Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][O:15][N:16]=[C:17]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][CH2:29][S:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH3:18])=[CH:11][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:32][C:20]1[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][CH2:29][S:28][CH2:27]2)[CH2:23][C:24](=[O:25])[C:19]=1[C:17](=[N:16][O:15][CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
In this example, 0.52 g (5.1 mmol) of triethylamine was admixed to a solution containing 1.46 g (3.7 mmol) of 2-[1-[(5-chlorothien-2-yl)methoxyimino]ethyl]-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one in 30 ml of methylene chloride at room temperature (about 20°-25° C.) followed by the dropwise addition of 0.35 g (4.4 mmol) of acetyl chloride. The mixture was stirred at room temperature overnight (about 14 hr) and then washed with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica gel to afford 1.0 g of the title compound as a pale yellow oil; IR (neat) 1775 cm-1 ; 1H NMR spectrum (90 MHz CDCl3) ε 1.00-2.60 (m, 14H), 1.93 (s, 3H), 2.00 (s, 3H), 5.07 (s, 2H) 6.73 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].C1(C)C(C)=CC=CC=1.C[Sn]([N:23]=[N+:24]=[N-:25])(C)C>CO>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]2[NH:25][N:24]=[N:23][N:7]=2)[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 135 °C
Reaction time: 8 h

Procedure:
The mixture consisting of 1.07 g of 4-amino-3-chlorobenzonitrile, 30 ml of xylene and 1.7 g of trimethyltin azide was stirred at 135° C. for 8 hours. After cooling, 25 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and the volatile constituents were removed on a rotary evaporator. On stirring, a solid precipitated out of the mixture obtained in this way, and was filtered off with suction and briefly dried under reduced pressure. This solid was dissolved in 1N sodium hydroxide solution and filtered, and the product was precipitated by acidifying with 2N hydrochloric acid, filtered off with suction and dried under reduced pressure.
Reaction SMILES: O[CH:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[BH4-].[Na+]>>[CH3:13][O:12][C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:2]=2
Reactant: COC(=O)CC1CCc2cc(OC)ncc2C1O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cc1ccc2cc(OC)ncc2c1

Procedure:
5-Aza-6-loweralkoxytetralone (Tetrahedron Letters No. 1, pp. 87-90, 1966) and 7-aza-6-loweralkoxytetralone (Tetrahedron Letters No. 9, 623, 1975) are suitable precursors for initiating the above indicated reaction Scheme I. In accordance with Scheme I 7-aza-6-methoxytetralone is reacted with glyoxylic acid to provide 7-aza-2-carboxyhydroxymethyl-6-methoxy-1-tetralone and this compound is dehydrated by heating in base to provide 7-aza-6-methoxy-α-carboxymethylidene-1-tetralone. This latter tetralone is reduced with zinc/acetic acid to provide 7-aza-2-carboxymethyl-6-methoxy-1-tetralone and acid catalysed esterification with methanol and sulfuric acid provides 7-aza-6-methoxy-2-methoxycarbonylmethyl-1-tetralone. 7-Aza-6-methoxy-2-methoxycarbonylmethyl-1-tetralone to methyl 8-hydroxy-3-methoxy-5,6,7,8-tetrahydro-2-azanaphthalene-7-acetate by reaction with sodium borohydride and reaction of this product with Pd(C)/anisole provides methyl 3-methoxy-2-azanaphthalene-7-acetate which is alkylated with methyl iodide and base to provide methyl 3-methoxy-2-azanaphthalene-7-α-methylacetate and hydrolysis of this ester provides 3-methoxy-2-azanaphthalene-7 -α -methylacetic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[O:10][C:9]([C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([F:1])([F:13])[F:14])=[N:11][N:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1cnccc1C(F)(F)F
Product: Cc1nnc(-c2cnccc2C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg of 4-trifluoromethylnicotinic hydrazide were heated under reflux in 3.5 ml of triethyl orthoacetate for 2 hours. The reaction mixture was subsequently concentrated and the residue was carefully admixed with 2 ml of phosphorus oxychloride. The mixture was stirred at room temperature for 1 hour and then poured on ice and extracted with ethyl acetate. Chromatographic purification of the crude product obtained after drying and concentrating gave the desired compound as a yellowish oil.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.C.[OH2:13]>>[O:9]=[C:5]1[NH:4][CH:8]([CH2:1][CH2:2][C:3]([OH:10])=[O:13])[CH2:7][CH2:6]1
Reactant: O
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: O=C(O)CCC1CCC(=O)N1
Temperature: 100 °C

Procedure:
A suspension (partial solution) of 25 g of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) in 150 ml of deionized water is treated with 0.1 ml of concentrated hydrochloric acid. The mixture is heated to reflux (100° C.) for 80 hours. Charcoal (0.5 g) is added and the mixture is filtered through filter aid. The solution is concentrated at reduced pressure, the 5-oxo-2-pyrrolidinepropanoic acid crystallizes and is isolated by filtration. After drying in vacuo the 5-oxo-2-pyrrolidinepropanoic acid has a melting point of 125°-127° C.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[O:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[O:11]1[CH:10]=[CH:9][CH:13]=[C:12]1[CH:14]([OH:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccco1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.96 g (10 mmol) of 2-furfural in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×3) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.77 g of the desired product (yield 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrCCCBr
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(F)c(OCCCBr)c1
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of 2,5-difluorophenol (2.60 g, 20.0 mmol), 1,3-dibromopropane (20.3 mL, 200 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in acetonitril (30 mL) was heated at 80° C. overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4.82 g of the title compound as a light yellow oil with a purity of ca. 80%. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[N:33]=[N:34][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:36][CH:37]=1)=[O:31]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nn1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 196 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) by alkylation with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No. 65202-50-8]. MS (m/e)=538.2 [M+H+].
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13]([OH:15])=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.[CH3:17]O.S(=O)(=O)(O)O>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13]([O:15][CH3:17])=[O:14])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CO
Reactant: Cc1ccc(N2CC(C(=O)O)CC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C1CC(=O)N(c2ccc(C)cc2)C1

Procedure:
1-(4-Tolyl)-5-oxo-3-pyrrolidinecarboxylic acid (45.50 g) is suspended in methylene chloride (460 ml) and thereto are added methanol (50.5 ml) and conc. sulfuric acid (0.77 ml) and the mixture is refluxed for 19 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the resulting residue is neutralized by adding water and aqueous sodium hydrogen carbonate solution thereto. The precipitated crystal is collected by filtration and washed with water to give the desired product (46.07 g), m.p. 71°-74° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([NH:27][C@H:11]1[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]1[O:5][CH2:4][CH2:3][CH2:2][F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(OCCCF)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCCCF)C1
Yield: 86.6 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-(3-fluoropropoxy)-4-oxopiperidine-1-carboxylate obtained in Example (127b) (1.71 g, 6.21 mmol), benzylamine (0.75 g, 7 mmol), sodium (triacetoxy)borohydride (2.54 g, 12 mmol) and 1,2-dichloroethane (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 1.97 g of the title compound as a colorless oily substance (87%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and propionyl chloride. m.p.: 152-155° C. 1H-NMR (CDCl3) δ: 10.02 (1H, br s), 8.36-8.20 (2H, m), 7.63-7.51 (2H, m), 7.48-7.38 (2H, m), 7.28 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.50 (2H, q, J=7.7 Hz), 2.46 (3H, s), 1.29 (3H, t, J=7.7 Hz)
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:20]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCC1
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added cyclobutanone (17 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E26). MS (ES+) m/e 311 [M+H]+.
Reaction SMILES: OC1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3O)C(=O)C=2C([N+]([O-])=O)=CC=1.N[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=1.NC1C=CC(C(CO)CO)=CC=1.NC1C=CC(C)=CC=1.COCCOCCO>>[CH:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][OH:34])=[CH:30][CH:31]=1
Reactant: Nc1ccc(CCO)cc1
Agent: Nc1ccc(C(CO)CO)cc1
Agent: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Solvent: COCCOCCO
Solvent: Cc1ccc(N)cc1
Product: OCCc1ccccc1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 19.4 g of 1,8-dihydroxy-4,5-dinitroanthraquinone, 25.0 g of a mixture consisting of about 72 % of 2-(4-aminophenyl)-ethanol, about 22 % of 2-(4-aminophenyl)propane-1,3-diol, about 3 % of 4-toluidine and by-products, and 140 g of diethylene glycol monomethyl ether is heated to 130° C. over a period of 2.5 hours. Stirring at 130-135° C. is continued for 6 hours, during which the water of the reaction is separated off by distillation. The reaction mixture is cooled to 100° C. and stirred into a mixture of 250 g of water, 250 g of ice and 110 g of 32 % hydrochloric acid. This crude dye suspension is filtered at about 20° C., and the product is washed with about 3 liters of water. After drying, 27 g of a dye mixture containing 65 % of the dye of the formula ##STR12## 13 % of the dye of the formula ##STR13## 3 % of the dye of the formula ##STR14## 7% of 1,8-dihydroxy-4-nitro-5-aminoanthraquinone, and 2-phenylpropane-1,3-diol and phenylethanol is obtained.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](OC(=O)C)(=[O:11])C>C(O)=O>[CH:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:11]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.0 g (0.0434 mol) of L-proline in 92 ml of 97% formic acid maintained at 5°-10° was slowly added 30 ml of acetic anhydride. The solution was stirred for 2 hr. at room temperature followed by the addition of 35 ml of ice-cold water. Evaporation of the mixture afforded (S)-(-)-N-formylproline ([α]D2: =-105°, c=2.885, methanol), a clear, viscous, pale-yellow oil utilized directly in the next step. The (S)-(-)-N-formylproline was reduced by adding a solution of it in 20 ml of tetrahydrofuran to a slurry of 8.23 g (0.217 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran under a nitrogen atmosphere. The addition was regulated such that a gentle reflux was maintained. Following addition, the mixture was refluxed for 48 hr. After cooling, the mixture was carefully treated with 8.3 ml of water, followed by 8.3 ml of 15% aq. sodium hydroxide, and finally 25 ml of water. The grey-white mixture was filtered, and the filtrate dried with magnesium sulfate and evaporated to an oil. Bulb to bulb distillation [oven temp 40°-55° (0.15 torr)] afforded 2.823 g of V (57% yield based on L-proline). The optical rotation was identical with that obtained by the synthesis via L-prolinol.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Clc1ccncn1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccncn2)C3)cc1

Procedure:
Compound (dw) was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 4-chloropyrimidine. LC-MS: m/z=+475 (M+H)−.
Reaction SMILES: [CH3:1]N(C)C(N1CC=C(C2NC3N=CN=C(C4C=C(F)C=C(N)C=4C)C=3C=2)CC1)=O.C1C2C(Cl)=NC=NC=2NC=1.CN(C)C(N1CC=C([C:50]2[NH:81][C:53]3[N:54]=[CH:55][N:56]=[C:57]([C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([N:64]5CC[C:71]6[C:66](=[CH:67][CH:68]=[C:69]([C:74](O)([CH3:76])[CH3:75])[CH:70]=6)[C:65]5=[O:78])[C:59]=4[CH2:79]O)[C:52]=3[CH:51]=2)CC1)=O>>[C:74]([C:69]1[CH:68]=[CH:67][C:66]([C:65]([NH:64][C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:57]3[C:52]4[CH:51]=[CH:50][NH:81][C:53]=4[N:54]=[CH:55][N:56]=3)[C:59]=2[CH3:79])=[O:78])=[CH:71][CH:70]=1)([CH3:1])([CH3:76])[CH3:75]
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(N5CCc6cc(C(C)(C)O)ccc6C5=O)c4CO)ncnc3[nH]2)CC1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Agent: Clc1ncnc2[nH]ccc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]ccc12

Procedure:
Intermediate 51 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with 6-chloro-7-deazapurine and Intermediate 5 with Intermediate 48.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[S:19][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:18]3[S:19][CH:20]=[C:16]([CH3:15])[N:17]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Cc1csc(-c2sccc2N)n1
Product: Cc1csc(-c2sccc2NC(=O)Cc2cccc3cnccc23)n1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (63 mg, 0.341 mmol) and 2-(4-methylthiazol-2-yl)thiophen-3-amine (67 mg, 0.341 mmol) according to protocol A. Retention time (min)=3.130, method [7], MS(ESI) 366.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.55 (s, 1H), 9.64 (s, 1H), 8.60 (d, J=6.8 Hz, 1H), 8.39 (d, J=6.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.05-8.08 (m, 2H), 7.88-7.91 (m, 1H), 7.24 (d, J=5.5 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:31][S:32]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:28])[CH3:29])[CH:21]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: CC(C)Oc1cccc(CC(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cccc(CC(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
1.81 g (4.00 mmole) of 2-{(2R)-(3,4-dichlorophenyl)-4-[(3-isopropoxyphenyl)acetyl]morpholin-2-yl}ethanol [prepared as described in step (a) above] were dissolved in 5 ml of pyridine, and 45 mg (0.40 mmole) of 4-dimethylaminopyridine and 0.46 ml (6.00 mmole) of methanesulfonyl chloride were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at 0° C. for 2 hours under a nitrogen atmosphere. At the end of this time, the reaction mixture was poured into ice-cooled 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:1 to 1:2 by volume as the eluent, to give 2.00 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26](=[CH2:32])[CH2:27][C@@H](O)CO>ClCCl>[I:25][C:26](=[CH2:27])[CH2:32][C@@H:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1
Reactant: C=C(I)C[C@@H](O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(I)C[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate (PPTS) are added to a solution of (R)-4-iodopent-4-ene-1,2-diol in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11.5 g, 38.4 mmol), imidazole (7.84 g, 115.2 mmol) and DMAP (234 mg, 1.92 mmol) in CH2Cl2 (200 mL) was added a solution of TBSCl (8.68 g, 57.6 mmol) in CH2Cl2 (100 mL) dropwise. The reaction mixture was stirred at rt for overnight. The reaction was washed with water (100 mL) and the aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (9 g, 57%).