Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Yield: 67.1 %

Procedure:
Reflux 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (3.0 g.) with aluminium isopropoxide in toluene and cyclohexanone according to the conditions of Oppenauer oxidation. Isolate and recrystallize the product from methanol to give 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (2.0 g.), m.p. 128°- 31° C. with softening at 125°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1.N1C=CC=CC=1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl>[S:16]([O:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1)([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CC(OS(C)(=O)=O)CC(=O)O1
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-6-methyltetrahydropyran-2-one (1.5 parts) in dichloromethane (40 parts) was added pyridine (1.1 parts) and then, over 15 minutes, mesyl chloride (1.65 parts). The reaction was set aside at ambient temperature under N2 for 18 hours at which point GLC analysis indicated less than 1.5% of the starting material remained. The reaction mixture was filtered and the organic phase then washed with water before evaporating to obtain 4-mesyloxy-6-methyl-tetrahydropyran-2-one (0.5 parts).
Reaction SMILES: [Br:1]CCCCCCCCC[CH2:11][CH2:12]O.C(N(CC)CC)C.CC(=C)C(Cl)=O.C[C:28](=[CH2:44])[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]CBr)=[O:30].[CH3:45][N:46]1C=[CH:49][N:48]=[CH:47]1.OC1C=CC(O)=CC=1>O1CCCC1>[Br-:1].[C:29]([O:31][CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:45][N+:46]1[CH:12]=[CH:11][N:48]([CH3:49])[CH:47]=1)(=[O:30])[CH:28]=[CH2:44]
Reactant: OCCCCCCCCCCCBr
Reactant: C=C(C)C(=O)OCCCCCCCCCCCBr
Reactant: Cn1ccnc1
Agent: C=C(C)C(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(CCCCCCCCC)C[n+]1ccn(C)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(From Yu et al., Macromolecules 2008, 41, 3389-3392.) 11-Bromoundecanol (10.00 g, 40 mmol) was dissolved in 40 ml of dry tetrahydrofuran (THF) in a two-necked round bottom flask. The flask was cooled in an ice-bath and triethylamine (5.13 mL, 40 mmol) in THF (40 mL) was added to the stirring solution. 2-methyl acryloyl chloride (4.08 g, 40 mmol) dissolved in 40 ml of THF was added dropwise to the stirring solution over a period of 15 min under N2 atmosphere. The mixture was further stirred for 2 days at room temperature and was filtered. The filtrate was washed with 2% sodium bicarbonate solution to remove any unreacted acid chloride and dried over anhydrous MgSO4. The dried solution was filtered and the filtrate was passed through a short column of neutral alumina, using CH2Cl2 as the light yellow liquid (yield 10.58 g, 87%). Under N2 atmosphere, a mixture of 11-bromoundecyl methylacrylate (6.08 g, 20 mmol) and 1-methylimidazole (1.64 g, 20 mmol) and a small amount of 1,4-dihydroxybenzene (inhibitor) was stirred at 40° C. for 48 h, and yielded a viscous liquid. The viscous liquid was purified by the precipitation method with diethyl ether to obtain yellow viscous liquid 1-(2-acryloyloxyundecyl)-3-methylimidazolium bromide. The viscous liquid was dried under vacuum at room temperature as the white waxy solid (5.73 g, 74%).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([N:13]=[C:14]=[S:15])(=[O:12])[CH3:11].O>CC(C)=O>[Br:9][C:4]1[N:3]=[C:2]2[S:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CC(=O)N=C=S
Reactant: Nc1ccc(Br)nc1Br
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(Br)nc2s1
Temperature: 67.5 °C
Reaction time: 2.5 h
Yield: 121.2 %

Procedure:
2,6-dibromopyridin-3-amine (4.235 g, 16.8 mmol) was dissolved in acetone and acetyl isothiocyanate (1.85 ml, 21.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (65-70° C.) and stirred under nitrogen for 2.5 hours. Then, the reaction was cooled to room temperature, poured into water, and filtered. The solid was washed with water, saturated sodium bicarbonate, and water again, and then collected and dried under high vacuum to afford N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (5.54 g, Yield >100%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[C:8](=[O:14])[C:7](Br)=[C:6]1[CH3:16].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>C1C=CC=CC=1.C(O)C.COCCOC.[OH-].[Ba+2].[OH-].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>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[C:8](=[O:14])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[C:6]1[CH3:16]
Reactant: Cc1c(Br)c(=O)c(C=O)c(C)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Solvent: c1ccccc1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(C)c(C=O)c2=O)c1
Reaction time: 8 h
Yield: 42.1 %

Procedure:
1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-pyrid-4-one (1.36 g, 3.8 mmol) stirred with 3-methoxyphenyl boronic acid (696 mg, 4.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (439 mg, 380 μmol) in benzene/ethanol/DME (76 ml, 10/1/11) and barium hydroxide (30 mL, sat., aq.) under N2 at 90° C., protected from light over 8 hours. The organic layer was then concentrated and purified using flash silica chromatography (ethyl acetate/hexane-1/9), giving the product as a cream-colored solid (622 mg, 1.6 mmol, 42% yield). 1H NMR (CDCl3, 300 MHz) δ 10.55 (s, 1H), 7.41-7.31 (m, 2H), 7.00-6.74 (m, 5H), 5.35 (s, 2H), 3.81 (s, 3H), 2.79 (s, 3H), 2.25 (s, 3H); MS: 384 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)C(C#N)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:29]([C:28]([OH:26])=[O:30])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C#N)cc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: COc1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C(=O)O)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
5-[(4-fluorophenyl)methyl]-3-{[4-(methyloxy)phenyl]amino}-2-pyridinecarbonitrile (505 mg, 1.52 mmol) was dissolved in ethanol (50 mL) and 50% sodium hydroxide was added and the mixture was heated at 100° C. for 1 hour. The reaction was cooled to ambient temperature, concentrated under reduced pressure, and acidified with 6 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organics were dried over sodium sulfate and concentrated under reduced pressure to yield 5-[(4-fluorophenyl)methyl]-3-{[4-(methyloxy)phenyl]amino}-2-pyridinecarboxylic acid (560 mg, 95% yield). 1H NMR (CDCl3/methanol-d4) δ 7.95 (s, 1 H), 7.32 (s, 1 H), 7.01-6.98 (m, 4 H), 6.93-6.83 (m, 4 H), 3.86 (s, 2 H), 3.75 (s, 3 H); MS m/z 353 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:25]3[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 87 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 4-ethylpiperazine (0.43 g, 3.7 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.10 g of the title product was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=O)=[O:11].C(N(CCCC)CCCC)CCC.[Cl:27]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([Cl:27])(=[O:13])=[O:11]
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Nc1c(I)cc(Br)cc1S(=O)(=O)Cl
Reaction time: 18 h

Procedure:
To a solution containing 7.6 g (20 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 4.8 ml (20 mmol) of tributylamine in 20 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, a solution of dichlorotriphenylphosphorane (9.7 g (37.5 mmol) in 45 ml of dichloromethane). The mixture is brought to room temperature, stirring is continued for 18 hours and the product is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (2:8).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=CC1=O.BrC1C=CC(C(Cl)=[O:18])=CC=1F.[K+].C([O:26][C:27](=[O:32])[CH2:28]C([O-])=O)C>>[C:27]([O:32][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)(=[O:26])[CH3:28]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: O=C(Cl)c1ccc(Br)c(F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OC(=O)c1ccccc1

Procedure:
As an alternative to the quinolone synthesis outlined above, the quinolone nucleus may be formed using the route illustrated in Scheme II. Similar methodology for the preparation of quinolones was first described in German patent application DE3142854. Starting from a 4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acid monoethyl ester monopotassium salt gives a benzoyl acetate that is subsequently reacted with triethyl orthoformate. The resulting ethoxymethylene derivative is reacted with a primary amine and cyclized to the quinolone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]([C:12](O)=[O:13])=[CH:11]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:46][CH2:47][CH2:48][CH2:49][NH:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12](=[O:13])[N:50]([CH2:49][CH2:48][CH2:47][F:46])[CH2:51][CH2:52][CH3:53])=[CH:11]2
Reactant: CCCNCCCF
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCCF)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 148.8 %

Procedure:
(1E,4E)-8-Bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid (0.275 g, 0.721 mmol) was dissolved in 7 mls of dry DMF. To this solution was added HOBT (0.107 g, 0.794 mmol) and EDCI (0.152 mmol, 0.794 mmol), and this mixture was stirred at room temperature for 20 minutes. 3-Fluoro-N-propylpropan-1-amine hydrochloride (0.124 mmol, 0.794 mmol) followed by triethylamine (0.211 mls, 1.515 mmol) were then added and the reaction mixture stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc, washed several times with brine, dried over sodium sulfate and concentrated under reduced pressure. Flash 40 Biotage (40S cartridge, 25% EtOAc/Hexane) afforded 0.089 g (26%) of tert-butyl (1E,4E)-8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. m/z (APCI-pos) M+1=481.8 and 483.8.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH2:27]=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C1C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([OH:21])=[C:20]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:27])[CH2:32][CH2:31]4)[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(O)ccc2[nH]1)c1c(F)cccc1F
Reactant: C=O
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Product: CN1CCN(Cc2c(O)ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc23)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,6-difluoro-N-[3-(5-hydroxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (50 mg), 37% aqueous formaldehyde (1 ml) and N-methylpiperazine (150 μL) in benzene (1 ml) was heated in a microwave at 100° C. and 50 W for 10 minutes, reduced in vacuo and submitted to preparative LC/MS for purification to give 2,6-difluoro-N-{3-[5-hydroxy-4-(4-methyl-piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (7 mg) as a yellow solid. (LC/MS: Rt 1.98, [M+H]+ 468.19).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Ca+2:5].[C:6]1([P:12](=[O:15])([OH:14])[OH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:1](=[O:2])([O-:4])[O-:3].[Ca+2:5].[C:6]1([P:12](=[O:13])([O-:15])[O-:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Ca+2:5]
Reactant: O=P(O)(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
An aqueous slurry of calcium carbonate was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (100 mmol) of calcium carbonate (Escalon #2300 (average particle size, 1.7 μm), available from Sankyo Seifun KK) and 90.0 g of water. An aqueous solution of 11.1 g (70 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 62.7 g of water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with water. The wet cake was subsequently dried at 200° C. for at least 12 hours, yielding a white powder of calcium phenylphosphonate-containing calcium carbonate.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]=[C:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[C:17]([Si](C)(C)C)#[N:18].[Br-].[Mg+2].[Br-].[C:26]([O-:29])(O)=O.[Na+]>C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:11]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:29][CH3:26])=[CH:4][CH:5]=1)([CH3:16])[C:17]#[N:18]
Reactant: O=C([O-])O
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(CN=C(C)C(F)(F)F)cc1
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC(C)(C#N)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a cooled (0° C.) solution of 1-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-ylidene)methanamine (4.41 g, 19.07 mmol) in DCM (100 ml) was added cyanotrimethylsilane (2.84 g, 28.6 mmol) and magnesium bromide. The mixture was stirred at RT for 90 h and then diluted with sat. NaHCO3 (200 ml). After stirring at RT for 1 h, the organic phase was separated, washed with a further portion of sat. NaHCO3 (100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.[S-][C:3]#[N:4].[Na+].Cl.[NH2:7][CH:8]([CH3:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:18](O)C>>[CH2:17]([C:8]1[NH:7][CH:3]=[N:4][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: N#C[S-]
Reactant: CC(N)C(=O)c1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]cnc1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
An aqueous solution (5 mL) of concentrated hydrochloric acid (0.6 mL) and sodium thiocyanate (1.62 g, 20.03 mmol) was added to a solution of 2-aminopropiophenone hydrochloride (2.00 g, 10.02 mmol) in ethanol (20 mL). The obtained mixture was stirred at 70° C. for 1 hour. The solvent was distilled away, and acetic acid (20 mL) was then added to the residue. The obtained mixture was stirred at 100° C. for 3 hours. Thereafter, water was added to the reaction solution, and the precipitated crude crystals were collected by filtration. Raney Ni was added to a solution of the obtained crude crystals in ethanol (40 mL), and the obtained mixture was then stirred at 70° C. for 2 hours. The reaction solution was filtered with celite, and the filtrate was then concentrated. The residue was washed with acetonitrile, so as to obtain the title compound (0.88 g, yield in two steps: 45%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]>ClCCl>[CH3:2][N:3]([CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6])[C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCC(=O)Cl
Reactant: CNCC(=O)OCC#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N(C)CC(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Cyanomethyl 2-(methylamino)acetate hydrochloride (Compound SP703) (3.00 g, 18.3 mmol) and triethylamine (6.34 ml, 45.5 mmol) were dissolved in dichloromethane (30 ml) under a nitrogen atmosphere, and pent-4-enoyl chloride (2.60 g, 22.0 mmol) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 2 hours and 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solid was removed by filtration. The solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=1:10→2:7) to afford cyanomethyl 2-(N-methylpent-4-enamido)acetate (Compound SP704) (3.40 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 21 mmol) was dissolved in DCM (70 ml). To this was added diisopropylethylamine (7.3 ml, 42 mmol) in one portion followed by the drop wise addition of acryloyl chloride (1.54 ml, 19 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to give the title compound (5.3 g, 20% yield) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([N+:35]([O-])=O)=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.S1C=CC=C1.N.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([NH2:35])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc1N
Yield: 94 %

Procedure:
A mixture of 10 parts of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine, 3 parts of a solution of thiophene in methanol 4% and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 9 parts (94%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]-2,3,6-pyridinetriamine as a residue (intermediate 154).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(O)c1
Yield: 93 %

Procedure:
A mixture of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone, 360 mg. of solid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. of ethanol is stirred under one atmosphere of hydrogen pressure for one hour. The reaction mixture is filtered through diamtomaceous earth with ethyl acetate and the filtrate evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 50% ether-cyclohexane to yield 247 mg. (93%) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.P([O-])(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]2[O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:2]=1)=[O:7]
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: COC(=O)c1nc[nH]n1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (12.7 g., 100 mmole) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (55.4 g., 110 mmole) was heated in an oil bath maintained at 160-165°. After the sugar had melted, bis(p-nitrophenyl) phosphate (400 mg.) was added with stirring and the mixture was heated under diminished pressure at 160-165° for 15-20 min. Crystallization of the residue from ethyl acetate-ethanol provided 42.5 g. (74.5%) of product with M.P. 137-139°.