Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(#N)C.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]3[CH2:20][CH2:19][C:18]4([CH2:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2c(c1)COC1(CCNCC1)C2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COC1(CCN(CCCOc3cccc4[nH]ccc34)CC1)C2

Procedure:
A solution of 1-chloro-3-(4-indolyloxy)propane, 1,4-dihydrospiro[3H-2-benzopyran-3,4′-piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 62% overall yield. FDMS m/e=376 (M+ of free base).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH:16](Cl)Cl>O1CCCC1.[Cl-].[Na+]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH:16]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: COCCOC(Cl)Cl
Reactant: CCOP([O-])OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(OCCOC)P(=O)(OCC)OCC
Reaction time: 0.25 h

Procedure:
Diethyl phosphite (18.0 ml) was added dropwise at 20° C. to a stirred suspension of 55% sodium hydride (5.45 g) in dry tetrahydrofuran (100 ml). After stirring for a further 15 minutes, the mixture was cooled in ice, and dichloromethyl 2-methoxyethyl ether (7.15 g) was added during 15 minutes. The mixture was stirred at room temperature for 1 hour, diluted with saturated aqueous sodium chloride and extracted with chloroform. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The pure title compound was isolated as a colourless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=O)C(F)(F)F)[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12].CI.O>CN(C=O)C>[CH3:16][NH:15][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]([F:12])([F:13])[F:14])=[C:4]([Br:3])[CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Br)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 870 mg, 21.7 mmol) was added to a stirred, cooled (0° C.) solution of N-[3-Bromo-4-(trifluoromethoxy)phenyl]trifluoroacetamide (Description 50, 6.3 g, 18.0 mmol) in DMF (50 ml). The mixture was stirred at 0° C. for 20 min. and methyl iodide (1.35 ml, 21.7 mmol) was added over 5 min. The mixture was stirred at 0° C. for 45 min. and at room temperature for 4 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with water (3×100 ml) and brine (100 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (3:1 increasing to 1:1) to give the title compound as a tan oil (1.20 g, 25%). 1H NMR (250 MHz, CDCl3) δ7.11 (1H, dq, J 8.9, 1.2 Hz), 6.86 (1H, d, J 2.8 Hz), 6.56 (1H, dd, J 8.9, 2.8 Hz), and 2.83 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH2:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN
Yield: 65.1 %

Procedure:
A solution of tert-butyl 2-(4-chloro-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (1.55 g, 3.83 mmol) in a solution of 4 M hydrogen chloride in dioxane (15 mL) was stirred at room temperature for two hours. An aqueous solution of 2 M sodium hydroxide was added to adjust the reaction to pH 13. The solution was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 97:3 to 97:5 dichloromethane/methanol) to afford 2-(4-chloro-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethylamine (760 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:4]=1)#[CH:2].C[Si]([N:41]=[N+:42]=[N-:43])(C)C>CN(C)C=O.CO>[NH:41]1[C:1]([C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=5)=[O:20])=[CH:16][CH:17]=4)=[CH:9][CH:10]=3)[N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[N:4]=2)=[CH:2][N:43]=[N:42]1
Reactant: C#Cc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cnn[nH]2)c2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of Example 21C (90 mg, 0.180 mmol) in N,N-dimethylformamide (4 ml) and methanol (0.7 ml) under argon was treated with Cu(I)I (5.00 mg, 0.026 mmol) and trimethylsilyl azide (0.249 ml, 1.798 mmol), then heated at 100° C. in an oil bath in a sealed tube for 3 hours. An additional amount of trimethylsilyl azide (0.5 ml) was added and the vial was recapped and heated at 100° C. for 4 hours and then stirred at room temperature for 16 hours. The resulting mixture was partitioned between ethyl acetate and brine, and the organic extract was dried with MgSO4, concentrated and the residue was purified on a 12 gram Silicycle column eluting with 2 to 3% methanol in CH2Cl2 to afford the title compound.
Reaction SMILES: [C-:1]1([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:14])=O)=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:14][C:12]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:6]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:7].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: O=C(Cl)CCCCC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C1=C(Cl)CCC1)[c-]1cccc1

Procedure:
This brown oil (ferrocenoyl valeroyl chloride) assumed to be 0.01 mole from the above preparation in methylene chloride (100 ml) was stirred at 0°-5° and aluminium chloride (1.3g; 0.01 mole) was added. Ice was then added and the organic layer was separated. The aqueous layer was extracted with chloroform. The combined organic fractions were washed with water, dried (magnesium sulphate) and evaporated to yield a red oil which was purified by dry-column chromatography on silica, which had been deactivated to Grade III by the addition of water, using 1:10 ethylacetate: petroleum ether as eluent, to yield pure 1-chloro-2-ferrocenoylcyclopent-1-ene, 150 mg; mp 102°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 48.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.160 g, 0.282 mmol) obtained in Example 142, step 2 and cyclopropanesulfonamide (0.170 g, 1.41 mmol), the title compound (0.087 g, 48%) was obtained.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:32]=[N:2][N:1]([C:3]3[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:8])=[CH:5][N:4]=3)[C:27]=2[OH:28])[CH:25]=1)#[N:20]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c1
Reaction time: 15 h
Yield: 34.2 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (107 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1423 μl) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred overnight (15 h) and then Hunig's base (297 μl, 1.708 mmol) was added and the reaction was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜20 mL). The solid was filtered and dried in vacuum to give the title compound (57.4 mg, 34.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (qd, J=12.21, 4.29 Hz, 2H) 1.62 (d, J=12.88 Hz, 2H) 1.81 (m, J=10.96, 7.29, 3.76, 3.76 Hz, 1H) 3.20 (t, 2H) 3.27 (t, J=10.86 Hz, 2H) 3.86 (dd, J=11.24, 2.65 Hz, 2H) 8.29 (s, 1H) 8.42 (br. s., 3H) 8.74 (t, J=5.68 Hz, 1H) 8.93 (s, 2H) 13.41 (br. s., 1H). MS m/z [M+H]+394.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([O:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[NH:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[NH:20]1[CH2:21][CH2:22][C@H:18]([O:17][C:15]2[N:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cc3cccnc3c(O[C@H]3CCNC3)n2)[nH]1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To (S)-tert-butyl 3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate (100 mg, 0.251 mmol) suspended in dioxane (10 mL) was added 4M HCl in dioxane (0.251 mL, 1.004 mmol). The reaction mixture was stirred for 30 minutes and concentrated to give an HCl salt of the title compound (74 mg, 88%). This material was used directly in next step.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[CH2:22]([O:24][C:25]([N:27]=[C:28]=[S:29])=[O:26])[CH3:23]>O1CCCC1>[CH2:22]([O:24][C:25](=[O:26])[NH:27][C:28]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]([OH:17])=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:12]=2)=[N:4][N:3]=1)=[S:29])[CH3:23]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(5-amino-1,3,4-thiadiazole-2-yl)-2,6-bis(1,1-dimethylethyl)phenol (1.5 g, 0.005 mole) in tetrahydrofuran (10 ml) is added ethoxycarbonylisothiocyanate (0.64 g, 0.005 mole) dropwise. The resulting mixture is stirred 18 hours at room temperature, before concentrating in vacuo. The residue is recrystallized from ethanol/water to provide 1.7 g (2.2 g theor., 78%) of the title compound after drying in vacuo at 50° C., mp >25° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28]Br.BrCC1CCCCO1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COc1ccc(CBr)cc1OC
Agent: BrCC1CCCCO1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1OC

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 3,4-dimethoxybenzyl bromide (Oguri, T., et al., Chem. Pharm. Bull. (1977), 25:2287-91) to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (100%) as a colorless solid: mp 209-211° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.80 (m, 4H), 6.51 (s, 1H), 6.21 (s, 1H), 5.09 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.68 (d, J=15.3 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 149.5, 148.8, 144.7, 142.2, 138.4, 132.4, 128.9, 128.4, 124.0, 123.5, 121.3, 120.0, 111.5, 111.2, 110.5, 109.5, 99.6, 80.1, 64.6, 64.0, 58.2, 56.02, 55.99, 44.1; MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+]>>[CH2:24]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: CCCCCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 30 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0260 g, 0.0874 mmol), hexanal (0.0195 mL, 0.162 mmol), and sodium borohydride (0.0076 g, 0.200 mmol) provide 0.0100 g (30%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C23H32N3O2 382.2495, found 382.2513; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.35 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (d, 1H, J=8.3 Hz), 3.23-3.16 (m, 2H), 2.95 (tt, 1H, J=3.4, 11.7 Hz), 2.63-2.56 (m, 2H), 2.35-2.22 (m, 2H), 2.05-1.90 (m, 2H), 1.83 (tq, 1H, J=3.9, 13.7 Hz), 1.70-1.56 (m, 3H), 1.45-1.30 (m, 6H), 0.96 (t, 3H, J=6.3 Hz).
Reaction SMILES: Br[CH2:2][CH2:3]Br.Cl.[CH3:6][O:7][C:8](=[O:15])[C@@H:9]([C:11]([SH:14])([CH3:13])[CH3:12])[NH2:10].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[S:14][CH2:3][CH2:2][NH:10][C@H:9]1[C:8]([O:7][CH3:6])=[O:15]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1NCCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 1,2-dibromoethane (6.77 g, 36 mmol) in dimethylformamide (25 ml) was added, over a period of 30 minutes, a solution of D-penicillamine methyl ester hydrochloride (6 g, 30 mmol) and 1,8-diazobicyclo[5.4.0]undeca-7-ene (13.7 g, 90 mmol) in dimethylformamide (50 ml). The resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give 5.5 g (97%) of the product.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[N:8][CH:7]=1)(=[O:5])[CH3:4].Br>C(O)(=O)C>[C:13]([NH:12][CH2:11][C:9]1[S:10][C:6]([C:3](=[O:5])[CH2:4][Br:1])=[CH:7][N:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)NCc1ncc(C(C)=O)s1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)NCc1ncc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.4 %

Procedure:
A solution of bromine (1.61 g) in acetic acid (4 ml) was added dropwise to a mixture of 5-acetyl-2-acetylaminomethylthiazole (2.00 g), 30 (W/W) % hydrobromic acid solution in acetic acid (5 ml) and acetic acid (40 ml) at ambient temperature. After stirring for 24 hours at ambient temperature, the resulting precipitate was collected by filtration and washed with acetic acid to give 2-(acetylaminomethyl)-5-bromoacetylthiazole (3.00 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Product: COc1c(OCCOC2CCCCO2)cc(C(C)=O)cc1C(C)(C)C
Yield: 84.7 %

Procedure:
Analogously to O2.071, 1-(3-tert-butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 5.0 g) was reacted with 2-(2-bromoethoxy)tetrahydropyran (5.64 g). However, the crude product was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 6.68 g of the title compound were obtained.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:29][NH:30][C:31](=O)[CH2:32][N:33]([CH3:35])[CH3:34].C[O-].[Na+]>CO>[CH3:34][N:33]([CH2:32][C:31]1[NH:30][N:29]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:35]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)C)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4n[nH]c(CN(C)C)n4)cc23)c1

Procedure:
The title compound was prepared according to example Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3-methylbutanamide hydrochloride (0.400 g, 0.997 mmol), N-amino-2-(dimethylamino)acetamide (0.350 g, 2.99 mmol) and sodium methoxide in methanol (0.348 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.074 g, 18% yield): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.75 (t, 2H), 7.69 (d, 1H), 7.51 (t, 1H), 3.81 (s, 2H), 2.45 (s, 6H), 2.3 (d, 2H), 2.21 (m, 1H), 1.04 (d, 6H); ES-MS (m/z) 418 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:30]=[CH:29][C@:28]2([C:31](=[O:34])[CH2:32][OH:33])[C@H:7]1[CH2:8][C@H:9]1[C@H:22]3[C@@:13]([F:26])([C@:14]4([CH3:25])[C:19]([C@@H:20]([F:23])[CH2:21]3)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]4)[C@@H:12]([OH:27])[CH2:11][C@@:10]12[CH3:35])=[O:5])[CH3:2].[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([CH:6]1[NH:30][CH2:29][C@:28]2([C:31](=[O:34])[CH2:32][OH:33])[C@H:7]1[CH2:8][C@H:9]1[C@H:22]3[C@@:13]([F:26])([C@:14]4([CH3:25])[C:19]([C@@H:20]([F:23])[CH2:21]3)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]4)[C@@H:12]([OH:27])[CH2:11][C@@:10]12[CH3:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1N=C[C@]2(C(=O)CO)[C@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1NC[C@]2(C(=O)CO)[C@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 0 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of intermediate 118 (629 mg; 1.28 mmol) in methanol (13 ml; 0.1 M), NaCNBH3 (169 mg; 2.56 mmol) is added at 0° C.; pH is adjusted to 5 by addition of acetic acid. The reaction mixture is stirred at 0° C. for 2 hours and at RT for 5 hours, then it is poured into brine (50 ml), and pH is adjusted to 7 by addition of a saturated solution of NaHCO3. The aqueous phase is extracted with AcOEt (3×60 ml) and the combined organic layers are concentrated. The crude material is purified by silica gel flash chromatography in gradient elution from DCM to DCM/MeOH 88:12, to afford pure title compound (335 mg, 53% yield mixture of stereoisomers).
Reaction SMILES: [NH3:1].N.N.N.N.N.[OH2:7].O.O.O.[OH:11][Mo:12](O)(=O)=O.[OH:16][Mo](O)(=O)=O.[OH:21][Mo](O)(=O)=O.[O:26]=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>O>[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[OH2:11].[OH2:16].[OH2:21].[OH2:26].[OH2:7].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12]
Reactant: O=[Mo](=O)=O
Reactant: O=[Mo](=O)(O)O
Agent: N
Solvent: O
Product: [Mo]

Procedure:
A first aqueous solution of ammonium heptamolybdate was prepared by dissolving 83.3 g of (NH4)6Mo7O24.4H2O in 380 ml H2O at ambient temperature; a second aqueous solution of nitrates by mixing at the ambient temperature the following three solutions: