Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:11](O)=[O:12])#[N:2].[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:39][CH2:40][N:41]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=[C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][CH:28]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)[CH2:42][CH2:43]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc(C#N)c3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(OCc3cccc(C#N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 59.7 %

Procedure:
Following the procedure of Example 5(c) 3-(3-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.75 g (2.02 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.46 g, 2.02 mmol) were used to afford 0.7 g of the required product. Percentage purity (LCMS): 62.3%, (M+1)=480.2+1 (de-Boc mass, −100).
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[CH2:14]([S:15]([NH2:2])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CN1CCOCC1
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To a solution of 5 (7.54 g, 0.0298 mole; see Example 5) and 4-methylmorpholine (9.04 g, 0.0894 mole, 9.83 mL) in 300 mL of anhydrous acetonitrile at 0° C. under N2 was added α-toluene-sulfonyl chloride (11.36 g, 0.0596 mole) in one portion. The solution was stirred at 0° C. for 1 hour and allowed to warm to and stir at ambient temperature for 19 hours. The solution was filtered and evaporated. The crude residue was purified by flash chromatography on silica gel using a hexane, CH2Cl2 : 4,1 to CH2C12 gradient system and afforded 12.05 g (99% yield) of product 6 as waxy reddish solid, mp 62-63° C. TLC (silica; CH2Cl2), Rf=0.45.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25]C)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NCCc1ccccc1O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
620 mg (1.54 mmol) of 4-(4-fluorophenoxy)-N-[2-(2-methoxyphenyl)ethyl]benzene-sulfonamide are dissolved in 10 ml of dichloromethane and, at −40° C., 3.09 ml (3.09 mmol) of a 1 M solution of boron tribromide in dichloromethane are added. The solution is warmed to room temperature and stirred for a further four hours. It is subsequently added to water, the phases are separated, and the organic phase is washed twice more with H2O. The dichloromethane phase is dried with MgSO4 and concentrated, allowing the desired phenol to be isolated as a brown oil. Crude yield 89%.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:10]=1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 80.7 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.07 g), 1-{5-chloro-2-[(1-methylethyl)sulfonyl]phenyl}methanamine hydrochloride obtained in Step 3 (3.0 g) and potassium carbonate (3.65 g) were stirred in ethanol (50 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (3 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.56 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(CC(=O)O)on1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)on1

Procedure:
Following General Procedure I' above, and using (3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([CH2:30][CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CCc1ccccc1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (2 g) was dissolved in dimethylformamide (50 ml). Potassium carbonate (0.5 g) was added followed by (2-bromoethyl)benzene (2.7 g). The mixture was stirred at 95° C. overnight, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 2.3 g, (84%) of product. Recrystallization from methanol gave the analytical sample, mp 157°-158° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13].[CH3:31][O:32][C:33]1[CH:61]=[CH:60][C:36]([C:37](C2C=CC=CC=2NC(=O)CNC(NC2C=C(C)C=CC=2)=O)=[O:38])=[CH:35][CH:34]=1>>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:37](=[O:38])[C:36]1[CH:60]=[CH:61][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2I)c1
Reactant: COc1ccc(C(=O)c2ccccc2NC(=O)CNC(=O)Nc2cccc(C)c2)cc1
Product: COc1ccc(C(=O)c2ccccc2N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)cc1

Procedure:
According to the synthesis method of the compound 24, the compound 42a is used to synthesize the titled compound. Mp, 228°-230° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:26]1([C:32]2[C:33]([C:41]3[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=3)=[N:34][C:35]3[N:36]([N:38]=[CH:39][CH:40]=3)[CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.ClCCl.CN(C=O)C>[C:26]1([C:32]2[C:33]([C:41]3[CH:42]=[CH:43][C:44]([CH2:45][N:2]4[CH2:3][CH2:4][CH:5]([C:8]5[NH:9][C:10]6[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:11]=6[N:12]=5)[CH2:6][CH2:7]4)=[CH:47][CH:48]=3)=[N:34][C:35]3[N:36]([N:38]=[CH:39][CH:40]=3)[CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Reactant: N#Cc1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2nc(C3CCN(Cc4ccc(-c5nc6ccnn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
265 mg (1 mmol) 2-piperidine-4-yl-3H-benzimidazole-5-carbonitrile hydrochloride salt was dissolved in 5 mL methanol. 204 mg (2 mmol) triethylamine, 250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde, 5 mL DMF, 12.5 mL dichloromethane and 131 mg (2.2 mmol) acetic acid were added and after 30 minutes stirring 355 mg (1.68 mmol) NaBH(OAc)3 was added. Additional NaBH(OAc)3 has been added after one, two, three and four hours (two equivalents each) and the reaction mixture has been stirred overnight at room temperature. Usual work-up and purification as described in previous experiments yields 138 mg of the desired material.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O[CH2:23][C:24]23[CH2:31][CH2:30][C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:33]=4)([CH2:28][CH2:29]2)[O:26][CH2:25]3)(=O)=O)=CC=1.[NH4+].[Cl-]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[O:38]([C:34]1[CH:33]=[C:32]([C:27]23[CH2:30][CH2:31][C:24]([CH2:23][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH2:29][CH2:28]2)[CH2:25][O:26]3)[CH:37]=[CH:36][CH:35]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Product: CCOC(=O)C(CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Sodium (5 mg, 0.215 mmol) was dissolved in EtOH (2 mL) to form a solution of NaOEt and then diethyl malonate (0.033 mL, 0.215 mmol) was added. The reaction mixture was stirred at rt for 30 min and (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (10 mg, 0.022 mmol) was then added. The reaction was stirred at 120° C. under microwave conditions for 30 min. Catalytic amount of n-Bu4NI was added and the reaction was stirred at 120° C. under microwave conditions for 18 h. The reaction was added sat′d aq NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (8 mg, 82% yield) as a clear oil. LCMS, [M-Et+H]+=425.4.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OC(C)C)(C)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:28]([C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]3[CH2:7][CH2:8][CH2:9][CH2:10]3)[C:27]=2[CH:26]=1)=[O:30]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
Thionyl chloride (3.6 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (2.7 g) in methylene chloride (70 cc). The suspension is stirred for 3 hours at 25° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up with methylene chloride (50 cc) at 5° C. 3-Chlorobenzylamine (6.9 g) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a brown oil which is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica (0.06-0.2 mm), eluting with methylene chloride (1 liter) and collecting 40-cc fractions. Fractions 12 to 24 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a cream-coloured solid which is taken up in isopropyl ether (20 cc). The solid is separated by filtration, washed with isopropyl ether (2×5 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-(3-Chlorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (2 g) is obtained in the form of a yellow solid, m.p. approximately 80° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH:20]3[CH2:22][CH:17]2[CH2:18][N:19]3C(=O)C)=[CH:13][CH:12]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:19]1[CH2:18][C@@H:17]2[CH2:22][C@H:20]1[CH2:21][N:16]2[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:27][CH:26]=1)(=[O:38])=[O:37]
Reactant: CC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.2 %

Procedure:
To a solution of 1-[5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone (0.2 g, 0.49 mmol) in CH2Cl2 (5 mL) was added Et3N (0.41 mL, 3.0 mmol) and methanesulfonyl chloride (57 μL, 0.74 mmol) and the resulting solution was stirred at rt for 14 h. The reaction mixture was concentrated and the crude residue was partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was separated, dried (Mg2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 15% CH3OH in CH2Cl2) afforded the title compound as clear oil (0.13 g, 62%). MS (ESI): mass calcd. for C21H23N3O2S2, 413.56; m/z found, 414.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.8, 0.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (d, J=2.0 Hz, 2H), 4.31 (br s, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.75 (d, J=13.8 Hz, 1H), 3.62-3.60 (m, 1H), 3.57 (br s, 1H), 3.24 (dd, J=9.3, 2.3 Hz, 1H), 2.90-2.89 (br m, 4H), 2.85-2.83 (br m, 1H), 1.96-1.94 (m, 1H), 1.74-1.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[NH:5][C:6]=1[Cl:7].Br[CH2:12][C:13]1[CH:32]=[CH:31][C:16]2/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=3[O:20][CH2:21][C:15]=2[CH:14]=1>>[Cl:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[N:5]([CH2:12][C:13]2[CH:32]=[CH:31][C:16]3/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=4[O:20][CH2:21][C:15]=3[CH:14]=2)[C:6]=1[Cl:7]
Reactant: CC(C)c1nc(Cl)c(Cl)[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(C)C)nc(Cl)c3Cl)cc2COc2cc(F)ccc21
Yield: 90.6 %

Procedure:
[step 2] Using 4,5-dichloro-2-isopropyl-1H-imidazole (68 mg, 0.381 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (130 mg, 0.363 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (150 mg, 91%) was obtained.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C@H:8]1[C@@H:12]([O:13][C:14]([CH3:16])=[O:15])[CH2:11][O:10][CH2:9]1.N1C=CC=CC=1.ClCCl>O>[C:14]([O:13][C@H:12]1[CH2:11][O:10][CH2:9][C@H:8]1[O:7][C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])(=[O:15])[CH3:16]
Reactant: CC(=O)O[C@H]1COC[C@H]1O
Reactant: CC(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1COC[C@H]1OC(=O)C(C)Cl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
12.4 g of (±)-2-chloropropionyl chloride were added dropwise at 0°-5° C. to an ice-cooled mixture of 15.0 g of (±)-(3R,4S)-3-hydroxy-4-methylcarbonyloxytetrahydrofuran, 8.1 g of anhydrous pyridine and 200 ml of anhydrous dichloromethane. After addition was complete, the reaction mixture was stirred at 23° C. for a further 4 hours, after which it was poured onto 400 ml of water. The organic phase was then separated off, washed twice with 50 ml of water each time, dried over sodium sulfate and finally concentrated. The crude product was purified by distillation at a pressure of 10 mbar.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2n1C1CCCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC(C)C)nc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (210 mg) in dry MeOH (2.1 mL) was added TFA (0.21 ml) and the mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to give a yellow residue which was triturated with Et2O (15 mL) and filtered under reduced pressure to give the title compound as an off-white solid (143 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=1)=[O:7])[CH3:4].[CH2:14](I)[CH2:15][CH2:16][CH3:17]>C(#N)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:10]=[C:11]([NH2:13])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc(N)[nH]n1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCn1nc(N)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (920 mg, 21 mmol) was added to a solution of 5-aminopyrazol-3-carboxylic acid ethyl ester (3.10 g, 20 mmol) in acetonitrile (100 mL) under a nitrogen atmosphere, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, and butyl iodide (2.3 mL, 20 mmol) was then added thereto. The obtained mixture was stirred at room temperature for 1 hour, and then at 60° C. for 1 hour. The reaction solution was left at room temperature overnight. Thereafter, the solvent was distilled away, and water was then added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated saline, and it was dried over sodium sulfate and was then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (1.60 g, yield: 38%) in the form of a pale yellow oily substance.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(Br)ccc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Bromo-2-chloro-benzoic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:32]=[N+:33]=[N-:34])=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCl)c(F)c3)oc2c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CN=[N+]=[N-])c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-(chloroacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.00 g, 2.20 mmol) in dimethylformamide (50 mL) was added sodium azide (715 mg, 11 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added thereto, and the crystals precipitated were collected by filtration to afford 7-(acetoxymethyl)-5-amino-2-[4-(azidoacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.01 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].[OH-].[NH4+:24]>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([NH2:24])=[O:21]
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 2 h

Procedure:
To 3.5 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride is added 50 ml of conc ammonium hydroxide at 0° C. After stirring for 2 hr the precipitate is filtered and washed with ice-cold acetonitrile. Recrystallization of the filter cake from acetonitrile gives {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp 172° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.