. to a solution of 3.00 g of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetra-hydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 50 ml of dry tetrahydrofurane were added 1.2 ml of Hünig's base, followed by slow addition of 0.7 ml of ethyl chlorformate. After 30 min at 0° C. the resulting suspension was filtered. Under argon atmosphere to the filtrate were added 290 mg of sodium borohydride and 15 ml of water. After 2 h at 0° C. sat. aqueous ammonium chloride solution was added. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. 1.60 g (55%) of the title compound were obtained.
Reaction SMILES: S(=O)(=O)(O)O.[OH2:6].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1>[O-2].[Cr+6].[O-2].[O-2].CC(C)=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:6])=[O:17])=[CH:12][CH:11]=1)=[O:18]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liter). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](=[S:12])=[S:11]>C(O)(C)C>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[S:11])[SH:12])[CH2:2][CH2:3][CH3:4]
Reactant: S=C=S
Reactant: CCCCNCCCC
Solvent: CC(C)O
Product: CCCCN(CCCC)C(=S)S
Reaction time: 1 h

Procedure:
5′-(Dibutyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole (i.e., formula (I) where X is hydrogen and R1 and R2 are n-butyl radicals) was prepared in the following manner. In 100 grams of isopropyl alcohol 26 grams of dibutyl amine was combined with 16 grams of CS2 and held at a temperature of about 40° C. for about 1 hour to yield a dibutyl dithiocarbamic acid intermediate. Subsequently, 30 grams of 2,5-dimercapto-1,3,4-thiadiazole was added to the mixture along with 20 grams of 35 wt. % hydrogen peroxide. The mixture was reacted for about 1 hour at a temperature of about 28° C. to yield the liquid end product 5′-(dibutyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole.
Reaction SMILES: [CH2:1]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>O.CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCS(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The general method of procedure A was followed with 1-pentanesulfonamide (10 g), acetone (200 ml), 1N NaOH (66 ml) and 4-chlorophenyl isocyanate (9.6 g). 1N HCl (66 ml) was used to acidify the solution. Additional water was added and after standing overnight the solid was isolated and dried to provide 14 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1cc(-c2ccc(CN)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4ccccn4)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-methylpyridin-4-yl)phenyl)methanamine 13-3 (10 mg, 0.05 mmol), 4-(pyridin-2-yl)benzoic acid 13-4 (10 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(4-(2-methylpyridin-4-yl)benzyl)-4-(pyridin-2-yl)benzamide 13 as white powder. MS m/z 380.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.65-8.60 (m, 1H), 8.41 (d, 1H), 7.99-7.85 (m, 4H), 7.80-7.70 (m, 2H), 7.65-7.50 (m, 3H), 7.45 (d, 2H), 7.34 (bs, 1H), 7.32-7.27 (m, 2H), 4.66 (d, 2H), 2.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([F:23])[CH:25]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (39%). MS (ESI): m/z=509.091 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[C:28]([Cl:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1cccnc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2cccnc2Cl)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation IX, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=21%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:19]=O)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N+:25](CC)([O-])=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:25])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Temperature: 115 °C
Yield: 44.5 %

Procedure:
To a solution of 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbaldehyde (45 mg, 0.17 mmol) from step 3 in acetic acid (0.38 mL, 6.6 mmol) was added nitroethane (0.24 mL, 3.4 mmol) and sodium acetate (270 mg, 3.4 mmol). The reaction mixture was heated at a sealed tube at 115° C. overnight. Added some water and extracted it with ether. Combined organic layer and evaporated under vacuum. It was purified by prep TLC eluting with 10% ethyl acetate-hexane and providing 20 mg (45%) of the title compound. 1H-NMR (CDCl3) δ 7.36-7.21 (m, 3H), 7.18-7.14 (m, 2H), 6.99 (s, 1H), 5.98 (s, 1H), 4.48 (s, 2H), 3.41 (t, J=5.7Hz, 2H), 2.70 (t, J=6.4Hz, 2H), 1.97 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][C:21]=2[Cl:31])=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=2[Cl:31])=[O:18])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(NC(=O)c2cn(Cc3ccccc3)c3ccccc23)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2cn(Cc3ccccc3)c3ccccc23)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
In THF (7.0 ml) was dissolved methyl 4-((1-benzyl-3-indolylcarbonyl)amino)-3-chlorophenylacetate (341.3 mg, 0.788 mmol). To the resulting solution was added 0.25N NaOH (7.0 ml). The resulting mixture was stirred at 50° C. for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was acidified with 1N HCl (2.5 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 4-((1-benzyl-3-indolylcarbonyl)amino)-3-chlorophenylacetic acid (285.8 mg, 86%) as a light pink amorphous substance.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:27])[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:7]=1[CH2:32][NH:33]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[ClH:45]>>[ClH:45].[NH2:33][CH2:32][C:7]1[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9](=[O:27])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1)=[CH:12][CH:11]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)OCC)s3)cc12
Agent: CC(=O)[O-]
Agent: Cl
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)OCC)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Ethyl 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate (0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl; acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give ethyl 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylate hydrochloride (0.14 g, 93.3%) as crystals.