Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O.C1COCC1>O>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Reactant: NC(=O)Cc1nc(N2CCNC3(CC3)C2)cc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Reaction time: 1.5 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide (4.95 g, 16.70 mmol) and (7-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (5.44 g, 25.05 mmol) are azeotroped twice with dry THF. Dry THF (100 ml) is then added, and under an atmosphere of argon KOtBu (1.0 M in THF, 50 ml, 50 mmol) is added dropwise during 20 min. After an additional 90 min, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with H2O and extracted twice with EtOAc. The combined organic layers are washed twice with saturated aq NH4Cl solution (back extracted), dried over Na2SO4 and concentrated. Purification by FCC(CH2Cl2/MeOH 100:0 to 98:2 to 96:4 to 94:6 to 92:8 to 90:10) yields the title compound, which is converted to its acetate salt by concentration of a EtOH/AcOH solution. 1H NMR (DMSO, 400 MHz) δ 0.26-053 (br, 4H), 1.89 (s, 3H, CH3COOH), 2.36 (s, 3H), 2.80 (br m, 2H), 3.15-3.48 (br m, 2H), 6.14 (d, J=8.2 HZ, 1H), 6.44 (dd, J=8.2/7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 7.00 (s, 1H), 7.02 (dd, J=8.2/8.2 Hz, 1H), 7.40 (dd, J=8.2/8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.97 (d, J=2.9 Hz, 1H), 11.04-11.21 (br, 1H), 11.86 (d, J=2.9 Hz, 1H); ES-MS: 464 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=O>ClCCl.C(#N)C>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (69.1 g) in dichloromethane (200 mL) was added dropwise at 0° C. to a suspension of sodium hydride (11.9 g) in dichloromethane (700 mL). The mixture was stirred at 0° C. during 1 h. The cold (0-5° C.) solution of aldehyde [3a] in dichloromethane prepared in the previous stage was added dropwise to the stirred mixture at 0-5° C. The obtained mixture was stirred for 1 hour at the same temperature (TLC monitoring), filtered through Celite and acidified with acetic acid to pH 5 at 0-5° C. The organic layer was separated, washed with water until the pH of the water layer was not less than 6.8, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was triturated with ether (500 mL). The precipitated crystals were filtered and dried under reduced pressure to a constant weight to give 93.4 g (85% yield) of crude crystalline product. A solution of the product in acetonitrile was passed through Celite and evaporated under reduced pressure The crystalline residue was recrystallizated from methanol (2 L) gave 83.6 g (76.2% yield) of compound [4a] with mp 134-135° C. and [α]D20−141.7° (c 1.26, MeCN). 1H NMR (CDCl3, δ) 2.32-2.63 (m, 3H); 2.84-2.97 (m, 7H); 5.00-5.10 (m, 1H); 5.20-5.35 (m, 1H); 6.20 (d, J=16 Hz, 1H); 6.65 (dd, J=16 and 8 Hz, 1H); 7.15-7.67 (m, 12H); 8.03 (d, J=8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH2:25]N)=[CH:4][CH:3]=1.[C:27]([BH3-])#[N:28].[Na+]>CO.C1(=O)CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH2:25][NH:28][CH:27]2[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]2)=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: NCc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C1CCCCC1
Product: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(CNC4CCCCC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
C-[9-(4-Chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purin-6-yl]-methylamine I-(16A-1)b (19 mg, 0.047 mmol) was dissolved in methanol (1 ml) and to it was added cyclohexanone (1 drop) and acetic acid (1 drop). The reaction mixture was stirred at room temperature for 0.5 hour. and then sodium cyanoborohydride was added (5 mg) and the stirring continued until the reaction was complete (2 hours). The reaction mixture was concentrated and the residue diluted with saturated NaHCO3 solution and extracted into ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and 5% methanol in ethyl acetate as the solvent to give title compound 16A-1. The residue was dissolved in methylene chloride and treated with 2M HCl/ether to form the desired HCl salt. Ether was added to the reaction mixture to precipitate the product. The excess ether was decanted and the crystals pumped to dryness on high vacuum to afford the hydrochloride salt of compound 16A-1 (6.8 mg, 30%): +ESI MS (M+1) 486.6; 1H NMR (500 MHz, CD3OD) δ 9.07 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.8, 2.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 4.94 (s, 2H), 3.35 (m 1H), 2.28 (br d, J=12.4 Hz, 2H), 1.96 (br d, J=13.5 Hz, 2H), 1.78 (br d, J=13.0 Hz, 1H), 1.60–1.20 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][O:11][C:4]2[CH:5]=[CH:6][C:7]([CH:9]=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1OCCCCc1ccccc1
Yield: 37.5 %

Procedure:
A mixture of 860 mg of vaniline, 1.00 g of 4-bromobutylbenzene, 1.00 g of potassium carbonate and 8 ml of 2-butanone was heated under reflux for 3 hours. The reaction mixture was poured into water and the product was extracted with ether. The ethereal layer was washed with water, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 500 mg of 4-(4-phenylbutoxy)-3-methoxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:5][N:6]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O.[OH-].[Na+]>CN(C)C=O>[CH2:9]([N:8]([CH2:7][C:4]1[S:3][C:2]2=[N:1][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][N:6]2[N:5]=1)[CH2:11][CH3:12])[CH3:10]
Reactant: CCN(CC)Cc1nnc(N)s1
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1

Procedure:
18.6 g (0.1 mol) of 2-amino-5-diethylaminomethyl-1,3,4-thiadiazole and 19.9 g of ω-bromo-acetophenone in 70 mL of dimethylformamide are warmed at 150° C. for 3 hours. 150 ml of water are added to the cooled reaction mixture and the mixture is neutralised with 20% strength sodium hydroxide solution. The precipitate is filtered off with suction. After recrystallisation from acetonitrile, 11.5 g (40.2%) of melting point 138° C. remain.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Br:27][C:21]1[CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:18]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (300 mg, 1.36 mmol), 2,5-dibromo-3-nitropyridine (383 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), Na2CO3 (4.3 mL, 2 M aqueous), 4.3 mL toluene, and 2.1 mL EtOH was vigorously stirred at 55° C. for 2 h. After cooling to rt, the volatiles were removed under reduced pressure and the residue was purified with silica chromatography (EtOAc in hexane, 5% to 35%) to afford 4-(5-bromo-3-nitropyridin-2-yl)phenol as a yellow wax (285 mg, 71%). MS (ESI) m/z [M+H]+295, 297.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][NH:6][C:5]2=[O:10].[CH2:11]([I:13])[CH3:12]>C(#N)C>[I-:13].[CH2:11]([N+:2]1[CH:1]=[C:9]2[N:4]([C:5](=[O:10])[NH:6][CH2:7][CH2:8]2)[CH:3]=1)[CH3:12]
Reactant: O=C1NCCc2cncn21
Reactant: CCI
Solvent: CC#N
Product: CC[n+]1cc2n(c1)C(=O)NCC2
Product: [I-]
Temperature: 120 °C
Reaction time: 1 h

Procedure:
7,8-Dihydro-6H-imidazo[1,5-c]pyrimidin-5-one (1.00 g, 7.30 mmol) and ethyl iodide (3.42 g, 21.90 mmol) are placed in a 10-20 mL microwave vial. Acetonitrile (10 mL) is added and the reaction mixture is heated to 120° C. using microwave radiation. The reaction is shown to be complete by NMR after 1 hour. The crystalline material is filtered off and washed with ice-cold acetonitrile to give the title compound. 1H nmr (MeOD, 400 MHz); 7.60 (s, 1H), 4.35 (q, 2H), 3.65 (t, 2H), 3.15 (t, 2H), 1.60 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:19])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCCC1
Reactant: Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Product: Clc1ncnc2cc(OCCCN3CCCC3)cc(OC3CCOCC3)c12
Yield: 79.9 %

Procedure:
Using an analogous procedure to that described in Note [6] below Example 19, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.112 g) was reacted with 1-(3-hydroxypropyl)pyrrolidine (0.062 g) to give 4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.125 g); NMR Spectrum: (CDCl3) 1.7-1.9 (m, 4H), 1.95-2.2 (m, 6H), 2.55 (br s, 4H), 2.65 (m, 2H), 3.65-3.75 (m, 2H), 4.0-4.1 (m, 2H), 4.2 (m, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.95 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[C@@H:36]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:40][O:39][C:38]4=[O:41])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)OC[C@@H]4Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (S)-4-benzyl-oxazolidin-2-one.
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:8])([OH:7])[CH2:5][CH3:6])[CH3:3].C[Li].Cl[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].O>O1CCCC1.C(OCC)C>[C:12](=[O:13])([O:14][CH2:15][CH:16]=[CH2:17])[O:7][C:4]([CH3:8])([CH2:5][CH3:6])[CH:2]([CH3:3])[CH3:1]
Reactant: C=CCOC(=O)Cl
Reactant: CCC(C)(O)C(C)C
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)OC(C)(CC)C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of 11.62 grams (0.1 mole) of 2,3-dimethylpentan-3-ol in 75 milliliters of anhydrous tetrahydrofuran at 0° C was added one equivalent of methyllithium in diethyl ether, followed by 12.1 grams (0.10 mole) of allyl chloroformate in 25 milliliters of anhydrous tetrahydrofuran. During both additions the temperature was maintained at 0° C. After the last addition was complete the reaction mixture was stirred for about 18 hours and allowed to warm to ambient temperature. The reaction mixture was poured into water, and then extracted with ether. The ether solution was washed four times with water and dried over magnesium sulfate. Removal of solvent under reduced pressure yielded 18.27 grams (93.1% crude yield) of a yellow oil. Vacuum distillation gave 10.79 grams of 2,3-dimethylpent-3-yl allyl carbonate, b.p. 59°-60° C/0.15 mm.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](O)=[O:12])[C:6]1=[O:14])(=O)C.O[N:16]1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH2:16])=[O:12])[C:6]1=[O:14]
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Reactant: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.64 g of dicyclohexylcarbondiimide dissolved in 20 ml of chloroform are added at room temperature to 1.5 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid, 40 ml of chloroform and 0.86 g of N-hydroxysuccinimide. After 4 hours, the solid is filtered, whereupon the filtrate is concentrated and again filtered. The filtrate is evaporated. The residue is treated at room temperature with 40 ml of a saturated solution of ammonia in methanol. The mixture is stirred at room temperature for 5 minutes, 10 ml of ion-free water are then added thereto and the mixture is stirred at room temperature for an additional minutes. The precipitated solid is filtererd. The filtrate is evaporated, the residue is stirred in 30 ml of acetonitrile and the crystallized-out product is recrystallized two more times from acetonitrile. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 162°-164°.
Reaction SMILES: C([NH:8][C@@H:9]([C:13](O)=O)[C@@H:10]([CH3:12])[OH:11])(OC(C)(C)C)=O.[CH3:16][CH:17]([C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1)[CH3:18]>>[NH2:8][C@@H:9]([C:13]1[NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH:17]([CH3:18])[CH3:16])=[CH:20][C:21]=2[N:26]=1)[C@H:10]([OH:11])[CH3:12]
Reactant: C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc(N)c(N)c1
Product: CC(C)c1ccc2[nH]c([C@H](N)[C@@H](C)O)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-D-allo-threonine (Preparation 55) and 4-(1-methylethyl)-1,2-benzenediamine. The residue was purified using preparative HPLC using the following conditions:
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:39]CC1C=CC=CC=1)[C@H:10]([C@@H:19]([C@@H:28]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:11]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.N1C=CN=C1.[C:73]1([CH3:79])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.C(#N)C>>[CH2:79]([O:11][C@H:10]1[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[S:39][CH:9]1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: Cc1ccccc1
Reactant: O[C@H](COCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(SCc1ccccc1)SCc1ccccc1
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: c1ccc(COC[C@@H]2SC(SCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 4 (13.0 g, 20 mmol) in dry 2:1 toluene/acetonitrile (200 mL) were added triphenylphosphine (15.7 g, 60 mmol), iodine (12.7 g, 50 mmol) and imidazole (5.44 g, 80 mmol). The reaction mixture was stirred at 90° C. for 24 hours after which time the solution was evaporated to dryness. The crude product was purified by silica gel chromatography (cyclohexane/EtOAc, 4:1) to afford benzyl 2,3,5-tri-O-benzyl-1,4-dithio-L-Xylofuranoside as a syrup (5, 9.0 g, 72%). MS 543 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:25])[C:12]([CH3:24])=[C:13]([CH:16]([OH:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:14]=2[CH3:15])=[O:9])=[CH:4][CH:3]=1.[Cl:26]C1C=CC(C(C2N(C)C=C(C(C3[NH2+]CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3)=O)C=2)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:25])[C:12]([CH3:24])=[C:13]([CH:16]([OH:23])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:14]=2[CH3:15])=[O:9])=[CH:4][CH:3]=1.[ClH:26]
Reactant: Cn1cc(C(=O)C2=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[NH2+]2)cc1C(=O)c1ccc(Cl)cc1
Agent: Cc1c(C(O)c2ccncc2)c(C)n(C)c1C(=O)c1ccc(Cl)cc1
Product: Cl

Procedure:
By the method of Procedure 7 substituting (4-chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl )-1,3,5-trimethyl-1H-pyrrol-2-yl]-methanone for 5-[[2-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-4-yl]carbonyl]-3-(triphenylmethyl)-1H-imidazolium the title compound was prepared. Treatment with ethereal HCl gave 35% yield of the hydrochloride salt. Mp. 174-176° C. ES-MS m/z=353 (M++H). 1HNMR (CDCl3) δ 8.9 (ar, 2H); 8 (ar, 2H); 7.7 (ar, 2H); 7.5 (ar, 2H); 3.75 (s, 3H); 2.3 (s, 3H); 2.65 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1.[ClH:41].COC(C)(C)C>CC(O)C.O1CCOCC1>[ClH:41].[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-[({7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e1 (2.72 g; 4.95 mmol) is dissolved in dry 2-propanol (50 mL). After addition of 4M HCl in dioxane (5.0 mL) the stirred reaction mixture is heated to 80° C. for two hours. At ambient temperature tert.-butyl methyl ether (100 mL) is added. The precipitated product is isolated by suction filtration, washed with several portions of tert.-butyl methyl ether and dried in high vacuo at 40° C. to yield of the title compound as yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[ClH:12].[NH2:13][OH:14]>CO>[ClH:12].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:13][OH:14])[CH2:6]2
Reactant: CN1C2CCCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CO
Product: CN1C2CCCC1CC(=NO)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) d 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[O:15][CH2:14][C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[CH2:7]1)(=O)C.C[O-].[Na+].Cl.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>CO.O1CCOCC1>[CH3:27][S:28]([O:4][CH2:5][C@@H:6]1[O:15][CH2:14][C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[CH2:7]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate (0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol) of sodium methoxide (25% wt. in methanol) dropwise at room temperature. After 5 min., 1.6 mL (6.43 mmol) of 4.0M hydrogen chloride in dioxane was added and a pink precipitate formed. The solution was concentrated in vacuo and the pink solid was taken up in 30.0 mL dichloromethane. This slurry was cooled in an ice bath and triethylamine (3.0 mL, 21.5 mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71 mmol). The resultant yellow solution was stirred for 30 minutes at room temperature. The mixture was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate then the aqueous layer was extracted (3×50 mL dichloromethane). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide crude (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl methanesulfonate which was taken on to the following reaction without purification.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc2ncccc2c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and quinolin-6-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C21H21NO5 [M+H]+: 368.3.