Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[H-].[Na+].[Li]C(C)(C)C.[CH3:19][C:20]1([CH3:31])[C:24]([CH3:26])([CH3:25])[O:23][B:22](OC(C)C)[O:21]1>O1CCCC1>[CH3:11][C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([B:22]1[O:23][C:24]([CH3:26])([CH3:25])[C:20]([CH3:31])([CH3:19])[O:21]1)=[CH:10][CH:9]=2
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 5-bromo-2-methyl-1H-indole (3.0 g, 14.35 mmol) in dry tetrahydrofuran (20 ml) was added sodium hydride (900 mg, 22.5 mmol) with ice-cooling. After stifling for about 30 min, a solution of t-BuLi (27.5 ml, 1.3 M solution in hexane) was added dropwise with stifling at −78° C. under an inert atmosphere of nitrogen. The reaction mixture was warmed slowly to −40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C., followed by the addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (5.3 g, 28.49 mmol) dropwise. After warming to room temperature, the mixture was quenched with NH4Cl solution (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by a silica gel column (2% ethyl acetate in petroleum ether) to afford 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 g, 38%). 1H NMR (300 MHz, CDCl3): δ 8.06 (s, 1H), 7.91 (s, 1H), 7.58-7.60 (t, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.24 (s, 1H), 2.46 (s, 3H), 1.39 (s, 12H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC2C=CC=CC=2)[CH:13]=1.C(O)(C)C>[C].[Pd].O>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2cccc(OCc3ccccc3)c2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2cccc(O)c2)cc1OC
Yield: 91 %

Procedure:
2 g of α-(3,4-dimethoxyphenethylaminomethyl)-3-benzyloxybenzylalcohol hydrochloride, 0.5 g of 10 % palladium-carbon, 100 ml of isopropanol and 15 ml of water are treated in the same manner as described in Example 1-(c). 1.45 g of α-(3,4dimethoxyphenethylaminomethyl)-3-hydroxybenzylalcohol hydrochloride are obtained. M.p. 161° -162° C.(recrystallized from a mixture of isopropanol and ether).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.I[CH2:18][CH:19]([CH3:24])[O:20][CH2:21][CH2:22]I>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:24])[CH2:18]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1
Reactant: CC(CI)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cc(F)cc(F)c2)CCOC(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 9.17 g) was added portionwise to a solution of ethyl 3,5-difluorophenylacetate (17 S) in THF (400 ml) and the mixture was stirred at ambient temperature for 1 hour. A solution of 1,5-diiodo-2-methyl-3-oxapentane (30.3 g) in THF (20 ml) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 19:1 v/v mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained, as a mixture of diastereoisomers, 4-ethoxycarbonyl-4-(3,5-difluorophenyl)-2-methyltetrahydropyran (16.5 g). The mixture of diastereoisomers was separated by further chromatography using a 10:1 v/v mixture of petroleum ether (b.p 40°-60° C.) and ethyl acetate as eluent. There was thus obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:20]=[C:13]2[CH:14]=[N+:15]([O-])[CH:16]=[C:17]([F:18])[C:12]2=[N:11]1.P(Br)(Br)([Br:23])=O>ClCCCl.C(Cl)Cl>[Br:23][C:14]1[C:13]2=[CH:20][N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[C:17]([F:18])=[CH:16][N:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Solvent: ClCCl
Solvent: ClCCCl
Product: Fc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a cooled (0° C.) suspension of 2-(2,6-dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine-5-oxide (2.95 g, 9.3 mmol) in DCE (50 mL) was added phosphorus oxybromide (8.0 g, 28 mmol). The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 3 hours. The reaction mixture was diluted with DCM and washed with sodium carbonate (sat. aq.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (1.0 g, 28% yield). LCMS (Method D): RT=3.82 min, m/z: 380 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][C:7](=[O:11])[CH2:6][C:5]=2[CH:4]=[N:3]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:6]1[C:7](=[O:11])[CH2:8][CH2:9][C:10]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]1=2)[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: Cn1ncc2c1CCC(=O)C2
Product: CN(C)C=C1C(=O)CCc2c1cnn2C

Procedure:
The above procedure was repeated using 1,4,6,7-tetrahydro-1-methyl-5H-indazol-5-one and N,N-dimethylformamide dimethyl acetal. The crude product was flash chromatographed (5% methanol in dichloromethane) on silica gel to give a thick amber oil which was triturated with etherhexane to give 4-(dimethylaminomethylene) 1,4,6,7-tetrahydro-1-methyl-5H-indazol-5-one as a tan powder melting at about 94°-100° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2cccc([N+](=O)[O-])c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(3-nitrophenoxy)benzoate and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 34 mg of 2-(benzamido)-4-(3-nitrophenoxy)benzoic acid as pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:17]([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(4-bromo-phenyl)-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([NH:8][CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)[CH2:6][CH3:7].C(N(CC)CC)C>>[CH2:5]([N:8]([CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)[C:1]([Cl:4])=[O:2])[CH2:6][CH3:7]
Reactant: CCCNC1CCOC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)Cl)C1CCOC1

Procedure:
94 g (0.95 mol) of phosgene, 41 g (0.32 mol) of N-propyl-N-(tetrahydrofuran-3-yl)amine and 32 g (0.32 mol) of triethylamine were reacted by the method of the process described in Intermediate 1.2. Yield 54 g. 1H NMR (270 MHz, in CDCl3): δ=0.92 (t, 3H), 1.70 (sext., 2H), 2.02 (s, 1H), 2.30 (s, 1H), 3.20-3.40 (m, 2H), 3.65-3.85 (m, 3H), 4.05 (m, 1H), 4.50-4.70 and 4.85-5.05 (2 m, together 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[NH:37]1[CH:41]=[CH:40][CH:39]=[N:38]1>>[C:35]([C:32]1([NH:31][C:29]([CH:14]2[CH2:13][CH:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:37]4[CH:41]=[CH:40][CH:39]=[N:38]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: c1cn[nH]c1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Product: Cc1cc(N2CC(S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)CC2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 416, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with pyrazole (CAS Reg. No. 288-11-9) to give the title compound as colorless oil. MS (ESI): m/z=584.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][CH:14]([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH2:15][CH:14]([F:17])[F:13]
Reactant: NCC(F)F
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)CNc1nc2ccncc2nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (50 mg, 0.250 mmol) in dioxane (250 μL) was treated with 2,2-difluoroethanamine (21.0 μL, 0.275 mmol) and DIPEA (131 μL, 0.750 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h then purified by flash silica gel chromatography using a gradient of 0% to 60% EtOAc in hexanes to give the title compound (52 mg, 85%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[CH:21]=O)[CH:9]=2)[N:3]=1.[CH3:23][NH:24][C:25]1[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.CC(O)=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:24]([CH3:23])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N:31]=3)[CH:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)nc(C(F)(F)F)n2)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the mixture of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropanecarbaldehyde (16-6, 280 mg, 0.899 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (0.11 mL, 0.989 mmol, 1.1 eq.) in anhydrous ethanol (5.0 mL) at room temperature was added glacial AcOH (0.062 mL, 1.08 mmol, 1.2 eq.) followed by anhydrous CuSO4 (158 mg, 0.989 mmol, 1.1 eq.). The resulting brownish mixture was stirred at room temperature for 4 hours under an atmosphere of nitrogen gas. The mixture was concentrated in vacuo and neutralized with 7 M NH3 in methanol (1.0 mL). Then it was filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (16-7) as a light brown solid. 1H NMR (300 MHz, CDCl3) 8.07 (s, 1H), 7.74-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 3.08-2.99 (m, 1H), 2.98-2.88 (m, 1H), 2.93 (s, 3H), 2.42 (s, 3H), 2.13-2.02 (m, 2H). LRMS m/z (M+H) 414 found, 414 required. m.p. 151-153° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(=O)=O.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[CH2:19][C:20]([OH:22])=[O:21]>CO>[N+:1]([C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:8])=[CH:14][CH:15]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CC1CCc2ccccc2C1=O
Agent: O=C=O
Solvent: CO
Product: O=C(O)CC1CCc2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.67 h

Procedure:
To nitric acid (density=1.50) cooled with dry ice and methanol is added 1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid at -10 to -15° C. The resulting mixture is stirred below 0° C. for 40 minutes and poured into ice. The precipitated crystals are collected by filtration to give 7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29]>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Reactant: CNCCN(C)C
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(N(C)CCN(C)C)c1C2=O
Yield: 43.4 %

Procedure:
This procedure was carried out as described previously in Example 19, using Compound 17 (500 mg, 1.52 mmol) and N,N,N′-trimethylethylenediamine (988 μL, 7.6 mmol). The dye was obtained as a red solid (260 mg) after Biotage purification using a gradient of methanol in chloroform. Abs (max, PBS pH 7.4)=530 nm; Em=646 nm. The structure of Compound 41 is given below:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[F:18][C:19]1[CH:20]=[C:21]([C:25]#[C:26][C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:38]=2)[C:32](N(OC)C)=[O:33])[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:25]#[C:26][C:27]2[CH:38]=[C:31]([CH:32]=[O:33])[CH:30]=[N:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)c1cncc(C#Cc2cccc(F)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cncc(C#Cc2cccc(F)c2)c1
Yield: 63.6 %

Procedure:
Prepare essentially as described in EXAMPLE 5 using a 1 M solution of diisobutylaluminum hydride in toluene (1.2 mL, 1.20 mmol), 5-(3-fluorophenylethynyl)-N-methoxy-N-methylnicotinamide, (prepared as described in PREPARATION 18), (170 mg, 0.60 mmol) to give the title compound (86 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[C:11]([CH3:14])([CH3:13])[CH3:12]>C1COCC1.[NH4+].[Cl-]>[CH3:10][C:11]([CH3:14])([CH3:13])[CH2:12][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)CC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 4-methylbenzaldehyde (1.51 g, 12.6 mmol) in THF (30 mL) at 0° C., add neopentyl magnesium chloride (33.0 mL, 16.34 mmol, 0.5-1M in ether) and continue stirring at 0° C. for 1 h. Dilute with saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) to give the desired intermediate as a colorless oil (2.15 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:38])[CH3:37])[O:8]1)[O:9][CH2:10]2
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CNC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane, was added acetic anhydride (45 μL, 0.048 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 5 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.25 (s, 1H), 7.11 (s, 1H), 6.99 (s, 4H), 5.00 (d, J=12.6 Hz, 1H), 4.95 (d, J=12.6 Hz, 1H), 4.00 (d, J=15.4 Hz, 1H), 3.95 (d, J=15.4 Hz, 1H), 3.71-3.57 (m, 3H), 3.45 (dd, J=14.4, 2.8 Hz, 1H), 3.17-3.11 (m, 2H), 2.48 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H); MS ESI (m/z) 484 (M+Na)+, calc. 461.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)[CH:8]=[CH:7]2)([O-])=O>ClCCl.CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(C3CCCCN3)ccc2c1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2nc(C3CCCCN3)ccc2c1

Procedure:
Prepared analogously to Example 3.1.b. from 6-nitro-2-piperidin-2-yl-quinoline. Yield: 0.79 g (59.6% of theory); C14H17N3 (M=227.31); calc.: molecular ion peak (M+H)+: 228; found: molecular ion peak (M+H)+: 228; Rf value: 0.37 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[OH-].[NH4+:12]>C(O)C>[F:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8]
Reactant: [NH4+]
Reactant: Nc1nc(Cl)c(F)c(Cl)n1
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N)c(F)c(Cl)n1
Temperature: 100 °C
Yield: 65 %

Procedure:
5-Fluoro-4,6-dichloro-2-pyrimidineamine (4) (204 mg, 1 mmol) and ammonium hydroxide (15 ml) were charged to a sealed tube and ethanol (1.5 ml) added. The tube was heated at 100° C. for 24 hours. The solution was concentrated. The residue was absorbed on silica gel and chromatographed (elution with ethyl acetate), yielding (5) as a white powder (118 mg, 65%): MS (70 eV, EI) m/z (relative intensity) 162 (M+, 100), 43 (92), 164 (33), 127 (29), 135 (16). Exact Mass Calcd for C4H4N4ClF: 162.0108. Found: 162.0100.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:10](=[O:27])[CH2:11][NH:12][C@H:13]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]([OH:27])[CH2:11][NH:12][C@H:13]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CN[C@@H](CC(C)C)C(=O)OCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
To a solution of 5.0 g (10.9 mmol) of N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-oxo-5-methylhexyl]-L-leucine, 2-(trimethylsilyl)ethyl ester in a mixture of 150 ml of tetrahydrofuran and 50 ml of water cooled in an ice-water bath was added 2.1 g (54.5 mmol) of sodium borohydride. After 5 minutes, the reaction was poured into 300 ml of water and extracted with 600 ml of ethyl acetate. The organic extract was rinsed further with water and brine, dried (magnesium sulfate) and concentrated in vacuo to yield 4.7 g of crude product. Flash chromatography on 140 g of LPS-1 silica gel eluted with 10:1, petroleum ether:acetone yielded 3.5 g of the title compound as an oil. By 13C-NMR analysis, material prepared in this manner is essentially a 1:1 mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2cc(-c3ccccc3)ccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2cc(-c3ccccc3)ccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-H), the title compound was prepared as a solid having a melting point >240° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5]([F:8])=[CH:4][CH2:3]1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][CH:5]([F:8])[CH2:4][CH2:3]1
Reactant: COC(=O)C1(N)CC=C(F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(N)CCC(F)CC1

Procedure:
Methyl 1-amino-4-fluoro-3-cyclohexenecarboxylate (52 mg) was dissolved in the mixed solvents of methanol (2 mL) and ethyl acetate (2 mL), and 10% palladium-carbon (35 mg) was added and hydrogen gas was introduced for 14 hours. The insoluble matter was filtered and the solvent was removed by distillation under reduced pressure, and a mixture of the desired matter (BB09, 38 mg) was obtained.