Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:36]=[CH:37][CH:38]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13]1)=[O:7].Cl>O1CCOCC1>[O:17]=[C:16]1[C:15]2([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:38]=[CH:37][CH:36]=1)[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:39])[CH3:1])=[O:7]
Reactant: CN(C)CCOC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCOC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To tert-butyl 3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.17 g, 0.32 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 90 minutes, the reaction mixture was concentrated in vacuo to obtain 2-(dimethylamino)ethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:16]>C(O)C.C(OCC)(=O)C.O.[Pd]>[ClH:16].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cn2cncn2)cc1
Yield: 100 %

Procedure:
A solution of 1-(4-nitrophenyl)methyl-1,2,4-triazole (10.0 g, 49 mmol) in ethanol (50 ml), ethyl acetate (50 ml), 5N HCl (10 ml) and water (10 ml) was hydrogenated over 10% Pd/C (1.0 g) at 40 p.s.i., in a Parr apparatus, until an uptake of 188 p.s.i., had been observed (approx 10 mins). The catalyst was removed by filtration through hyflo and the solvent removed under vacuum. The residue was azeotroped with ethanol (×2) to give the titleamine hydrochloride (10.6 g, 100%). δ (360 MHz, D2O) 5.53 (2H, s, CH2), 7.37-7.48 (4H, m, Ar-H), 8.12 (1H, s, Ar-H), 8.66 (1H, s, Ar-H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](=[O:19])[C:6]([C:7]([OH:9])=[O:8])=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:2][CH3:3].[OH-].[Na+:27]>CO>[CH2:1]([N:4]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10](=[O:19])[C:6]([C:7]([O-:9])=[O:8])=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:2][CH3:3].[Na+:27]
Reactant: CCCn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(-c2ccccc2)cc(=O)c(C(=O)[O-])c1-c1ccccc1
Yield: 93.8 %

Procedure:
1.5 gms of 1-propyl-2,6-diphenyl-4-oxonicotinic acid, 0.202 gms of NaOH and 50 mls of dry methanol were mixed. Evaporation of the solvent yielded 1.5 gms of sodium 1-propyl-2,6-diphenyl-4-oxonicotinate as a white glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1Br.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O>[Cu]I.O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:26][C:21]1[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc(C)cc(O)c1
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Br
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(C)cc(OC)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
A mixture of 1 mmol of 2-Bromo-3,5-dimethoxy-4-methyl-benzoic acid methyl ester, 1.5 mmol of 3-methoxy-5-methylphenol, 2 mmol of Cs2CO3, 1 mmol of CuI, and 1 mmol of N,N-dimethylglycine was added to 4 mL of dioxane under nitrogen atmosphere, and then the mixture was heated to 90° C. and monitored by TLC. Upon completion, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4, and evaporated by a rotary evaporator. The residue was purified by column chromatography to afford 3,5-Dimethoxy-2-(5-methyl-3-methoxy-phenoxy)-4-methyl-benzoic acid methyl ester (50%): 1H NMR (DMSO-d6) δ 7.18 (s, 1H), 6.35 (s, 1H), 6.22 (t, 1H, J=2 Hz), 6.18 (bs, 1H), 3.88 (s, 3H), 3.75 (s, 6H), 3.73 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[N:11][CH:12]=1)=[O:6].C(N)C(C)C>>[NH2:27][C:26]1[C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:13]([C:10]3[CH:9]=[CH:8][C:7]([C:5](=[O:6])[NH:4][CH2:3][CH:2]([CH3:1])[CH3:30])=[CH:12][N:11]=3)=[O:14])[CH2:20][CH2:19]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Solvent: CC(C)CN
Product: CC(C)CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)nc1
Yield: 72 %

Procedure:
By the same procedure as described in the step (2) of example 27, the synthesis was carried out starting with 5-[N-(2-methylpropyl)carbamoyl]-2-[1-(3-nitro-2-pyridyl)piperazin-4-yl-carbonyl]pyridine, so prepared by Step (1) and using isobutylamine. And then, the product was recrystallized with ethanol and ether to give a desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25].O>ClCCl>[Cl:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: O=C=NCCCCl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)NCCCCl)cc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-aminobenzoate (496 mg) and pyridine (60 μL) was dissolved in dichloromethane (3 mL), 1-chloro-3-isocyanatopropane (323 μL) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg). The obtained ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (250 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated from the organic layer. To the obtained residue was added diisopropyl ether, and the precipitate was collected by filtration to give the title compound (84 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH3:29])=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CCCN(C)C)c(=O)n(CC3CC3)n2)cc1F
Yield: 64.7 %

Procedure:
Following the procedure of Example 7, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 64.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[O:33][CH3:34])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+].C(O)C>O1CCCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][C:24]=3[O:33][CH3:34])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Ethyl 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (100 mg, 0.173 mmol) was diluted with tetrahydrofuran (1 mL) followed by the addition of sodium hydroxide (692 μL of a 1 M aqueous solution, 0.692 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using two 0.5 mm preparative silica gel plates eluting with 10% methanol/dichloromethane to yield 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (61 mg, 0.111 mmol, 64.1% yield). 1H NMR (400 MHz, D6 DMSO) δ 8.48 (t, 1H), 7.82 (d, 2H), 7.44 (s, 1H), 7.35 (d, 1H), 7.23 (m, 2H), 6.96 (d, 2H), 6.61 (s, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 3.87 (s, 3H), 3.82 (t, 1H), 3.47 (q, 1H), 3.17 (d, 1H), 2.89 (t, 2H), 2.21 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]([CH3:26])([CH3:25])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[C:27]1([C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:34][CH2:35][CH2:36][CH:37]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH2:23]([O:22][CH2:21][C:8]1[N:7]([CH2:6][C:5]([CH3:25])([O:4][CH2:3][CH2:2][NH:1][CH2:37][CH2:36][CH2:35][O:34][C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:26])[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=1)[CH3:24]
Reactant: O=CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (50 mg, 140 μmol) and 3-(triphenylmethoxy)-propanal (CAN 67057-68-5; 44.3 mg, 140 μmol) were combined with ethanol (500 μL) to give a light yellow suspension. The mixture was stirred for 2 hours at room temperature. Afterwards sodium borohydride (5.82 mg, 154 μmol) was added and stirring at room temperature continued overnight. The mixture was stirred with water (2 mL) and ethyl acetate (5 mL), dried by passage through a ChemElut® cartridge and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) followed by another flash chromatography (silica gel, 0 to 10% methanol in ethyl acetate) to give the title compound (10 mg, 11%) as yellowish gum; LC-MS (UV peak area, ESI) 89%, 658.5 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=O)[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([NH:67][CH2:66][CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: NCC1CCOCC1
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
Solvent: O
Product: COc1ccc(-c2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 93.3 %

Procedure:
A solution of the compound (780 mg, 2.10 mmol) obtained in step 13, HATU (958 mg, 2.52 mmol), DIEA (0.439 ml, 2.52 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (290 mg, 2.52 mmol) in DMF (10 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (918 mg, 1.959 mmol, 93%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][CH:16]1[CH2:15][C@H:14]1[C@@H:10]2[CH2:11][N:12](CC2C=CC(OC)=CC=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][CH:16]1[CH2:15][C@H:14]1[C@@H:10]2[CH2:11][NH:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(CN2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CC1C[C@@H]1CNC[C@@H]12
Yield: 95.2 %

Procedure:
To a methanol (20 ml) solution of the (1R,2R,6S)-1-t-butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo[6.1.0.02,6]-nonane (453 mg, 1.26 mmol) was added 10% palladium-on-carbon (400 mg), and the mixture was stirred vigorously in a pressurized (5 kg/cm2) hydrogen atmosphere for 30 hours. The insoluble matter was removed by Celite filtration, and the filtrate was concentrated to give 286 mg (1.20 mmol, 95%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH:23]1[CH2:25][CH2:24]1)[C:20]([NH2:22])=[O:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:23]1[CH2:25][CH2:24]1)(=[O:21])[NH2:22]
Reactant: NC(=O)C(N)C1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: NC(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% 2-propanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 330.1806 (M+H)+; αD20 (MeOH)=−40.1°.
Reaction SMILES: C(B1[O:7][CH2:6][CH2:5][O:4]1)C.[CH2:8]([OH:11])[CH2:9][OH:10]>>[O:10]=[CH:9][C@@H:8]([C@H:5]([C@@H:6]([C@@H:6]([CH2:5][OH:4])[OH:7])[OH:7])[OH:4])[OH:11]
Reactant: CCB1OCCO1
Reactant: OCCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h
Yield: 72 %

Procedure:
20 ml of ethane-1,2-diol are added dropwise at 50° C. to 11 g of residue and at the same time the 2-ethyl-1,3,2-dioxaborolane formed is distilled off in vacuo (10 Torr). The excess ethane-1,2-diol is removed in vacuo (10-3Torr, bath 80° C.). Approximately 40 ml of hexane are added to the highly viscous residue, the mixture is stirred for about 30 minutes and the white glucose is filtered off. 5 g (72%) of pure D-glucose are obtained after drying, mp. 146° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[CH:73]([O:76][CH2:77][CH2:78]O)([CH3:75])[CH3:74]>C1COCC1>[CH:73]([O:76][CH2:77][CH2:78][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([CH3:75])[CH3:74]
Reactant: CC(C)OCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 55.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.102 g, 0.221 mmol) was dissolved in THF (5.1 mL), and the solution was treated with triphenylphosphine (0.116 g, 0.442 mmol), 40% DEAD-toluene solution (0.201 mL, 0.442 mmol) and 2-isopropoxyethanol (0.126 mL, 1.10 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-(2-isopropoxyethoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0677 g, yield 59%).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1>>[N:1]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH:11][C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccsc1-n1cccn1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cccn2)cc1

Procedure:
The title compound was prepared from 2-(1H-pyrazol-1-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B. The solution was directly purified by HPLC to yield N-(2-(1H-pyrazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Method [7] Retention time 5.22 min by HPLC (MH+ 314). 1H NMR (300 MHz, CDCl3) δ 9.94 (broad s, 1H), 8.00 (d, J=5.7 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 6.94 (m, 3H), 6.35 (t, J=2.4 Hz, 1H), 3.87 (s, 3H), 3.71 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][OH:39])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: NCCO
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCO)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 290 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and 2-aminoethanol (142 mg, 2.31 mmol), the title compound was obtained as a white solid (110 mg, 39%). MS (ESI): 564 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH3:28])[C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]1>C1COCC1>[CH3:21][N:20]([CH3:28])[CH:17]1[CH2:16][CH2:15][N:14]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH2:7])[CH2:19][CH2:18]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccncc2N)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of LiAlH4 (49.57 mg, 1.306 mmol) was added dropwise to a solution of tert-butyl N-[1-(3-amino-4-pyridyl)-4-piperidyl]-N-methyl-carbamate (100 mg, 0.3264 mmol) in THF at room temp. The reaction was stirred at 50° C. for 3 h, then at room temperature, the reaction mixture was quenched by the dropwise addition of wet THF. The reaction mixture was partitioned between 1N NaOH (50 mL) and diethyl ether (50 mL). The combined organics was dried (MgSO4) and evaporated to leave 4-(4-(dimethylamino)piperidin-1-yl)pyridin-3-amine as a yellow oil. MS (ES+) 221.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.S(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Chloro-5-nitro-2-hydroxy-pyridine (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100° C. within 1 hour, stirred at 100° C. for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3×200 mL) and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give 2,3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C.CCCCCC>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1OC
Yield: 462.8 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.0 g, 0.327 mmol) in ethylene glycol dimethylether (35 mL) was added 3,4-dimethoxyphenyl boronic acid (892 mg, 4.9 mmol), potassium phosphate (6.9 g, 33 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (267 mg, 0.33 mmol). The reaction was heated to reflux for 12 hours when the solvent was removed under vacuo and the crude reaction mixture subjected to chromatography on silica gel eluting with 25% ethyl acetate/hexane to give the title compound (550 mg, 46% yield). ES-MS (m/z) 364 [M+1]+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:31][C:32](=[CH2:37])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH2:31])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C=C(CBr)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (7, R2=H) 508 mg, 1.4 mmol) was dissolved in THF (5 mL) under N2 and cooled to 0° C. Sodium hydride (143 mg, 60% suspension in mineral oil, 3.57 mmol) was added and the mixture was stirred at 0° C. for 5 min, when a solution of methyl 2-(bromomethyl)acrylate (276 mg, 1.54 mmol) in THF (1.5 mL) was added dropwise. Stirring was continued for 30 min at 22° C. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL) and extracted with EtOAc (2×30 mL) and CH2Cl2 (30 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using hexane/ethyl acetate (0-20%) to afford the title compound as a pale yellow solid (641 mg, 99%). ESI-MS m/z 458 (MH+).