Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[CH:8][N:7]=1)[CH3:4]>C(O)C.ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][N:7]=1)[CH3:4]
Reactant: CCOC(=O)c1ccnc(OCC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOc1cc(CO)ccn1
Reaction time: 3 h
Yield: 75.4 %

Procedure:
0.508 g of sodium borohydride is added portionwise to a solution of 0.524 g of ethyl 2-ethoxypyridine-4-carboxylate in 5.2 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 50 ml of dichloromethane and then washed with 50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 0.310 g of 2-ethoxy-4-(hydroxymethyl)pyridine is thus obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH3:15])=[C:17]([CH3:25])[C:18]=1[CH3:24]
Reactant: COc1ccc(C(C)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)N2CCNCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice chilled solution containing 4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.4 g 1.38 mmol) and 10 ml dichloromethane, was added trifluoroacetic acid (2 ml) dropwise. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by flash chromatography on silica gel eluted with 10% MeOH(NH3)/dichloromethane. 1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine was obtained as a yellow oil (0.16 g 47%). Analysis H1 NMR (400 MHz, CDCl3): 7.23 (1H, d), 6.69 (1H, d), 3.8 (3H, s), 3.55 (1H, q), 3.484 (2H, s), 2.838 (4H, m), 2.47 (2H, m), 2.38 (2H, m), 2.271 (3H, s), 2.167 (3H, s), 1.26 (3H, d). MS (LC-MS): Calculated for C15H24N2O 248.36. Found 249.25 (M+).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)C.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].C(OOC(C)(C)C)(=O)C.C([O-])(=O)CCCCCC(C)(C)C>C(C(C)=O)C>[CH:1]([CH:19]=[CH:18][C:17]([OH:21])=[O:20])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(=O)OOC(C)(C)C
Agent: CC(C)(C)CCCCCC(=O)[O-]
Solvent: CCc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 446.8 %

Procedure:
Into a polymerization reactor equipped with an agitator and a reflux condenser were charged 580 grams of styrene, 3.0 grams of terpenolene and 200 ml of ethylbenzene. Then 80 grams of high cis-polybutadiene from Goodyear Tire & Rubber Company (Budene 1208) was dissolved in the mixture. After the rubber had dissolved, a solution of 40 grams of acrylic acid in 60 ml of methyl ethyl ketone (335 ml) was introduced into the mixture. The temperature of the reaction mixture was raised to 85° C. and maintained at this level during the ensuing polymerization. Polymerization was initiated by introducing into the system a mixture of 0.2 ml of tert-butyl peracetate and 0.2 ml of tert-butyl per-neo-decanoate. One hour later, continuous addition of a solution of 40 grams of acrylic acid and 60 ml of methyl ethyl ketone was initiated and this addition was continued over a four hour period. At one hour and again at four hours after the start of the continuous addition of the acrylic acid solution, additional 0.2 ml portions of tert-butyl peracetate were introduced into the polymerization mixture. Polymerization was terminated 5.5 hours after initiation and the resultant polymer was recovered and dried, first in air and then in a vacuum oven, to yield 432 grams of rubber-modified styrene-acrylic acid graft copolymer. In order to produce enough copolymer for the compounding and ensuing test work this polymerization procedure was repeated four more times and the products from the five runs were combined and mixed in a Waring blender. The resultant polymer contained about 84.2 weight percent styrene and about 15.8 weight percent acrylic acid. Its rubber content was approximately 18.5 percent based on the weight of the resin phase.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(O)C>ClCCl.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1cc(N)c2occc2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)c2c(c1)CCO2
Yield: 87.6 %

Procedure:
5-Methylbenzofuran-7-ylamine (1.3 g, 8.8 mmol) and 10% palladium carbon (500 mg) were added to ethanol (50 ml), followed by conduction of catalytic reduction at room temperature under ordinary pressure. The catalyst was removed by celite filtration, and the obtained filtrate was condensed under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, giving a white powder of 5-methyl-2,3-dihydrobenzofuran-7-ylamine (1.15 g, yield: 87%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19]1)[CH3:16].[C:32]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>O>[C:32]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:33]=[CH:34][C:35]([CH2:38][CH2:31][S:28]([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][CH:18]([CH2:17][N:15]([CH3:14])[CH3:16])[CH2:19]2)(=[O:29])=[O:30])=[CH:36][CH:37]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1Cc2ccccc2N(S(C)(=O)=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1Cc2ccccc2N(S(=O)(=O)CCc2ccc(-c3ccccc3)cc2)C1
Yield: 10.7 %

Procedure:
LDA (1.9 M/THF, 1.2 ml) was added dropwise to a THF solution of 3-(N,N-dimethylamino)methyl-1-methylsufonyl-1,2,3,4-tetrahydroquinoline (0.24 g). The reaction mixture was stirred under ice-cooling for 30 minutes. A THF (1 ml) solution of 4-biphenylylmethyl bromide (0.16 g) was added to the reaction mixture, which was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, Lil then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate), which was further recrystallized from hexane-ethyl acetate to give the entitled compound (30 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2Cl)=[O:16])C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH2:60].[Na].P(O)(O)([O-])=O.[Na+]>CN(C=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[SH:60])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CS[C@H]23)c(Cl)s1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S)CS[C@H]23)c(Cl)s1
Yield: 190.7 %

Procedure:
To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate diphenylmethyl ester (4.0 g, 4.72 mmol) in DMF (30 mL) cooled to -20° C. was added in one portion powdered sodium hydrogen sulfide hydrate (1.1 g, 19.6 mmol). After 15 min the reaction mixture was poured into 0.5M monosodium phosphate (about 100 mL), extracted with ethyl acetate and the organic layer was washed thoroughly with water. After concentrating in vacuum the crude title product was obtained as yellow foam 3.8 g (95%). 1H NMR (CDCl3 /CD3OD) δ 3.38 (d, 1H, J=15), 4.43 (d, 1H, J=15), 5.03 (d, 1H, J=5), 5.80 (d, 1H, J=5), 5.99 (br s, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C.[Cl:51]C1C=CC=CC=1S>>[Cl:51][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1
Reactant: Sc1ccccc1Cl
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 2-chloro-thiophenol.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:24])[CH:13]([N:21]=[N+]=[N-])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C.C(OC)(=O)C.[Re]([O-])(=O)(=O)=O.[Na+]>[CH3:10][O:11][C:12](=[O:24])[C:13]([N:21]=[C:2]=[O:1])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(Cc1ccccc1)N=[N+]=[N-]
Agent: O=[Re](=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)=O
Product: COC(=O)C(=Cc1ccccc1)N=C=O

Procedure:
27.3 mg (0.1 mmole) of sodium perrhenate and 1.04 grams (5.25 mmoles) of diphosgene were present at 80° C. in 1 ml of ethyl acetate saturated with hydrogen chloride. Then there were added within 20 minutes with vigorous stirring 2.05 grams (10 mmoles) of 2-azido-3-phenylpropionic acid methyl ester dissolved in 5 ml of methyl acetate. After reaction for 1 hour at 80° C., the mixture was worked up analogous to Example 1. The crude produce was distilled in a high vacuum (0.0013 mbar) at 90° to 110° C. apparatus temperature in a bulbed tube. There resulted 1.08 grams (53.2% of theory) of analytically pure 2-isocyanato-3-phenylpropenoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was slowly added to a vial (40 mL) containing 5 mL of a saturated aqueous solution of sodium bicarbonate, dichloromethane (5 mL) and 1-methylpiperazine (100 mg, 1.00 mmol). The reaction was stirred at room temperature overnight. The phases were separated and the organic layer was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the required product, which was used in the next step without further purification. ESI-MS m/z calc. 318.0, found 318.9 (M+1)+. Retention time of 1.30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 3.03 (t, J=4.2 Hz, 4H), 2.48 (t, J=4.2 Hz, 4H), 2.26 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[NH:10][CH:11]=2)[CH:2]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C.C1COCC1>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([N:10]2[CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=[C:9]2[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COc1cc(-c2cc(-c3cccnc3)c[nH]2)cc(OC)c1OC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(-c3cccnc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 4-(3-pyridyl)-2-(3,4,5-trimethoxyphenyl)-pyrrole (155 mg, 0.5 mmol, Example 76a) in dry DMF or THF (1.5 ml) NaH dispersion (48 mg, 2 equiv.) and p-methoxyphenylsulfonyl chloride (103 mg, 0.5 mmol) is added under a stream of nitrogen at 4° C. The reaction mixture is subsequently stirred for 12-18 h at room temperature and extracted with saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried and purified by flash chromatography and preparative HPLC. RT (program 1) 3.79. MS: 480.7.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)C>CN(C=O)C>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=1)[CH3:13]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(OCOC(=O)C(C)(C)C)ncc1F
Yield: 9.3 %

Procedure:
N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was treated with diethyl ether (3-4 mL) to produce a solid. The solid was removed and the ether solution was placed onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 14 mg, 0.05 mmol (9%) of the title compound as a white solid: mp 86-88° C.; 1H NMR (CDCl3) δ 8.73 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 6.04 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H), 1.16 (s, 9H); HPLC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: COc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)cn1
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C. After 3 hours, 100 mL of H2O was added and the resulting solution neutralized with cold 2.5 M NaOH. The suspension was extracted with ether (2×200 mL), the combined organics were dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3%) of 5-bromo-2-methoxy-pyridine as a clear colorless liquid.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)=[O:6].[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([N:36]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH3:16])=[O:6])=[CH:8][CH:9]=2)=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCC(C)COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(N=Cc2ccc(C(=O)OCC(C)CC)cc2)cc1

Procedure:
44.3 g of said p-(2-methylbutoxycarbonyl)benzaldehyde, 32 g of p-n-tetradecyloxyaniline, and 0.1 g of p-toluenesulfonic acid were dissolved in toluene. The solution was heated under reflux, and water generated in the dehydrating condensation was removed with a Dean-Stark condenser. After the reaction solution was cooled, the organic layer was washed with water, and the solvent (toluene) was distilled off in vacuum. The solid residue was recrystallized from ethanol to obtain yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[CH2:44][CH2:43]1>ClCCl>[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][N:50]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[CH:1]=[O:2])=[O:8])[CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:44]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5 mmol), 1-hydroxybenzotriazole (466 mg, 3.45 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (629 mg, 3.3 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 94%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73-1.76 (m, 1H), 3.47-3.77 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.70-7.72 (d, J=7.6 Hz, 1H), 7.95-7.98 (m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([N:26]1[CH2:49][CH:48]([C:50]([OH:52])=O)[O:47][C:28]2([CH2:33][CH2:32][N:31]([C:34](=[O:46])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([CH3:45])[CH:36]=3)[CH2:30][CH2:29]2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O[N:54]=[C:55]([NH2:57])[CH3:56].C(N(CC)CC)C>CC1CCCO1>[CH2:19]([N:26]1[CH2:49][CH:48]([C:50]2[O:52][N:57]=[C:55]([CH3:56])[N:54]=2)[O:47][C:28]2([CH2:33][CH2:32][N:31]([C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:43])[CH3:44])=[C:37]([CH3:45])[CH:36]=3)=[O:46])[CH2:30][CH2:29]2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Reactant: CC(N)=NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: Cc1noc(C2CN(Cc3ccccc3)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)n1
Temperature: 75 °C
Yield: 39.1 %

Procedure:
T3P (546 mg, 510 μL of 50% w/w, 0.86 mmol) was added to a solution of 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (160 mg, 0.34 mmol), N′-hydroxyacetamidine (25 mg, 0.34 mmol) and triethylamine (173 mg, 239 μL, 1.71 mmol) in 2-methyltetrahydrofuran (800 μL) and the reaction mixture was heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-30% EtOAc in DCM as eluent to afford [8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (67 mg, 39%) as a white solid. ESI-MS m/z calc. 504.6. found 505.3 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2ccc(OCc3cc(Cl)ccc3Br)cc21
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1 (2H)-one (27.8 g, 89% yield) was isolated by filtration.
Reaction SMILES: [C:1]([C:3]#[C:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:26]=[O:27])CC1)#N>>[C:1]([C:3]#[C:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:9]=1)[CH:26]=[O:27])([CH3:7])[CH3:6])#[N:2]
Reactant: COc1ccc(C(C)(C)C#CC#N)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C(C)(C)C#CC#N)cc1C=O

Procedure:
This compound was prepared from Compound 63 in the same manner of Compound 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Reactant: CSc1nccc(I)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
KN(TMS)2 (1.42 g 7.16 mmol) in toluene (7 ml) is added at 0° C. to a solution of 5Chloro-2-(4fluorophenyl)imidazo[4,5-b]pyridine (1.9 g 6.66 mmol) in DMF (25 ml). After stirring 1 h at room temperature, 2-methylthio-4-iodopyrimidine (1.8 g 7.1 mmol) in toluene (7 ml) is added dropwise and heated for 20 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crystalline crude product, which after recrystallisation from ethyl acetate yields the title compound as colorless crystals (1.76 g 67%).