Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]=[N+]=[N-])=[C:14]([O:24][CH3:25])[CH:13]=1.C(N)C.[BH4-].[Na+]>C(O)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(S)CCS>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH2:21])=[C:14]([O:24][CH3:25])[CH:13]=1
Reactant: COc1cc(CC(=O)NCCOCc2ccc(C)c(C)c2)ccc1OCCN=[N+]=[N-]
Agent: CCN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: SCCCS
Solvent: CC(C)O
Product: COc1cc(CC(=O)NCCOCc2ccc(C)c(C)c2)ccc1OCCN
Yield: 72 %

Procedure:
2.70 g (6.54 mmol) of N-{2-(3,4-dimethylbenzyloxy)-ethyl}-4-(2-azidoethoxy)-3-methoxyphenylacetamide obtained in step 1 was dissolved in 100 ml of isopropanol and 1.82 ml (13.31 mmol) of ethylamine was added thereto with stirring. 66 ml(6.54 1nmol) of 1,3-propanedithiol was dissolved in isopropanol to a concentration of 0.1M, to which the solution prepared above and 2.48 g (6.54 mmol) of NaBH4 were slowly added. The resulting mixture was stirred at an ambient temperature for 1 hour and then the solvent was removed under a reduced pressure to produce a residue, which was dissolved in 10% citric acid. The resulting solution was washed with 30 ml of a mixture of ether: hexane (1:1) three times. The pH of the aqueous layer was adjusted to 12 with sodium hydroxide solution, and a saturated sodium chloride solution was added thereto. The resultant was extracted with 30 ml of dichloromethane 3 times and the organic layer was dried and concentrated under a reduced pressure to produce a solid, which was recrystallized from ethyl acetate/hexane to obtain 1.82 g (yield 72%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in methylene chloride (25 mL) was added to a suspension of activated manganese dioxide (27 g) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde, as an oil. NMR and IR were consistent with the structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][CH:20]1[CH:32]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccnc1C(O)C1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of N-methylimidazole (84.0 ml) in tetrahydrofuran (1.25 l) was added dropwise n-butyllithium (1.56N, 500 ml and 1.60N, 120 ml) in hexane keeping the temperature below -65° C. After stirring for 30 minutes, to the mixture was added dropwise a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (259 g) in THF (1.25 l) at -65°~-60° C. for 30 minutes. The mixture was stirred at -60°~0° C. for 1.5 hours and at 0°~5° C. for 30 minutes. The reaction mixture was poured into a mixture of cold water (5 l) and ethyl acetate (5 l). The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added ethyl acetate (180 ml) and n-hexane (620 ml). The precipitate was collected by filtration to give isomer A of 1-{(4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-[1-methylimidazol-2-yl]methanol (480 g). The filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (2.6 kg, eluent; AcOEt:n-hexan=3:2 to 10:0), and the eluate was evaporated to give isomer B of the same (147.4 g) containing 17% of isomer A, as a solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:18]([N:6]1[CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Reaction time: 8 h

Procedure:
1-Benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid methyl ester and LiOH are dissolved in THF/H2O, and then stirred overnight. After removal of solvent, the residue is neutralized to PH=6-7, and then extracted by EA. The organic layer is washed with water and brine, dried, and concentrated to afford 1-benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid (4).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5].[OH-].[Na+].[F:19][C:20](=[C:24]([F:26])[F:25])[CH2:21][CH2:22]Br>CS(C)=O.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:22][CH2:21][C:20]([F:19])=[C:24]([F:26])[F:25])=[O:10])[CH3:8])=[O:5]
Reactant: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)O
Reactant: FC(F)=C(F)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)OCCC(F)=C(F)F
Temperature: 20 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
6.4 g (28 mmol) of N-(2,6-difluorobenzoyl)alanine are dissolved in 50 ml of dimethyl sulphoxide (DMSO) and admixed with 1.2 g (31 mmol) of sodium hydroxide dissolved in a little water. 5.7 g (30 mmol) of 3,4,4-trifluorobut-3-enyl bromide are subsequently added, and the mixture is stirred at 20° C. overnight. The mixture is then poured into water and the product is extracted with ethyl acetate and subsequently purified by column chromatography over silica gel using the system ethyl acetate. In this manner, 2.5 g (26.5% of theory) of 3,4,4-trifluorobut-3-enyl N-(2,6-difluorobenzoyl)-alaninate are obtained as an oil. log p (pH 2)=2.42.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH2:35][CH:34]([NH2:36])[CH2:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH2:33][CH:34]([NH:36][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:35]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)C4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Cyclopropane carbonylchloride (16 uL, 19 mg, 0.18 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (52 mg, 0.12 mmol) (see Example 102 for preparation) and DIPEA (41 uL, 31 mg, 0.24 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with EtOAc (50 mL), washed with NaHCO3 (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 60 mg (99%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.66-0.71 (m, 2 H), 0.71-0.77 (m, 2 H), 1.38-1.48 (m, 1 H), 1.51-1.64 (m, 2 H), 1.65 (s, 9 H), 1.68-1.86 (m, 4 H), 1.99-2.13 (m, 2 H), 2.19-2.35 (m, 1 H), 3.67 (dd, J=8.69, 6.15 Hz, 2 H), 4.00 (dd, J=8.8, 7.8 Hz, 2 H), 4.23-4.37 (m, 1 H), 4.53 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.79, 1.76 Hz, 1 H), 8.03 (d, J=8.59 Hz, 1 H), 8.16 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=509.3; Anal. Calcd for C25H34F2N4O3S+1.20 TFA+0.1H2O (647.26): C, 50.85; H, 5.51; N, 8.66. Found: C, 50.81; H, 5.52; N, 8.43.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([B:15]([OH:20])[OH:16])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)COc1ccc(Br)cc1C#N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)COc1ccc(B(O)O)cc1C#N
Temperature: 25 °C

Procedure:
5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1M hydrochloric acid was added, followed by stirring at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][C:6](=[O:49])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:42]([C:44]([O:46]CC)=[O:45])[CH3:43])([O:39]C)=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C(N)(C)(C)C>>[CH3:50][Si:2]([CH3:1])([CH3:51])[CH2:3][CH2:4][O:5][C:6](=[O:49])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:42]([C:44]([OH:46])=[O:45])[CH3:43])([OH:39])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Solvent: CC(C)(C)N
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC(C)C(=O)O)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C

Procedure:
A solution of 2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) in tert-butylamine (1 mL, 9.6 mmol) was heated at 65° C. for 16 hours. The solution was allowed to cool to room temperature and concentrated to provide the crude product as an oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 0.04 (s, 9H), 0.86-0.98 (m, 2H), 1.22-1.33 (m, 2H), 1.50 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.05-2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m, 3H), 3.40 (d, 2H, J=7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=9 Hz), 4.25-4.33 (m, 2H), 4.75-4.84 (m, 1H), 5.13 (s, 2H), 5.15-5.23 (m, 1H), 5.33-5.55 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 28.9 ppm; MS (m/z) 725.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](O)=[O:26])=[O:14])[N:4]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:25]([C:17]1[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:29])([F:28])[F:1])=[N:4]1)=[O:26]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (50 mg, 0.117 mmol) was dissolved in a solution of DCM (2 mL) and DMF (0.4 mL). O-(7-azabenzotriazol-1-yl)-N,N′,N′,N′-tetramethyluronium hexafluorophosphate (54 mg, 0.141 mmol) was added, followed by N,N-dimethylethylenediamine (15.5 μL, 0.141 mmol) and N,N-diisopropylethylamine (24.6 μL, 0.141 mmol). The resultant mixture was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue obtained purified by preparative reverse phase HPLC, to afford the title compound, a colourless oil, as the TFA salt (52 mg, 0.084 mmol, 72%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:21][N:22]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([N:22]([CH3:21])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)O)ccc1I
Reactant: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2OCCCC)c1
Temperature: 80 °C
Yield: 20.7 %

Procedure:
0.2 g (0.5 mmol) of (Z)-3-(3-butoxy-4-iodophenyl)-2-ethoxyacrylic acid prepared as described in Example 23a and 0.2 g (0.6 mmol) of 3-(1-methyl-3-pentylureido)phenylboronic acid prepared as in Example 24h are dissolved in 4 mL of a 75/25 solution of ethylene glycol dimethyl ether/water. After addition of 0.2 mL (1.2 mmol) of aqueous 2M potassium carbonate solution, 0.004 mg (0.005 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium is added and the reaction medium is heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2, 7/3 and then 5/5 heptane/ethyl acetate mixture. 50 mg (20%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-ethoxyacrylic acid are obtained in the form of a beige-colored solid with a melting point of 59° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([C:16](OC)=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][CH2:2][C:3]1([CH2:16][OH:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(CCl)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(CCl)CC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 93.9 %

Procedure:
A solution of 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (11.7 g, 40.2 mmol) in anhydrous THF (100 mL) was cooled to 0° C. Lithium aluminum hydride (1N in THF, 44.3 mL, 44.3 mmol), was added slowly (15-20 min) and the solution was stirred at 0° C. for 25 minutes. The mixture was quenched by adding water (1.8 mL) dropwise with great caution. Aqueous 1N NaOH (1.8 mL) was added dropwise, and the mixture was stirred for 5 minutes. The cooling bath was removed, the solids were filtered off, and the cake was washed with Et2O (2×100 mL). The filtrate was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate as a solid (9.96 g, 93.8%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.55 (m, 4H), 3.36-3.41 (m, 4H), 3.57 (s, 2H), 3.59 (br s, 2H).
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[S:8][C:4]=2[C:3](=[N:13]O)[CH2:2]1.[OH2:15]>>[C:3]1(=[O:15])[C:4]2[S:8][C:7]3[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:5]=2[CH2:1][CH2:2][NH:13]1
Reactant: O
Reactant: ON=C1CCc2c1sc1c2CCCC1
Product: O=C1NCCc2c1sc1c2CCCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 103d (285 mg, 1.38 mmol) and polyphosphoric acid (15 g). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature, and water (30 mL) was added. The resulting mixture was stirred for 30 min and filtered. The filter cake was washed with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 75% yield (215 mg) of 103e as an off-white solid: mp 203° C. dec; 1H NMR (500 MHz, CDCl3) δ 5.62 (s, 1H), 3.59 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=7.0 Hz), 2.48 (t, 2H, J=6.0 Hz), 1.84 (m, 4H). MS (APCI+) m/z 208.3 (M+H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:28]=[C:29]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[N:36][C:35]3[CH:47]=[CH:48][CH:49]=[N:50][C:34]2=3)[CH:30]=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O1CCOCC1.C(OCC)(=O)C>[CH2:40]([C:37]1[C:38](=[O:39])[N:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH:28]=2)[C:34]2[N:50]=[CH:49][CH:48]=[CH:47][C:35]=2[N:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
A mixture of 2-quinolinecarboxylic acid (520 mg) and 1,1′-carbonyldiimidazole (243 mg) in tetrahydrofuran (5 ml) was stirred at room temperature for 1.5 hours. A solution of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (493 mg) in 1,4-dioxane (5 ml) was added to the mixture and stirring was continued for 5 days. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate, concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-3-oxo-4-[3-(quinolin-2-yl)carbonylaminophenyl]-3,4-dihydropyrido[2,3-b]pyrazine (87 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]1[O:15][Si](CC)(CC)CC)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:6]1[OH:15])=[O:4]
Reactant: CC[Si](CC)(CC)OC1C(C(=O)OC)CCC12CCCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1CCC2(CCCCC2)C1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To a solution of 1-triethylsiloxy-spiro[4.5]decane-2-carboxylic acid methyl ester (5.0 g) obtained in Step 2 in tetrahydrofuran (30 mL) was added a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (18.4 mL), followed by stirring the reaction mixture at room temperature for 30 minutes. Then, after addition of aqueous ammonium chloride solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=5:1) to give 1-hydroxy-spiro[4.5]decane-2-carboxylic acid methyl ester (less-polar isomer; 1.6 g, more-polar isomer; 0.95 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](C2C=CC=CC=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:17]#[N:18])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:17][NH2:18])=[CH:10][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 5 °C
Yield: 89.5 %

Procedure:
To a 5 liter flask stirring under nitrogen, fitted with a mechanical stirrer, was charged 18 g (0.45 mole) of lithium aluminum hydride in 1000 mL of dry tetrahydrofuran which was then cooled to 5° C. To the slurry was added 152 g (0.45 mole) of alpha-(2-(4-chlorophenyl)ethyl)-alpha-phenyl-1H-1,2,4-triazole- 1propanenitrile in 2000 mL of dry tetrahydrofuran over 3 hours. The reaction was kept at 5°-10° C. during the addition then allowed to warm to room temperature and stirred overnight. The reaction was cooled in an ice bath and quenched with the slow addition of sodium sulfate. The solvent was removed and the residue was extracted with ethyl acetate and washed with 1000 mL water and 1000 mL brine. After drying, and removal of the solvent, 137 g (89.5% yield) of a very viscous oil resulted.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][C:11]1([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.O.[OH-].[Na+]>O1CCCC1>[CH2:17]([N:14]1[CH2:13][CH2:12][C:11]([CH2:10][CH2:9][OH:8])([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:16][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC1(N2CCCC2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1(N2CCCC2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (324 mg) was suspended in tetrahydrofuran (25 mL). A solution of (1-benzyl-4-pyrrolidine-1-ylpiperidine-4-yl)acetic acid methyl ester (2.70 g) in tetrahydrofuran (25 mL) was added thereto at 0° C. After stirring at 0° C. for 1 hour, to the reaction solution were sequentially added with water (0.35 mL), 10% aqueous sodium hydroxide (0.35 mL) and water (1.05 mL). The insoluble material was filtrated and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound. The obtained objective substance was provided to the next reaction without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([NH2:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(CC(N)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1cc(CC(N)=O)ccc1N
Yield: 89 %

Procedure:
2-(4-Amino-3-methylamino-phenyl)-acetamide (554 mg) was prepared by following General Procedure B beginning with 2-(3-methylamino-4-nitro-phenyl)-acetamide (727.0 mg) and Pd/C (20% by weight, 140.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.