Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:11][CH:10]2[O:12][CH:6]([CH2:7][N:8]([CH2:13][C@H:14]([OH:25])[CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:9]2)[CH2:5]1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(N(CC)CC)C.C(#N)C>[C:21]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:14]([OH:25])[CH2:13][N:8]2[CH2:9][CH:10]3[O:12][CH:6]([CH2:5][N:4]([CH2:3][CH2:2][NH:1][S:33]([CH2:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:35])=[O:34])[CH2:11]3)[CH2:7]2)=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCN)CC(C2)O3)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCNS(=O)(=O)Cc4ccccc4)CC(C2)O3)cc1
Yield: 72 %

Procedure:
4-{(2S)-3-[7-(2-Aminoethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile (0.096 g, 0.28 mmol; see step Preparation A above) was dissolved in a 1:2 ratio of DCM:acetonitrile (3 mL). Triethylamine (0.17 g, 1.68 mmol) was added, followed by phenylmethanesulfonyl chloride (0.068 g, 0.36 mmol). The mixture was stirred at room temperature overnight with K2CO3 (0.38 g, 2.77 mmol) to ensure that the free base of triethylamine was in the reaction mixture. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. Purification by preparative HPLC gave 0.1 g (72%) of the title compound.
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][C:6](O)=[O:7])#[N:2].O1CCCC1.C(=O)([O-])O.[Na+]>CO>[C:1]([C:3]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH:9]([CH3:10])[CH3:11])[CH2:4][CH2:5][CH2:6][OH:7])#[N:2]
Reactant: CC(C)C(C#N)(CCC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(C#N)(CCCO)c1ccccc1
Temperature: -25 °C

Procedure:
A 4-cyano-5-methyl-4-phenylhexanoic acid (500 mg, 2.16 mmol)/tetrahydrofuran (3.84 ml) solution was slowly added dropwise into a 1M-borane tetrahydrofuran complex/tetrahydrofuran solution (2.70 ml, 2.70 mmol) cooled to −25° C., while keeping the bulk temperature at −15° C. or less. After the completion of the dropwise addition, the bulk temperature was elevated to room temperature. After the completion of the reaction, it was cooled again and methanol (0.33 ml) was added dropwise thereinto. Further, a saturated aqueous sodium hydrogen carbonate solution (200 ml) was added thereinto, followed by extracting with ethyl acetate. The organic layer was successively washed with water, brine and saturated aqueous sodium hydrogen carbonate, followed by drying over magnesium sulfate and evaporating the solvent. The residue was purified by 20 g of Cromatorex NH silica gel (ethyl acetate/hexane system), to give the title compound as a colorless highly viscous oil (426 mg, 1.96 mmol, yield: 90.8%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([F:28])[CH:6]=1)(=O)C.O.[OH-].[K+]>CO>[CH2:21]([O:20][C:13]1[CH:14]=[C:15]([CH2:18][CH3:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[F:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCc1ccc(Oc2ccc(OC(C)=O)cc2F)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(Oc2ccc(O)cc2F)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate (1.6 g, 4.2 mmol) in MeOH:H2O (35 ml:35 ml), was added KOH (0.83 g, 14.8 mmol). The mixture was heated at 65° C. for 4.5 hours, concentrated in vacuo, then extracted with EtOAC (25 ml*2). Combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by column chromatography, (pet ether: EtOAC 95:5), to yield the title compound as a white solid (630 mg; 44%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:10]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([C:11]3[NH:12][C:13](=[O:14])[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: C#Cc1cccc(Cl)c1F
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C#Cc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 27.3 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-45, 0.070 g, 0.15 mmol) in DMSO (3.0 mL) was added 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.035 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol). The reaction mass was stirred at 80° C. for 5-6 h. The reaction mass was quenched in water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 2.0% EA:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.92 (s, 3H), 7.29 (t, J=8.4 Hz, 1H), 7.48-7.72 (m, 8H), 12-13 (br s, 1H); MS (m/z): 488.00 (M+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (preparation see below) and amine 5.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:17]C(=O)C)([CH3:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=O)C.[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[ClH:30].NC(CCC1C=CC=CC=1OCCCCCCC)(CCC)CO>>[ClH:30].[NH2:17][C:6]([CH3:16])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:10]=1)[CH2:5][OH:4]
Reactant: CC(=O)NC(C)(CCc1cccc(O)c1)COC(C)=O
Reactant: CCCCCCCCBr
Agent: CCCCCCCOc1ccccc1CCC(N)(CO)CCC
Agent: Cl
Product: CCCCCCCCOc1cccc(CCC(C)(N)CO)c1

Procedure:
2-Acetamido-4-(3-hydroxyphenyl)-2-methylbutyl acetate and octyl bromide were used in the same manner as working example 52 (9) and (10) to give the subject compound as white crystals, melting at 130-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][C@@H:18]3[C:33]([O:35]C)=O)=[O:16])[N:12]=[C:11]2[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].CC([CH:47]1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CN[C:48]1=[O:49])C.CN1C=CN=C1.CS(Cl)(=O)=O.C[C@@]1(C([O-])=O)NCCN(C(OCC2C=CC=CC=2)=O)C1>ClCCl>[C:48]([O:35][CH2:33][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:15]([C:13]1[N:12]=[C:11]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:14]=1)=[O:16])(=[O:49])[CH3:47]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3C(=O)OC)nc2-c2ccc(C)cc2)c1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: CS(=O)(=O)Cl
Agent: C[C@]1(C(=O)[O-])CN(C(=O)OCc2ccccc2)CCN1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C

Procedure:
1-Benzyl 3-methyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylate To a solution of 3.18 g (9.88 mmol) of Intermediate 1 in 75 mL of anhydrous dichloromethane at 0° C. was added 1.5 mL (19 mmol) of 1-methylimidazole followed by 0.80 mL (9.9 mmol) of methanesulfonyl chloride. The resulting mixture was stirred with gradual warming to ambient temperature over 20 min, then re-cooled to 0° C. A solution of 2.39 g (8.59 mmol) of 1-benzyl 3-methyl-(3R)-piperazine-1,3-dicarboxylate in 25 mL of anhydrous dichloromethane was then added and the reaction mixture was allowed to warm to ambient temperature over 1 h. The reaction was then quenched with a saturated aqueous ammonium chloride solution (25 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on a Biotage® purification apparatus (silica gel, 40 to 50% ethyl acetate in hexanes gradient) to yield the title compound as a colorless solid. LC/MS 583.5 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].CO.C(O)(=O)C>[CH:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1=C(c2cscc2-c2cc(Nc3ccccc3)n[nH]2)CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(Nc2cc(-c3cscc3C3CCCCC3)[nH]n2)cc1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
Hydrogenation of [5-(4-cyclohex-1-enyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine (50 mg, 0.156 mmol) was carried out using 10% palladium on activated carbon (˜20 mg) in methanol (5 mL) and acetic acid (0.5 mL) under a balloon of hydrogen. After stirring for 16 h, the reaction was filtered through Celite. The filtrate was diluted with ether (50 mL), washed with saturated NaHCO3 solution (2×25 mL) and brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 29 mg (58%) of [5-(4-cyclohexyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine as a white solid.
Reaction SMILES: CS(C)=O.[CH:5]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:26]1([NH:32][C:17]2[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11][N:10]3[CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][C:16]=2[F:21])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCC1
Reactant: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(F)c(F)cc12
Solvent: O
Solvent: CS(C)=O
Product: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 40 ml DMSO solution of 2.0 g of 1-cyclopentyl-6,7-difluoro-3-nitroquinolin-4(1H)-one was added 2.3 ml of cyclohexylamine, followed by overnight stirring at 90° C. The reaction mixture was cooled to room temperature and poured into ice-cooled water, and then the insoluble materials were collected by filtration. By recrystallizing the resulting solid from ethanol, 2.5 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-nitroquinolin-4(1H)-one was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH2:12](Br)[C:13]#[CH:14].O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][CH2:14][C:13]#[CH:12])[CH2:6][O:5]1
Reactant: CC1(C)OCC(CO)O1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (1.32 g, 55 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich) in THF (60 mL), and the resulting mixture was heated at reflux for 90 min then cooled to 0° C. Tetrabutylammonium iodide (370 mg), and propargyl bromide (80% in toluene, 6.22 mL, 50 mmol) (Aldrich) were added successively. After stirring for 150 min. at room temperature, 20 mL water was added and the THF was evaporated in vacuo. The aqueous layer was then extracted with diethyl ether (4×50 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield rac-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1-propyne.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Br)cn1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cn2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
1-(5-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (936.0 mg, 2.8 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (508.0 mg, 2.8 mmol), and piperidine (560.0 uL, 5.7 mmol) were added to ethanol (28.4 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 450.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:2].C(O)(=O)C(O)=O.[CH2:17]([NH:21][NH2:22])[CH2:18][CH2:19][CH3:20].CC([O-])=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[N:22][NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]([CH3:8])[CH3:7])[CH3:2]
Reactant: CCCCNN
Reactant: CCOC(=O)C(=O)C(C)C
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCCCNN=C(C(=O)OCC)C(C)C
Yield: 85.4 %

Procedure:
To a solution of 3-Methyl-2-oxo-butyric acid ethyl ester (1c) (1.88 g, 13.04 mmol) in 45 mL of CHCl3, butyl-hydrazine oxalate salt (2.11 g, 11.85 mmol) was added followed by NaOAc (1.94 g, 23.4 mmol) and MgSO4 (1.43 g, 11.88 mmol). The mixture was heated to reflux for 3.5 hours under N2 atmosphere with stirring. After cooling, the solid was filtered off and the filtrate was concentrated under reduced vacuum. The residue was first cleaned by an extraction between EtOAc (50 mL×3) and H2O (20 mL). The organic layer was concentrated under reduced pressure and dried under high vacuum overnight to give 2.17 g of the crude product (3b) in 85.4% yield as a mixture of the E- and Z-isomers. This crude product was directly used in the next step without further purification. LC-MS (ESI+): m/e=215.4 [M+1]+, 237.1 [M+Na]+ (exact ms: 214.17).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([NH:31][CH2:29][CH3:30])=[O:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccc(O)cc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(O)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Intermediate 22 (383 mg, 1.00 mmol), ethylamine hydrochloride (163 mg, 2.0 mmol), HATU (457 mg, 1.20 mmol) and DIPEA (0.349 mL, 2.0 mmol) were dissolved in DMF (2 mL) and stirred at RT overnight. More ethylamine hydrochloride (163 mg, 2.0 mmol) and DIPEA (0.349 mL, 2.0 mmol) were added and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL), water and brine. The organic phase was dried and evaporated under vacuum. Purification of the residue by flash chromatography on silica gel (DCM-methanol 10 to 20% gradient) gave the title compound as an off-white solid (200 mg, 0.488 mmol, 49% yield). LC/MS (M(35Cl)+H)+ 410, (M(37Cl)+H)+ 412; RT 0.76 min (using LC/MS apparatus c)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C[O-].[Na+].[C:4]1([SH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[C:24]1[NH:25][C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2>CO>[C:4]1([S:10][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[C:24]2[NH:25][C:26]3[C:27]([N:32]=2)=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCCl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCSc2ccccc2)c1

Procedure:
A solution of 2.0 gm (0.036 mol) of sodium methylate in 50 ml of absolute methanol was admixed with 1.85 ml (0.018 mol) of thiophenol and 4.6 gm (0.015 mol) of 2-[2-(2-chloroethoxy)-4-methoxyphenyl]imidazo[4,5-b]pyridine hydrochloride. After refluxing for 4 hours, the reaction mixture was evaporated in vacuo, the residue was dissolved in water/methylene chloride, and the organic phase was separated and dried over magnesium sulfate. A pre-purification was carried out on 50 gm of silicagel with methylene chloride/acetone (100:0 to 80:20). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+].ClCCl>CO.O>[Br:1][C:2]1[C:3]([O:10][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncncc1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ncncc1Br
Temperature: 5 °C

Procedure:
Twenty grams (0.13 mol) of 5-bromo-4-chloropyrimidine were dissolved in 100 mL of methanol and the solution was cooled to 5° C. by means of an ice bath. A solution consisting of 29.5 mL of a 25 percent solution of sodium methoxide in methanol and 20 mL of methanol was added with stirring and cooling. The temperature rose to 37° C. and then began to fall. The mixture was stirred for 4 hours at ambient temperature and was then diluted with 200 mL of water (which caused the formation of a white precipitate) and 200 mL of dichloromethane (which dissolved the precipitate). The phases were separated and the organic phase was washed with 150 mL of water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 18.2 g (93.8 percent of theory) of the title compound as a white crystalline solid melting at 73°-75° C.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.CC(C)=O.Cl>O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([SH:2])=[CH:7][C:8]=1[C:15]([F:18])([F:17])[F:16])([O-:14])=[O:13]
Reactant: [S-2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(S)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
A stirred solution of sodium sulfide monohydrate 65.4 g. (0.276 moles) in 1 liter of water is treated with 50 g. (0.222 moles) of 4-chloro-2-trifluoromethylnitrobenzene in 500 ml. of acetone over 11/2 hour. The reaction mixture is stirred for 141/2 hours and the resultant solution treated with 25 ml. of concentrated hydrochloric acid. An oil separates from the reaction mixture which is dissolved in 200 ml. of ether, washed with water and extracted with 2.5 N sodium hydroxide solution. The aqueous solution is washed with ether and acidified with 25 ml. of hydrochloric acid. The resulting oil is extracted with ether and the ether solution washed with water affording 47 g. of 4-nitro-3-trifluoromethylbenzenethiol which is used in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]1=2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[S:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:8]
Reactant: c1ccc2sccc2c1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCCBr)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.4 %

Procedure:
6-Bromohexanoyl chloride (2 g) and benzo[b]thiophene (1.26 g) were dissolved in methylene chloride (20 ml), and aluminum chloride (1.31 g) was added under ice-cooling, which was followed by stirring at room temperature for 1.5 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to give 0.45 g of 6-bromo-1-(2-benzo[b]thienyl)-1-hexanone.