Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46].N1C=CC=CC=1.Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([NH:43][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(NS(C)(=O)=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 108.7 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene (126 mg) obtained in Example 197-(1) was dissolved in dichloromethane (3 ml) and added thereto were methanesulfonyl chloride (48 mg) and pyridine (48 mg). The mixture was stirred at room temperature for 3.5 hours. To the mixture was added 2N hydrochloric acid aqueous solution at 0° C. and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzene (154 mg) as yellow caramel. ESI-Mass m/Z 706/708 (M−H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 50%), MS (ISP) m/z=431.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (RS)-3-methoxybutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(4-fluoro-3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.370 g, 0.73 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature 2 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[NH:23][C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH:31]([CH3:35])[C:32](=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[N:23]([CH:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(C)(C)C4=O)cc3)CC2)cc1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)N(C(C)C(C)=O)C(C)(C)C4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A mixture of 21.3 parts of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4-imidazolidinedione, 7.5 parts of 3-chloro-2-butanone, 6.0 parts of potassium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at 100° C. After cooling, the reaction mixture was diluted with 700 parts of water. The crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. After trituration of the residue in methanol, the product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 7.77 parts (30.9%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-1-(1-methyl-2-oxopropyl)-2,4-imidazolidinedione; mp. 225.9° C. (intermediate 20).
Reaction SMILES: C([C:4]1([CH2:10][N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)C.[OH-].[Na+]>[Cl-].C([N+](C)(C)CC1C=CC=CC=1)CCCCCCCCCCCCCCC.C(OCC)C>[CH2:12]([N:11]([CH2:10][CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)C1(CN(Cc2ccccc2)Cc2ccccc2)CCOC1=O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1OCCC1CN(Cc1ccccc1)Cc1ccccc1
Yield: 58 %

Procedure:
To 6.8 g of 3-acetyl-N,N-dibenzyl-3-aminomethyltetrahydrofuran-2-one, 33.8 g of diethyl ether and 0.68 g of cetyldimethylbenzylammonium chloride were added, followed by dropwise addition of 8 g of 10% by weight NaOH aqueous solution at 0° C. The resulting diethyl ether layer was separated, was concentrated under reduced pressure, the residue was subjected to column chromatography on a silica gel, was eluted with hexane-ethyl acetate and thereby yielded 3.45 g of N,N-dibenzyl-3-aminomethyltetrahydrofuran-2-one as a light yellow liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[ClH:31].[C:25]1([C:23]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:24]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3)c3nccnc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2nc(NC3CCNCC3)nc3nccnc23)cc1

Procedure:
A solution of 4-(4-phenyl-pteridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.23 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 307.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: OC/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A vigorously stirred solution of ethyl trans-3-(3-bromophenyl)-2-propenoate (26.71 g, 0.105 mol) in dry toluene (150 ml) at -5° C. (ice-EtOH) under nitrogen was treated with lithium aluminium hydride (3.98 g, 0.105 mol) in one portion. The reaction temperature was allowed to gradually warm to room temperature over 30 min., at 25° C. the reaction became quite exothermic (25°-40° C.) with the formation of a grey gelatinous precipitate. Stirring was continued for 1 h, after which the reaction was carefully quenched with water (300 ml) and ice (200 g) then allowed to stand at 25° C. for 30 min. The mixture was filtered through Celite (Registered Trade Mark) and the residue was washed with ethyl acetate (2×200 ml). The filtrate was extracted with the organic washings, the combined organic phases were washed with brine (3×300 ml), water (300 ml), dried (Na2SO4) and evaporated to give the title compound as a pale yellow oil (21.42 g, 96%). Distillation at 120° C. at 0.05 mmHg. gave a colourless oil. (Found C, 50.73; H, 4.12; Br, 37.53. C9H9BrO requires C, 50.73; H, 4.26; Br, 37.50%); νmax (thin film)/cm-1 3325.5 (br. OH), 2862.0, 1653.0, 1591.0, 1562.5; δH (270 MHz) 2.15 (1H, bs, 1-OH), 4.30 (2H, dd, 2×1-H, 3J1,2 =5.5, 4J1,3 1.5 Hz), 6.33 (1H, dt, 2-H, 3J2,3 =15.8, 3J2,1 =5.3 Hz), 6.53 (1H, dt, 3-H, 3J3,2 =16.2, 4J3,1 =1.3 Hz), 7.15 (1H, t, 5'-H, Jo =7.8 Hz), 7.26 (1H, dt, 6'-H, Jo =7.6, Jm =1.3 Hz), 7.35 (1H, dt, 4'-H, Jo =7.9, Jm =1.6 Hz), 7.50 (1H, t, 2'-H, Jm =1.6 Hz). δC (67.8 MHz) 63.2 (1-C), 122.7 (3'-C), 125.0 (2-C), 129.2 (5'-H), 138.8 (1'-C). The remaining signals fall in the narrow range 130.0 to 130.4 ppm; m/z 214.1, 212.1 (44.86,49.78, M+), 196.0, 194.0 (1.47, 1.03), 185.0, 183.0 (10.81, 12.19), 172.0, 170.0 (46.47, 49.07), 158.0, 156.0 (15.47, 15.80), 133.1, 131.1 (36.29, 25.66), 104.1 (100).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=[C:7]([Cl:14])[CH:6]=1)([O:3]C)=[O:2].[OH-].[K+]>CO>[Cl:14][C:7]1[CH:6]=[C:5]([C:1]([OH:3])=[O:2])[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc2ccoc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 7-carbomethoxy-5-chlorobenzo[b]furan (6c) (3.02 g, 14.3 mmol) containing potassium hydroxide (3.22 g) in 100 ml of aqueous methanol (CH3OH/H2O=3/2) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was acidified with conc. HCl to pH of about 1, cooled in freezer for several hours and filtered to give 7c as an off-white solid (2.65 g, 94.3%), mp 212°-215° C. NMR (DMSO-d6) δ8.0-6.87 (m, 5H, aromatic protons and OH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)C(C)C)(C)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.O>O1CCCC1>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cccc(OCCCCN)c1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(OCCCCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-(4-aminobutoxy)benzoate (4.81 g) was dissolved in 50.0 mL of tetrahydrofuran and N,N-diisopropylethylamine (2.90 g, 22.4 mmol) was added. Under cooling, 2-chlorobenzoxazole (3.44 g, 22.4 mmol) was added dropwise thereto and stirred overnight at room temperature. Following the addition of water, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:ethyl acetate=4:1) to give a compound of interest (3.22 g, 50.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][N:10]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CC(C)=O.Cl>CC(C)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][NH:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3)cc2)C(=O)O1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)NC3)cc2)C(=O)O1
Yield: 91.9 %

Procedure:
The N-trityl compound (Example 30, 0.528 g, 0.79 mM) in acetone (8 ml) at 0° C. was treated with freshly prepared HCl/acetone (4 ml) and stirred. The mixture was periodically treated with 10% HCl in water until TLC indicated consumption of starting material. The reaction mixture was then diluted with EtOAc (30 ml) and taken to pH 11 with NH4OH solution. The aqueous layer was extracted with EtOAc and the combined organics dried (MgSO4) and evaporated to a residue which was triturated with diethyl ether to give the title amine (0.309 g, 92%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][CH2:10][N:9]2[S:20]([CH3:19])(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CCN2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
To a mixture of 2-(4-bromophenyl)azetidine (200 mg, 0.808 mmol) and triethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (6 mL) was added methanesulfonyl chloride (111 mg, 0.97 mmol). The mixture was stirred at rt for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, concentrated in vacuo to give the title compound (200 mg, 85% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ7.50 (d, 2H), 7.25 (d, 2H), 5.30-5.20 (m, 1H), 420-4.00 (m, 2H), 3.63 (s, 3H), 2.70 (m, 1H), 2.15 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCN2CCOCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(4-morpholinyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-aminoethylmorpholine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[S:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].O.[OH-].[Na+].C>O1CCOCC1>[CH3:11][C:9]1[S:10][C:5]2[CH:4]=[C:3]([O:12][CH3:13])[C:2]([CH3:1])=[CH:7][C:6]=2[N:8]=1
Reactant: COc1ccc(NC(C)=S)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2sc(C)nc2cc1C

Procedure:
120 g of 2-methyl-4-thioacetamino-anisole were dissolved in 80 ml of dioxane, 1 l. of water and 600 ml of 6N NaOH. After decantation of the liquid phase, the residue was redissolved with a mixture of 300 ml of water and 50 ml of 6N NaOH. The two solutions containing pure 2-methyl-4-thioacetamino-anisole were cleaned by addition of animal charcoal and stirring. A water solution of K3Fe(CN)6 was then added dropwise to the filtrate under stirring. After such addition, the solution, thus obtained, was stirred for 2 hours at room temperature. The reaction mixture was then poured into a Rutscher-Stendall liquid-liquid type extractor and the base was extracted with ether. The ethereal solution, thus obtained, after having been dried an anhydrous Na2So4, was concentrated and the residual oil was finally distilled under vacuum collecting the 158° C./3 mm. Hg fraction. Yield: 65 g. The product thus obtained was purified upon crystallization from ligroin in the presence of animal charcoal, thus obtaining a pure product melting at 89°-90° C.
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:16][C:15]2[N:14]=[CH:13][C:12]([CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=2[CH2:9][CH2:8]1.[CH3:22][NH:23][CH2:24][C:25]1[NH:26][C:27]2[C:32]([C:33]=1[C:34]#[N:35])=[CH:31][CH:30]=[CH:29][CH:28]=2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:34]([C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]=1[CH2:24][N:23]([CH3:22])[C:19](=[O:21])/[CH:18]=[CH:17]/[C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:7](=[O:6])[CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:35]
Reactant: CNCc1[nH]c2ccccc2c1C#N
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1[nH]c2ccccc2c1C#N)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 72 h
Yield: 62 %

Procedure:
EDC (250 mg, 1.3 mmol) was added to a solution of 3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (267 mg, 1.05 mmol), 2-methylaminomethyl-1H-indole-3-carbonitrile (186 mg, 1.0 mmol), HOBt.H2O (135 mg, 1.0 mmol) and DIPEA (510 μL, 3.0 mmol) in dry DMF (4 mL). After 3 days of stirring, the mixture was diluted with water (50 mL) at 10° C. The precipitate was filtered, washed with water and dried. The solid was stirred in MeOH (10 mL), filtered and dried to afford 239 mg (62%) title compound. NMR (300 MHz, DMSO-d6, 8): 12.28 and 12.09 (rotamers, 2 s, 1H), 10.66 (s, 1H), 8.37 (s, 1H), 8.11 and 8.05 (rotamers, 2s, 1H), 7.52 (m, 3H), 7.22 (m, 3H), 5.13 and 4.90 (rotamers, 2s, 2H), 3.27 and 2.97 (rotamers, 2s, 3H), 2.92 (m, 2H), 2.55 (m, 2H). MS (ESI): m/e 386 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)#[N:2].[NH2:13][OH:14]>CCO>[OH:14][N:13]=[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)[NH2:2]
Reactant: N#Cc1ccc2c(c1)COC2=O
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of 5-cyanophthalide (1 g, 6.28 mmol) and hydroxylamine (50% in water, 0.77 cm3, 0.83 g, 12.6 mmol, 2 eq) in EtOH (50 cm3) was stirred at room temperature for 60 hours and then under reflux for 3 hours. After cooling to room temperature and standing overnight, the solid formed was collected by filtration and dried in high vacuum line to give the product N′-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboximidamide (1.04 g, 86.2%) as a white solid, mp 223-226° C. (decomposed).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:9]1[CH2:11][CH2:10]1)=[N:5][CH2:6][C:7]#[N:8])C.CC(C)([O-])C.[K+].C(OCC)=O>C1COCC1.CCOCC>[CH:9]1([C:4]2[O:3][CH:1]=[C:6]([C:7]#[N:8])[N:5]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=NCC#N)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1coc(C2CC2)n1
Temperature: -10 °C
Reaction time: 3 h
Yield: 23.2 %

Procedure:
To a solution of N-cyanomethyl-cyclopropanecarboximidic acid ethyl ester (4.54 g, 14.9 mmol) in THF (10 mL) at −10° C. were added potassium tert-butoxide (1.67 g, 14.9 mmol) and ethyl formate (1.2 mL, 14.9 mmol) successively. After being stirred at −10° C. for 3 h, the reaction mixture was left in the refrigerator overnight and then diluted with ether. The precipitated brown solid was filtered and dried under vacuum. The vacuum-dried solid was added to boiling acetic acid (45 mL) and refluxed for 2 min. The reaction mixture was cooled to room temperature, diluted with water, and adjusted to pH 7 by adding 1 N sodium hydroxide. The reaction mixture was extracted with ether (2×1 L). The combined organic fractions were dried (MgSO4), filtered, and concentrated. The crude brownish solid was chromatographed (silica gel, 0-50% EtOAc in Hexane, detection KMnO4 spray, Rf=0.3 in 10% EtOAc/Hexane) to give 2-cyclopropyl-oxazole-4-carbonitrile as a colorless liquid (463 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.7 %

Procedure:
To a solution of 4-bromobenzyl alcohol (2.8 g) and diisopropylethylamine (2.5 g) in dichloromethane (30 mL) was added chloromethyl methyl ether (1.3 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was water, and the mixture was extracted diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:3]([N:4]3[CH:8]=[N:7][CH:6]=[N:5]3)[CH:2]([CH3:19])[CH3:1])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[O:35])=[CH:29][CH:28]=1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1cncn1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Yield: 69.9 %

Procedure:
To a stirred and cooled (5° C.) solution of 10 parts of 4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrobenzenamine and 6.7 parts of pyridine in 195 parts of dichloromethane was added a solution of 14.4 parts of 4-chlorobenzeneacetyl chloride in 39 parts of dichloromethane under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 11 parts (69.9%) of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide (interm. 112).